A Phase 3b, Open-label, Single-arm Study in Adolescent and Adult Female Participants to Evaluate Clinical Symptom Improvement and the Safety of Gepotidacin During Treatment of Uncomplicated Urinary Tract Infections (Acute Cystitis)
Phase: PHASE3
Conditions: Urinary Tract Infections
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
219575 
Protocol Amendment 1 Final 
10 Sep 2024 
1 
CLINICAL STUDY PROTOCOL 
Primary study intervention 
Gepotidacin 
Other study intervention 
None 
Study identifier 
219575 
IND number 
111885 
Approval date 
10 Sep 2024 
Title 
A Phase 3b, open-label, single-arm study in 
adolescent and adult female participants to evaluate 
clinical symptom improvement and the safety of 
gepotidacin during treatment of uncomplicated 
urinary tract infections (acute cystitis) 
Compound number/name  
GSK2140944/gepotidacin 
Brief title 
A study in adolescent and adult female participants 
to evaluate clinical symptom improvement and the 
safety of gepotidacin during treatment of 
uncomplicated urinary tract infections (acute cystitis) 
Sponsor 
GSK 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Dr Aruni Mulgirigama, MBBS, MRCP, MFPM 
Global Medical Affairs Leader, Antibiotics 
GSK 
General Medicines 
 
Medical monitor name and contact can be found in local study contact 
information document. 
©2024 GSK group of companies or its licensor 

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Protocol Amendment 1 Final 
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Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other study 
conduct procedures and/or study conduct documents provided by GSK/PPD. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with Good Clinical Practices and all applicable 
regulatory requirements. 
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK/PPD and the express physical and/or digital 
informed consent of the participant and/or the participant’s legally authorized 
representative. 
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s). 
• 
To cooperate with representative(s) of GSK/PPD in the monitoring and data 
management processes of the study with respect to data entry and resolution of 
queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator(s)’ ownership interest 
in the sponsor or the study intervention(s), and more generally about their financial 
ties with the sponsor. GSK/PPD will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 

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Hence, I: 
• 
Agree to supply GSK/PPD with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
study and for 1 year following completion of the study. 
• 
Agree that GSK/PPD may disclose any information about such ownership interests 
and financial ties to regulatory authorities. 
• 
Agree to provide GSK/PPD with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 

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Study identifier 
219575 
IND number 
111885 
Approval date 
10 Sep 2024 
Title 
A Phase 3b, open-label, single-arm study in 
adolescent and adult female participants to evaluate 
clinical symptom improvement and the safety of 
gepotidacin during treatment of uncomplicated 
urinary tract infections (acute cystitis) 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 

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219575 
Protocol Amendment 1 Final 
10 Sep 2024 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
10 Sep 2024 
Original Protocol 
27 June 2023 
Amendment 1 (10 Sep 2024) 
This global amendment is considered to be substantial. 
Overall Rationale for the Amendment: This global amendment covers the following:  
i. 
Clarifies a perceived ambiguity about number of measurements of the clinical 
symptoms score at baseline,  
ii. Remove need to send a stool sample to central laboratory for confirmation testing of 
Clostridium difficile which is now confirmed by testing at local laboratories,  
iii. Remove reflex testing with urine culture from the urinalysis performed at baseline.  
iv. Adjust pregnancy notification form from a paper method to electronic and additional 
minor wording edits. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2. Schema Figure 1. 
Study design overview. Footnote a. 
 
Section 1.3. Schedule of Activities 
(SoA). Table 1. Footnote a and n.  
 
Section 4. Study design  4.1 Overall 
design. 
  
Section 8. Study assessment and 
procedures. Section 8.2.1. Clinical 
Symptom score and clinical 
outcomes.  
 
Section 10.1. Appendix 1. Clinical 
symptom score for uUTI.  
Rewording of the CSS assessment 
procedure performed at baseline.  
Clarification that only one baseline 
CSS assessment will be performed.  
 
To clarify procedures performed by 
VRCC and Study staff while 
assessing CSS at the different visit 
calls. 
Clarifies a perceived ambiguity 
about number of measurements of 
the clinical symptoms score at 
baseline.  
 
Clarifies a perceived ambiguity on 
responsible person performing the 
CSS at each visit.  
Section 10.6 Appendix 6. CDAD 
Testing and procedure, algorithm, 
and process flow.  
Remove need to send a stool 
sample to central laboratory for 
confirmation testing of Clostridium 
difficile which is now confirmed by 
testing at local laboratories. 
Protocol instructs to send a frozen 
sample to IHMA central laboratory, 
however based on (1) learnings 
from recently completed phase 3 
studies (EAGLE-1, -2 and -3) and 
(2) the current capabilities of C. 
difficile testing in local laboratories, 
recommendation is to follow the 
local laboratory C. difficile testing 
algorithm that is currently in the 
protocol but omitting the 

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confirmatory C. difficile testing at 
IHMA. Sites should send stool 
samples for C. difficile testing to 
their local or reference laboratory for 
testing according to the algorithm in 
the protocol. 
Section 10.7 Appendix 7. Clinical 
laboratory tests. Table 9. Protocol-
required clinical safety laboratory 
tests.  
Remove reflex testing with urine 
culture from the urinalysis 
performed at baseline.  
Correction of typographical error.  
Consistency with the planned 
statistical analysis and required 
outputs. 
Section 8.4.5 Regulatory reporting 
requirements for SAEs. Table 6. 
Timeframes for submitting SAEs, 
pregnancy and other events reports 
to GSK.  
 
Section 8.4.8 Contact information 
for reporting SAEs and pregnancies 
– Pregnancy event reporting.  
Adjust pregnancy notification form 
from a paper method to electronic. 
Collection of pregnancy information, 
instruct to submit a paper pregnancy 
notification report at 24  hours and 
at follow up, however based on (1) 
internal process optimization and (2) 
sustainability, the paper pregnancy 
notification report will be replaced by 
an electronic pregnancy notification 
report. These electronic pregnancy 
notification reports will be part of the 
eCRF which should be completed 
following the instructions provided in 
the protocol and the eCRF 
completion guidance. 
Section. Introduction 2.1. Study 
rationale. 
 
Superiority is changed to Non 
inferiority to accurately describe the 
primary objective of the global 
phase 3 studies and clarified 
reference to superiority met in study 
212390.  
Correction of typographical error  
Section 10.7. Appendix 7: Clinical 
Laboratory Test  
Removal of mention to laboratory 
results that could unblind the study,  
considered not applicable for this 
open label study. 
Correction of typographical error 
Section 1.3. Schedule of Activities 
(SoA). Table 1. Footnote o.  
 
To clarify removal of mention of not 
being required to collect the number 
of doses taken and the CSS 
assessment after the Visit 2 
assessment, part of secondary 
objectives, needed for compliance.  
Consistency with the planned 
statistical analysis and required 
outputs. 
Section 10.1. Appendix 1. Clinical 
symptoms score of uUTI  
To clarify CSS assessment is not 
performed at Visit 7.  
Correction of typographical error. 
Consistency with SoA.  
 

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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ........................................................................................... 12 
1. 
PROTOCOL SUMMARY ........................................................................................ 14 
1.1. 
Synopsis ..................................................................................................... 14 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 20 
2.1. 
Study rationale ............................................................................................ 20 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/risk assessment .............................................................................. 22 
2.3.1. 
Risk assessment .......................................................................... 23 
2.3.2. 
Benefit assessment ..................................................................... 28 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 28 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ................................................... 29 
4. 
STUDY DESIGN .................................................................................................... 35 
4.1. 
Overall design ............................................................................................. 35 
4.2. 
Scientific rationale for study design ............................................................. 36 
4.3. 
Justification for dose ................................................................................... 37 
4.4. 
End-of-study definition ................................................................................ 37 
5. 
STUDY POPULATION ........................................................................................... 37 
5.1. 
Inclusion criteria .......................................................................................... 38 
5.2. 
Exclusion criteria ......................................................................................... 39 
5.3. 
Lifestyle considerations ............................................................................... 42 
5.3.1. 
Meals and dietary restrictions ...................................................... 42 
5.4. 
Screen failures ............................................................................................ 42 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study intervention .................... 42 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 42 
6.1. 
Study intervention administered .................................................................. 42 
6.2. 
Preparation, handling, storage, and accountability ...................................... 43 
6.3. 
Assignment to study intervention ................................................................ 44 
6.4. 
Blinding ....................................................................................................... 44 
6.5. 
Study intervention compliance .................................................................... 44 
6.6. 
Dose modification ....................................................................................... 44 
6.7. 
Continued access to study intervention after the end of the study ............... 45 
6.8. 
Treatment of overdose ................................................................................ 45 
6.9. 
Prior and concomitant therapy .................................................................... 45 
6.9.1. 
Permitted medications and nondrug therapies ............................. 46 
6.9.2. 
Prohibited medications and nondrug therapies ............................ 46 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 47 
7.1. 
Discontinuation of study intervention ........................................................... 47 

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7.1.1. 
Liver chemistry stopping criteria ................................................... 48 
7.1.2. 
QTc stopping criteria .................................................................... 49 
7.1.3. 
Gastrointestinal evaluation criteria ............................................... 50 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 50 
7.3. 
Lost to follow-up.......................................................................................... 51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 52 
8.1. 
Administrative procedures .......................................................................... 56 
8.1.1. 
Collection of demographic data .................................................... 56 
8.1.2. 
Medical history ............................................................................. 56 
8.2. 
Efficacy assessments ................................................................................. 56 
8.2.1. 
Clinical symptom score (CSS) and clinical outcomes ................... 56 
8.2.2. 
 
 ................................................................................. 57 
8.3. 
Safety assessments .................................................................................... 57 
8.3.1. 
Physical examination ................................................................... 58 
8.3.2. 
Vital signs .................................................................................... 58 
8.3.3. 
Electrocardiograms ...................................................................... 58 
8.3.4. 
Clinical safety laboratory tests ..................................................... 59 
8.3.5. 
Pregnancy testing ........................................................................ 59 
8.3.6. 
Safety monitoring ......................................................................... 60 
8.4. 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 60 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 60 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 61 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 61 
8.4.4. 
AESIs .......................................................................................... 61 
8.4.5. 
Regulatory reporting requirements for SAEs ................................ 61 
8.4.6. 
Pregnancy ................................................................................... 62 
8.4.7. 
Cardiovascular and death events ................................................. 62 
8.4.8. 
Contact information for reporting SAEs and pregnancies ............. 63 
8.5. 
Pharmacokinetics ....................................................................................... 63 
8.6. 
Pharmacodynamics .................................................................................... 63 
8.7. 
Genetics ..................................................................................................... 63 
8.8. 
Biomarkers ................................................................................................. 63 
8.9. 
Immunogenicity assessments ..................................................................... 63 
8.10. 
Medical resource utilization and health economics ..................................... 64 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 64 
9.1. 
Statistical hypothesis .................................................................................. 64 
9.1.1. 
Multiplicity adjustment .................................................................. 64 
9.2. 
Analysis sets ............................................................................................... 64 
9.3. 
Statistical analyses ..................................................................................... 65 
9.3.1. 
General considerations/definitions ............................................... 65 
9.3.2. 
Primary analysis .......................................................................... 65 
9.3.3. 
Secondary endpoints analyses .................................................... 66 
9.3.4. 
Exploratory endpoints analysis .................................................... 67 
9.4. 
Interim analyses .......................................................................................... 67 
9.5. 
Sample size determination .......................................................................... 67 
.............................................................. 68 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 68 
10.1. 
Appendix 1: Clinical symptom score for uUTI .............................................. 68 
10.2. 
Appendix 2:
 .............................................. 70 
10.3. 
Appendix 3: Contraceptive and barrier guidance ......................................... 70 
10.3.1. 
Definitions .................................................................................... 70 
10.3.2. 
Contraception guidance ............................................................... 71 
10.3.3. 
Collection of pregnancy information ............................................. 72 
10.4. 
Appendix 4: Additional guidance on permitted and prohibited 
medications and Crediblemeds.org ............................................................. 73 
10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments ............................................................................................... 79 
10.6. 
Appendix 6: CDAD testing procedure, algorithm, and process flow............. 82 
10.7. 
Appendix 7: Clinical laboratory tests ........................................................... 84 
10.8. 
Appendix 8: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 86 
10.8.1. 
Definition of AE ............................................................................ 86 
10.8.2. 
Definition of SAE .......................................................................... 87 
10.8.3. 
Definition of CV events and cases of CDAD ................................ 88 
10.8.4. 
Definition of TEAE ....................................................................... 89 
10.8.5. 
Recording, assessment, and follow-up of AEs and SAEs ............ 89 
10.9. 
Appendix 9: Regulatory, ethical, and study oversight considerations .......... 93 
10.9.1. 
Regulatory and ethical considerations ......................................... 93 
10.9.2. 
Financial disclosure ..................................................................... 93 
10.9.3. 
Informed consent/assent process ................................................ 94 
10.9.4. 
Study conduct materials and support ........................................... 94 
10.9.5. 
Data protection ............................................................................ 95 
10.9.6. 
Committees structure ................................................................... 95 
10.9.7. 
Dissemination of clinical study data ............................................. 95 
10.9.8. 
Data quality assurance ................................................................ 96 
10.9.9. 
Source documents ....................................................................... 97 
10.9.10. Study and site start and closure ................................................... 97 
10.9.11. Publication policy ......................................................................... 98 
10.10. Appendix 10: Division of AIDS table for grading the severity of adult 
and pediatric AEs, version 2.1, July 2017 ................................................... 98 
10.11. Appendix 11: COVID-19 protocol information specifically for data 
management and monitoring ...................................................................... 99 
11. REFERENCES ..................................................................................................... 100 
 
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LIST OF TABLES 
PAGE 
Table 1 
Schedule of activities ............................................................................. 17 
Table 2 
Objectives and endpoints ....................................................................... 29 
Table 3 
Study intervention administered ............................................................. 43 
Table 4 
Clinical improvement and resolution at 24 ±4 hours (Visit 2) .................. 57 
Table 5 
Clinical improvement and resolution at 48 ±4 hours (Visit 3), 
72 ±4 hours (Visit 4), 96 ±4 hours (Visit 5), and 
 
(Visit 6) ................................................................................................... 57 
Table 6 
Timeframes for submitting SAE, pregnancy, and other events 
reports to GSK ....................................................................................... 62 
Table 7 
Contact information for reporting SAEs and pregnancies ....................... 63 
.......................................................................... 68 
Table 9 
Protocol-required clinical safety laboratory tests..................................... 85 
 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 16 
Figure 2 
Phase 3 liver chemistry stopping and increased monitoring 
algorithm ................................................................................................ 48 
Figure 3 
Phase 3 liver chemistry increased monitoring algorithm with 
continued therapy for ALT 3 × ULN but <8 × ULN ................................ 49 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AChE-I 
Acetylcholinesterase inhibition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the drug concentration-time curve 
BID 
Twice daily 
BMI 
Body mass index 
CDAD 
Clostridioides difficile-associated diarrhea 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration 
CSR 
Clinical study report 
CSS 
Clinical Symptom Score 
CV 
Cardiovascular 
CYP3A4 
Cytochrome P450 enzyme 3A4 
DAIDS 
Division of AIDS 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED 
Early discontinuation 
EDC 
Electronic data capture 
ePIP 
Electronic Protocol Inquiry Platform 
ER 
Extended release 
ESBL 
Extended-spectrum β-lactamase 
ESRD 
End-stage renal disease 
FPFV 
First participant first visit 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
h 
Hours 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HPLC 
High-performance liquid chromatography 
HRT 
Hormone replacement therapy 
IAF 
Informed assent form 
IB 
Investigator’s brochure 
ICE 
Intercurrent events 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IgM 
Immunoglobulin M 
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Abbreviation 
Definition 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LAR 
Legally authorized representative 
LFT 
Liver function test 
MDR 
Multidrug-resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett’s formula 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
QTL 
Quality tolerance limit 
SAE 
Serious adverse event 
SDV/SDR 
Source Data Verification/Source Document Review 
SoA 
Schedule of activities 
SRT 
Safety Review Team 
TdP 
Torsades de pointes 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
UTI 
Urinary tract infection 
uUTI 
Uncomplicated urinary tract infection 
VRCC 
Virtual Research Coordination Center 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol title: A Phase 3b, open-label, single-arm study in adolescent and adult female 
participants to evaluate clinical symptom improvement and the safety of gepotidacin 
during treatment of uncomplicated urinary tract infections (acute cystitis) 
Brief title: A study in adolescent and adult female participants to evaluate clinical 
symptom improvement and the safety of gepotidacin during treatment of uncomplicated 
urinary tract infections (acute cystitis) 
Rationale: uUTIs affect the quality of life of patients. Feedback from patients and 
medical providers has demonstrated the need to better assess the burden of UTIs in 
women and early clinical symptom improvement on a daily basis. 
The Phase 3 gepotidacin studies conducted in uUTI (Section 2.2) were conducted based 
on the need to identify new and effective oral antibiotic treatment options for uUTI, as 
such therapies are becoming limited due to the increase of MDR uropathogens and 
ESBL-producing Enterobacterales uropathogens, which are impacting the efficacy of the 
currently available oral antibacterial treatment options. The studies focused on a primary 
therapeutic response composite endpoint of both clinical resolution and microbiological 
eradication, which were measured at specific time points, in line with regulatory guidance 
[DHHS, 2019]. 
However, the Phase 3 studies did not measure symptom improvement on a daily basis 
after the start of study intervention to characterize the time profile of change in clinical 
symptomatology improvement. The present study will align with the study design and 
treatment aspects of the gepotidacin Phase 3 studies [Perry, 2022]; however, it will focus 
primarily on clinical symptom improvement in participants with a uUTI by assessing the 
CSS on a daily basis after the start of and during gepotidacin treatment. This study data 
will provide additional clinical data for gepotidacin in uUTIs. 
Refer to Section 2.1 for additional information on the study rationale and Section 4.2 for 
additional information on the rationale for study design. 
Objectives, endpoints, and estimands: The primary objective of this study is to evaluate 
the clinical symptom improvement with gepotidacin treatment in female participants with 
uUTI at (24 hours [±4 hours]). This will be evaluated by the number of participants who 
achieve clinical symptom improvement (without the need for other systemic 
antimicrobials), defined as a decrease from Baseline in CSS total score of at least 1 point 
at (24 hours [±4 hours]). For additional information on the primary, secondary, and 
exploratory objectives and endpoints, refer to Section 3. 

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Overall design: This is a Phase 3b, open-label, single-arm, multicenter study to evaluate 
clinical symptom improvement and the safety of gepotidacin in female participants 
≥12 years of age with clinical symptoms and urine dipstick findings suggestive of uUTI. 
Participants who meet eligibility requirements will receive gepotidacin 1500 mg 
administered orally as 2 × 750 mg tablets BID for 5 days. (Note: Each dose is to be taken 
after food consumption and with water to assist with tolerability.) Clinical symptom and 
safety assessments will be conducted throughout the study. The total duration of study 
participation is approximately 28 days, with at least 1 planned on site study visit and 
6 telephone call study contacts (see Section 1.3 and Section 8 for study visit details), with 
allowance for unscheduled visits. For additional information on the overall design, refer 
to Section 4.1. 
Number of participants: Approximately 90 participants will be enrolled in the study to 
ensure at least 82 evaluable participants are included in the primary analysis, such that 
the half width of the 95%  CI is approximately ≤10%, under an assumption that 74% of 
participants meet the primary endpoint criteria as observed in the Phase 3 studies. 
Data monitoring/other committee: This will be overseen by the GSK SRT 
(Section 10.9.6). 
 

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1.2. 
Schema 
Figure 1 
Study design overview 
 
a. 
During Visit 1, prior to first dose of study intervention, the Virtual Research Coordination Center (VRCC) will contact the participant by telephone to perform the CSS assessment 
and 
 
 (in that specific order). This will be used as the Baseline CSS. The CSS will be reviewed (but not remeasured) by a study physician or otherwise appropriate 
medically trained staff from the study site onsite along with determination of whether other eligibility criteria are met before the first dose of study medication. Only If VRCC cannot 
do the telephone call, then the study physician or otherwise appropriate medically trained staff from the study site will ask the CSS questions and complete the 
 
 before 
the first dose of study intervention. Only one CSS and 
 is to be performed at Visit 1.  
b. 
The first dose of study intervention will be administered at the study site during Visit 1; the remaining 9 doses over the 5-day treatment course will be self-administered as 
outpatients. Each dose is to be taken after food consumption and with water to assist with tolerability. 
c. 
At Visit 2, Visit 3, Visit 4, and Visit 5, the CSS assessment and 
 
 will be completed (in that order) by VRCC. 
 
. 
 
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1.3. 
Schedule of activities (SoA) 
Table 1 
Schedule of activities 
Visita, b, d 
 
Windowf 
Baseline/Day 1 
On-treatment 
Follow-up 
Unscheduledc 
Early 
Withdrawale 
1 
2 
3 
4 
5 
6 
7 
 
 
Predose 
Postdose 
24±4 h 
48±4 h 
72±4 h 
96±4 h 
28 days 
(±3 days) 
 
 
Mode of Visitb 
Onsite 
Onsite 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
(Onsite or 
Telephone) 
(Onsite or 
Telephone) 
Procedure 
 
Documented informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Participant demography 
X 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
 
 
 
 
 
 
 
X 
 
Medical, uUTI, and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
Urine dipstickh 
X 
 
 
 
 
 
 
 
X 
 
Hematology, chemistry, 
and urinalysisi 
X 
 
 
 
 
 
 
 
X 
 
Drug and alcohol screeni 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
 
Vital sign measurementsj 
X 
 
 
 
 
 
 
 
X 
 
Urine pregnancy testi, k 
X 
 
 
X 
 
 
 
 
 
 
Telephone call 
completed by VRCCl 
X 
 
X 
X 
X 
X 
 
 
 
 
Safety telephone call 
completed by the study 
sitem 
 
 
 
 
 
 
X 
X 
X 
X 
Xn 
 
Xo 
X 
X 
X 
X 
 
X 
X 
Xp 
 
X 
X 
X 
X 
 
 
X 
X 
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Visita, b, d 
 
Windowf 
Baseline/Day 1 
On-treatment 
Follow-up 
Unscheduledc 
Early 
Withdrawale 
1 
2 
3 
4 
5 
6 
7 
 
 
Predose 
Postdose 
24±4 h 
48±4 h 
72±4 h 
96±4 h 
28 days 
(±3 days) 
 
 
Mode of Visitb 
Onsite 
Onsite 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
Telephone 
call 
(Onsite or 
Telephone) 
(Onsite or 
Telephone) 
Study intervention 
dosingq 
 
X 
X 
X 
X 
X 
 
 
 
 
SAEsr 
X 
AEss 
 
Prior/concomitant 
medication reviewt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study intervention 
complianceu 
 
 
X 
X 
X 
X 
 
 
 
 
Schedule next 
visit/telephone visitv 
X 
 
X 
X 
X 
X 
X 
 
 
 
a. 
Prescreening activities may also be conducted, including a prescreening informed consent and urine testing, as detailed in Section 8. The Visit 1 telephone call to assess CSS and 
 (in that specific order) will be conducted by VRCC when the participant is onsite. The CSS will be reviewed (but not remeasured) by a study physician or otherwise appropriate 
medically trained staff from the study site onsite along with determination of whether other eligibility criteria are met before the first dose of study medication.  Only if VRCC cannot 
do the telephone call, then the study physician or otherwise appropriate medically trained staff from the study site  will ask the CSS questions and complete the 
 
 before 
the first dose of study intervention. Only one CSS and 
 is to be performed at Visit 1 
b. 
All planned postbaseline visits (i.e., On-treatment and Follow-up) are telephone visits. The study physician or otherwise appropriate medically trained staff from the study site will 
conduct a safety telephone visit at Visit 6 and Visit 7. VRCC will conduct the visits at Visit 1, Visit 2, Visit 3, Visit 4, and Visit 5 and assess CSS and 
 (in that specific order). 
c. 
An onsite or telephone Unscheduled Visit will be arranged at any point during the study if there are safety concerns or a lack of response to study intervention or for early 
withdrawal. An alternative antibiotic therapy may be prescribed/administered at the Unscheduled Visit. Additional investigations may be performed per investigator discretion. 
d. 
Each treatment visit will be assessed over a 24-hour period, starting with the first dose of study intervention received for an individual participant. For example, participants who 
only receive 1 dose of study intervention on their first calendar day in the study due to a late afternoon/evening Visit 1 will take the second dose on the following calendar day. This 
pattern will continue until all 10 doses are received; thus, the tenth/last dose will be taken prior to Visit 5 (may be 5 or 6 calendar days, depending on when the first dose is taken). 
e. 
Early withdrawal visits may be performed onsite and/or via telephone as needed; this will be determined by the medical monitor. If the Early Withdrawal Visit occurs before the end 
of On-treatment (Visit 5), then the CSS assessment and 
 
 will be collected. If a participant withdraws early from the study prior to Visit 7, then the Visit 7 assessments will 
be performed as the Early Withdrawal Visit. If the Early Withdrawal Visit is not performed, then the whole visit will not be active in the EDC (even if participant decided to terminate 
participation and the visit was to have been done). 
f. 
The start of each time window is the time from the first dose of study intervention taken. 
g. 
If an additional physical examination is performed (i.e., Unscheduled Visit), it may be symptom directed, and any clinically significant changes from Baseline or clinically significant 
new clinical signs will be reported as AEs. 
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h. 
Participants will provide a predose, clean-catch, midstream urine sample for a urine dipstick test to confirm nitrite or pyuria (presence of 3+/large leukocyte esterase) based on 
local laboratory procedures. See Section 8.3.4 for additional information. 
i. 
With the exception of the urine dipstick and baseline pregnancy testing, a central laboratory will be used. Any baseline results received while participants are On-treatment that are 
exclusionary will be assessed by the medical monitor. The medical monitor will contact the investigator and advise on appropriate action with the study intervention. 
j. 
Measure temperature, blood pressure, respiratory rate, and pulse rate. See Section 8.3.2 for additional details. 
k. 
For women of childbearing potential, a negative high sensitivity urine pregnancy test is sufficient for eligibility. A pregnancy test will be performed predose and just before taking 
the fifth dose. The pregnancy test before the fifth dose will be done at home using a test kit supplied at Baseline, with the result confirmed at Visit 4. 
l. 
VRCC will confirm the doses of study intervention taken the previous day and results of at home pregnancy tests. AEs will not directly be asked about by VRCC, and VRCC will 
direct any AEs, SAEs, or concomitant medications reported during telephone visits directly to the study site; the study physician or otherwise appropriate medically trained staff 
from the study site will follow-up with the participant. 
m. The study physician or otherwise appropriate medically trained staff from the study site will perform a safety telephone call at Visit 6 
), and at Visit 7 (±3 days). The study 
physician or otherwise appropriate medically trained staff from the study site will follow-up with participants who report an AE, SAE, or use of a concomitant medication to VRCC. 
n. 
o. 
Participants must have taken 2 doses of study intervention before the Visit 2 CSS telephone assessment. This will be confirmed during the Visit 2 telephone call. For any 
participants who have not received 2 doses of study intervention, a second telephone call will be scheduled to perform the CSS after the second dose has been taken.  
p. 
The 
 
 will be administered to participants via a telephone interview performed by VRCC. These assessments will be performed by the same interviewer who determines 
the CSS. See Section 8.2.2 for additional information. 
q. 
The first dose of study intervention will be administered at the study site during Visit 1; the remaining 9 doses over the 5-day treatment course will be self-administered as 
outpatients. Each dose is to be taken after food consumption and with water to assist with tolerability. The third dose of study intervention cannot be taken until the Visit 2 
assessments have been completed. 
r. 
Record SAEs from the start of study intervention. However, SAEs assessed as related to study participation or related to GSK product (non-IMP) will be recorded from the time of 
consent/assent. See Section 8.4.1 for details. During any postbaseline visit, if a participant reports an SAE, VRCC will refer the participant to the study site to record the SAE. 
s. 
Record AEs from the time of the first dose of study intervention. During any postbaseline VRCC telephone calls, if a participant reports an AE, VRCC will refer the participant to 
the study site to record the AE. 
t. 
Prior and concomitant medications will be collected and reviewed throughout the study. During any postbaseline visits if a participant reports concomitant medication use, VRCC 
will refer the participant to the study site to record the concomitant medication. 
u. 
Study intervention compliance will be determined via telephone on a daily basis. VRCC will ask the participant how many tablets have been taken and/or are remaining. 
Participants will return study intervention to the study site by Visit 7 using a prepaid envelope provided by the study site. 
v. 
Schedule the date and time of the next telephone visit. 
 
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2. 
INTRODUCTION 
Gepotidacin (GSK21409144) is a novel, bactericidal, first-in-class triazaacenaphthylene 
antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and 
binding site [Bax, 2010; Gibson, 2019] and provides well-balanced inhibition of 
2 different type II topoisomerase enzymes [Oviatt, 2022]. This provides activity against 
most strains of target uUTI uropathogens, such as Escherichia coli and Staphylococcus 
saprophyticus, including isolates resistant to current antibiotics [Biedenbach, 2016; 
Mushtaq, 2019]. Due to well-balanced binding at both enzymes, mutations in both 
enzymes are needed to significantly affect gepotidacin susceptibility [Oviatt, 2022]. 
uUTIs, also referred to as acute cystitis, are defined as UTIs in nonpregnant female 
patients with no known urological abnormalities or complicating comorbidities and not 
accompanied by signs or symptoms suggesting systemic (i.e., not localized to the 
bladder) infection, such as fever or costovertebral angle pain [Gupta, 2011; DHHS, 
2019]. Common symptoms of uUTIs are pain on urination (dysuria), frequent urination 
(frequency), sudden onset of the need to urinate (urgency), pain in the lower abdomen 
(suprapubic pain), inability to start the urine stream (hesitancy), and cloudy urine or 
blood in the urine (hematuria). In addition to the physical symptoms, uUTIs have been 
shown to affect a patient’s quality of life and their emotional and mental health 
[Grigoryan, 2022]. 
2.1. 
Study rationale 
The patient burden of uUTI is significant, with each episode of uUTI associated with 
approximately 6 symptomatic days, 2 to 3 days of restricted activity, and an unknown 
amount of time lost from work. Most of the symptoms experienced by patients were rated 
as moderate to severe in intensity and some of them were the most common associated 
with impairment of daily living. There is a need to better assess the burden of UTIs in 
women because few data are available that describe patient-reported outcomes regarding 
time to improvement and resolution of uUTI symptoms. Feedback from patients and 
providers states that patients want to feel better after the first dose of treatment and it has 
been shown that rapid reversal of the overall severity of uUTI symptoms allows the 
patient to resume normal work/social activities [Klimberg, 2005]. 
The Phase 3 gepotidacin studies conducted in uUTI (Section 2.2) were conducted based 
on the need to identify new and effective oral antibiotic treatment options for uUTIs, as 
such therapies are becoming limited due to the increase in MDR pathogens and 
ESBL-producing Enterobacterales pathogens, which are impacting the efficacy of the 
currently available oral antibacterial treatment options (see Section 2.2). 
More recently, two Phase 3 clinical studies (Study 204989 and Study 212390) that 
assessed gepotidacin (1500 mg BID for 5 days) compared with nitrofurantoin (100 mg 
BID for 5 days) in uUTI showed gepotidacin was non-inferior in the primary therapeutic 
response evaluated at a preplanned interim analysis in both studies and superior to 
nitrofurantoin in study 212390. Full data analyses and reporting activities are complete 
[Study 204989, (NCT04020341); Study 212390, (NCT04187144); Hall, 2023] for both 
Phase 3 trials. 

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The Phase 3 primary endpoint in the studies was a composite of both clinical and 
microbiological success captured at the Test of Cure Visit, 10 to 13 days after 
randomization. 
 
 
 
The purpose of this Phase 3b study for gepotidacin in female participants with uUTI is to 
evaluate clinical symptom improvement on each day during the 5-day treatment period, 
specifically including the 24-hour time point. The microbiological components of uUTIs 
were fully assessed in Study 204989 and Study 212390. These additional data are 
expected to align with current clinical practice and to inform practitioners on the potential 
use of gepotidacin in uUTIs. 
2.2. 
Background 
UTIs are one of the most common bacterial outpatient infections, with a lifetime 
incidence of 50% to 60% in adult females [Medina, 2019]. An estimated 11% of adult 
females experience at least 1 episode of uUTI per year, with half experiencing more than 
1 recurrent episode over their lifetime [Foxman, 2000]. Apart from a spike in young 
sexually active women, the incidence of uUTIs generally increases with age [Fihn, 2003; 
Schmiemann, 2010; Suskind, 2016]. 
The predominant uropathogen isolated in community-acquired UTIs is E. coli 
(approximately 75%) [Foxman, 2010; Foxman, 2014; Flores-Mireles, 2015]. Other 
uropathogens, including Staphylococcus, Enterococcus, Klebsiella, and Proteus species, 
are less common collectively, accounting for approximately 20% of uropathogens 
isolated in community-acquired UTIs [Foxman, 2010; Flores-Mireles, 2015]. 
Existing oral therapies for uUTI are becoming increasingly limited due to rising trends 
for MDR pathogens, including ESBL-producing Enterobacterales, which are impacting 
the efficacy of currently available oral antimicrobial treatment options. Treatment options 
are further limited for patients with an antibiotic allergy or intolerance or comorbidities 
such as renal impairment. Thus, there is an increasingly urgent unmet medical need for 
new therapeutic agents for the treatment of uUTI, particularly those with potent activity 
against MDR E. coli urinary pathogens and with a low propensity for collateral damage 
[Abadi, 2019; CDC, 2019; ECDC, 2022; Spellberg, 2015]. 
Gepotidacin has demonstrated activity against most strains of target uUTI uropathogens 
including E. coli and S. saprophyticus, including isolates resistant to current antibiotics 
[Biedenbach, 2016; Mushtaq, 2019]. With its ability to selectively inhibit 2 bacterial 
DNA enzymes, DNA gyrase, and topoisomerase 4, by a unique mechanism that is not 
utilized by any currently approved human therapeutic agent [Bax, 2010; Gibson, 2019], 
gepotidacin has the potential to address a significant and burgeoning unmet medical need 
by providing a new and effective oral treatment option for uUTI that might obviate the 
need for IV treatment. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the IB. 
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2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of gepotidacin may be found in the IB. 

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2.3.1. 
Risk assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Gepotidacin (GSK2140944) 
Cardiovascular Effects 
Based on nonclinical data, cardiovascular 
effects were reversible increases in heart rate 
and blood pressure (dog and monkey); a 
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 h 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 h after the end of the infusion 
(see Section 5.2.6 and Section 6 of the IB). 
In Phase 1 and 2 studies, 
concentration-dependent QT prolongation has 
been observed during clinical trials with 
gepotidacin; however, this increase has not 
translated into medically significant QTc values or 
changes from Baseline (QTcF >500 msec or 
change from Baseline >60 msec) or 
cardiovascular safety concerns. 
In Phase 1 and 2 studies, gepotidacin did not 
have a clinically relevant effect on cardiac 
conduction (PR and QRS intervals). 
See Section 5.2 for excluded cardiac 
conditions. Close monitoring of clinical 
parameters and AEs (Section 1.3) will be 
conducted, and treatment monitoring and 
evaluation criteria (Section 7.1.2) will be 
utilized to mitigate cardiovascular effects. 
Participants taking medications known to 
increase QT or potent CYP3A4 inhibitors will 
be excluded (see Section 6.9.2). 
See also the Renal and Hepatic sections in 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 
non-glandular 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 in this table below. 
Clostridioides difficile-associated diarrhea (CDAD) 
has been observed in clinical trials with 
gepotidacin. 
See Section 5.2 for excluded medical 
conditions. Close monitoring of clinical 
parameters and AEs (Section 1.3) will be 
conducted to mitigate and assess 
gastrointestinal effects. 
Suspected CDAD will be managed according 
to a prespecified algorithm provided in 
Appendix Section 10.6. 
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. 
AEs possibly consistent with AChE-I, including 
diarrhea, nausea, vomiting, gastrointestinal 
cramping and pain, dyspnea, bradycardia, 
lacrimation, salivation, dysarthria, and 
Participants who have medical conditions or 
require medications that may be impacted by 
inhibition of acetylcholinesterase will be 
excluded from participation in this study. See 
Section 5.2 for excluded medical conditions 
and Section 6.9.2, for prohibited medications. 
Close monitoring of clinical parameters and 
AEs will be conducted to assess effects 
potentially related to acetylcholinesterase 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
diaphoresis/sweating, have been reported during 
clinical trials with gepotidacin. 
The majority of these AEs have been mild and 
transient and have been reported in clinical trials 
with comparable Cmax levels expected in this 
study. 
The majority of events potentially caused by 
AChE-I were nonserious AEs and none were of a 
life-threatening nature (e.g., heart block). Most 
AChE events have been driven by gastrointestinal 
events. 
Hepatic Effects 
In preclinical studies, increases in liver 
enzymes and total bilirubin were observed in 
some rats at or above clinical exposure, in the 
absence of microscopic evidence of liver 
toxicity. Additionally, the weight of evidence, 
including studies in dogs and monkeys, 
suggests a low likelihood of liver toxicity in 
humans. 
In Phase 1 and 2 studies, 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 have not been 
suggestive of an adverse effect of gepotidacin, 
and none were considered related to study 
treatment. 
Participants with severe hepatic impairment are 
excluded. See Section 5.2 for excluded 
medical conditions. Monitoring and stopping 
criteria liver events have been implemented. 
Use in participants with hepatic dysfunction A substantial increase in Cmax and AUC and a 
decrease in clearance were observed in volunteer 
participants with severe hepatic impairment. 
Specific exclusion criteria related to liver 
conditions and laboratory results have been 
implemented in the protocol. 
Monitoring, including chemistry testing during 
treatment, and stopping criteria have been 
implemented as per protocol. 

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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. 
Participants with severe renal 
impairment/ESRD (including those who may 
require dialysis) are excluded. See Section 5.2 
for excluded medical conditions. Monitoring 
criteria have been implemented. 
Use in participants with renal dysfunction 
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). 
Specific exclusion criteria related to renal 
conditions and laboratory results have been 
implemented in the protocol. 

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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 not recommended in pregnant 
or nursing mothers. Pregnancy testing 
requirements in this study minimize the risk of 
exposure to a fetus. See Appendix 
Section 10.3 for contraceptive measures and 
for required pregnancy testing. 

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2.3.2. 
Benefit assessment 
uUTI is among the most common indications for which antimicrobials are prescribed for 
otherwise healthy women [Gupta, 2011]. 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 uropathogen in uUTI, 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 uUTI. 
In addition to routine medical monitoring appropriate for uUTI, participants will receive 
heightened monitoring to ensure safety when participating in a clinical study. 
2.3.3. 
Overall benefit-risk conclusion 
Antimicrobial resistance among uropathogens causing uUTI has increased in the past 
decades [Gupta, 2011; 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 
that are not utilized by any currently approved human therapeutic agent. 
Two Phase 3 clinical studies (Study 204989 [NCT04020341] and Study 212390 
[NCT04187144]) that assessed gepotidacin (1500 mg BID for 5 days) compared with 
nitrofurantoin (100 mg BID for 5 days) in uUTI recently stopped early after an interim 
analysis showed noninferiority in the primary efficacy endpoint of therapeutic response 
with no safety concerns identified by the Independent Data Monitoring Committee. In the 
Phase 3 studies, no new safety or tolerability concerns were identified from AEs. Very 
few SAEs were observed in the Phase 3 studies. There was a higher frequency of 
gastrointestinal AEs in the gepotidacin arm compared with the nitrofurantoin arm, which 
was expected based on the Phase 1/2 gepotidacin data and nitrofurantoin label; diarrhea 
was the most common AE overall and the most common gastrointestinal AE in the 
gepotidacin arm compared with the nitrofurantoin arm, and the AEs were generally mild 
to moderate and self-limited. 
None of the risks seen to date in participants dosed with gepotidacin preclude further 
clinical development or submission for regulatory approval. 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 intervention 
(Section 2.3.1). Furthermore, a GSK SRT will monitor safety data instream (see 
Appendix Section 10.9.6). Careful safety monitoring will also identify any emerging 
safety issues for gepotidacin and contribute to the benefit-risk profile of gepotidacin. 
The investigator may also, at their discretion, discontinue a participant from study 
intervention 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 are justified by the 
anticipated benefits that may be afforded to participants with uUTI. 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 2 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate clinical symptom 
improvement with gepotidacin treatment 
in female participants with uUTI at 
24 hours (±4 hours). 
• 
Achieving clinical symptom improvement, 
defined as a decrease from Baseline in 
CSS total score of at least 1 point at 
24 hours (±4 hours), without the need for 
other systemic antimicrobials. 
Secondary 
• 
To assess clinical symptom improvement 
with gepotidacin treatment over time in 
female participants with uUTI. 
• 
Achieving clinical symptom improvement, 
defined as a decrease from Baseline of at 
least 1 point in the CSS total score at 
48 hours (±4 hours), 72 hours (±4 hours), 
and 96 hours (±4 hours), without the need 
for other systemic antimicrobials. 
• 
To assess clinical symptom resolution 
with gepotidacin treatment over time in 
female participants with uUTI. 
• 
Achieving clinical symptom resolution, 
defined as a decrease from Baseline to a 
CSS total score of 0 at 24 hours 
(±4 hours), 48 hours (±4 hours), 72 hours 
(±4 hours), and 96 hours (±4 hours), 
without the need for other systemic 
antimicrobials. 
• 
To assess safety and tolerability of 
gepotidacin treatment in female 
participants with uUTI. 
• 
Participants with TEAEs, SAEs, and 
AESIs. 
 
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PRIMARY ESTIMAND: 
The primary clinical question of interest is to assess symptom improvement without the 
need for other systemic antimicrobials in participants at 24 hours (±4 hours) after the 
initial dose of gepotidacin and having received a second dose of gepotidacin prior to the 
primary CSS assessment at 24 hours (±4 hours). 
The primary estimand is described by the following attributes: 
• 
The population is female participants aged ≥12 years with suspected uUTI, who can 
adhere to 2 doses of treatment as prescribed. 
• 
The primary endpoint is achieving clinical symptom improvement, defined as a 
decrease from Baseline in CSS total score of at least 1 point at 24 hours (±4 hours), 
without the need for other systemic antimicrobials. 
• 
The treatment condition is gepotidacin 1500 mg BID. 
• 
The ICEs and estimand strategies are: 
• 
Participants unable to take 2 doses as prescribed before the CSS assessment at 
24 hours (±4 hours) (Principal Stratum Strategy). Interest lies in the group of 
participants who complied with the 2 doses as prescribed before the CSS 
assessment at 24 hours (±4 hours). 
• 
A participant using other systemic antimicrobials (for uUTI or other infections) 
on or before the CSS assessment at 24 hours (±4 hours) (Composite Strategy). 
This ICE is incorporated into the definition of the endpoint. 
• 
The population-level summary to be estimated is percentage of participants who 
achieve clinical symptom improvement and its 95% Exact Binomial CI. 
RATIONALE FOR PRIMARY ESTIMANDS: 
• 
Interest lies in evaluating study intervention benefit through a decrease in CSS total 
score in participants who achieve 100% compliance to study intervention before the 
CSS assessment at 24 hours (±4 hours). 
• 
Participants who take other antimicrobials for uUTI indicate lack of treatment benefit 
and will not be able to achieve symptom improvement (i.e., treatment failures). 
Participants who take other antimicrobials for other infections might confound the 
outcome by improving the symptoms. Therefore, such participants are also set to 
treatment failures. 
SUPPLEMENTARY ESTIMAND FOR PRIMARY ENDPOINT: 
A supplementary estimand will be considered if
participants are not able to comply 
with the 2 doses as prescribed before the CSS assessment at 24 hours (±4 hours). 
The additional clinical question of interest is to assess symptom improvement without the 
need for other systemic antimicrobials in participants at 24 hours (±4 hours) after the 
initial dose of gepotidacin. 
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The supplementary estimand is described by the following attributes: 
• 
The population is female participants aged ≥12 years with suspected uUTI. 
• 
The endpoint is achieving clinical symptom improvement, defined as a decrease 
from Baseline in CSS total score of at least 1 point at 24 hours (±4 hours), without 
the need for other systemic antimicrobials. 
• 
The treatment condition is gepotidacin 1500 mg BID. 
• 
The ICEs and estimand strategies are as follows: 
• 
Participants unable to take 2 doses as prescribed before the CSS assessment at 
24 hours (±4 hours) (Treatment Policy Strategy). Interest lies in the treatment 
effect regardless of compliance with the study intervention. 
• 
A participant using other systemic antimicrobials (for uUTI or other infections) 
on or before the CSS assessment at 24 hours (±4 hours) (Composite Strategy). 
This ICE is incorporated into the definition of the endpoint. 
• 
The population-level summary to be estimated is percentage of participants who 
achieve clinical symptom improvement and its 95% Exact Binomial CI. 
RATIONALE OF SUPPLEMENTARY ESTIMAND FOR PRIMARY ENDPOINT: 
• 
Interest lies in evaluating study intervention benefit through decrease in CSS total 
score in all participants whether or not compliant with the study intervention. 
• 
Participants who take other antimicrobials for uUTI indicate lack of treatment benefit 
and will not be able to achieve symptom improvement (i.e., treatment failures). 
Participants who take other antimicrobials for other infections might confound the 
outcome by reducing the symptoms. Therefore, such participants are also set to 
treatment failures. 
ESTIMANDS SUPPORTING SECONDARY EFFICACY OBJECTIVES: 
The secondary efficacy clinical questions of interest are to assess the following: 
• 
The improvement of clinical signs and symptoms without the need of any other 
systemic antimicrobials during the 5 days of treatment with gepotidacin in 
participants who complied with at least 80% of the total prescribed doses before each 
timepoint. 
• 
The resolution of clinical signs and symptoms without the need of any other systemic 
antimicrobials during the 5 days of treatment with gepotidacin in participants who 
complied with at least 80% of the total prescribed doses before each timepoint. 
The estimand attributes for the secondary efficacy objectives are as follows: 
• 
The population is female participants aged ≥12 years with suspected uUTI, who can 
comply with ≥80% doses of treatment as prescribed. 

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The endpoints are as follows: 
• 
Achieving clinical symptom improvement, defined as a decrease from Baseline of at 
least 1 point in the CSS total score at 48 hours (±4 hours), 72 hours (±4 hours), and 
96 hours (±4 hours), without the need for other systemic antimicrobials. 
• 
Achieving clinical symptom resolution, defined as a decrease from Baseline to a CSS 
total score of 0, at 48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours), 
without the need for other systemic antimicrobials. 
• 
The treatment condition is gepotidacin 1500 mg BID. 
The ICEs and estimand strategies are as follows: 
• 
Participants unable to take ≥80% doses of gepotidacin up to 48 hours (±4 hours), 
72 hours (±4 hours), and 96 hours (±4 hours) (Principal Stratum Strategy). Interest 
lies in the group of participants who complied with ≥80% of the total prescribed 
doses of gepotidacin up to 48 hours (±4 hours), 72 hours (±4 hours), and 96 hours 
(±4 hours). 
• 
A participant using other systemic antimicrobials (for uUTI or other infections) on or 
before 48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours) (Composite 
Strategy). This ICE is incorporated into the definition of the endpoint. 
• 
Study intervention discontinuation (due to any reason) (Treatment Policy Strategy). 
Interest lies in the treatment effect regardless of study intervention discontinuation. 
• 
The population-level summary to be estimated is percentage of participants who 
achieve clinical symptom improvement and its 95% Exact Binomial CI. 
RATIONALE OF ESTIMANDS SUPPORTING SECONDARY EFFICACY 
OBJECTIVES: 
• 
Interest lies in evaluating study intervention benefit through decrease in CSS total 
score in participants who had at least 80% compliance to study intervention up to 
48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours). 
• 
Participants who take other antimicrobials for uUTI on or before 48 hours 
(±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours) indicate lack of treatment 
benefit and will not be able to achieve symptom improvement/resolution (i.e., 
treatment failures) at the respective time points. Participants who take other 
antimicrobials for other infections before 48 hours (±4 hours), 72 hours (±4 hours), 
and 96 hours (±4 hours) might confound the outcome of the timepoints by reducing 
the symptoms. Therefore, such participants are also set to treatment failures at the 
respective time points (Composite Strategy). 
• 
Interest lies in the treatment effect regardless of the 5-day treatment completion, 
which reflects how participants may be treated in clinical practice. Hence, a 
treatment policy strategy is appropriate for treatment withdrawal before completing 
the 5 days of treatment. 

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SUPPLEMENTARY ESTIMANDS FOR SECONDARY EFFICACY OBJECTIVE: 
Supplementary estimands will be considered if 
participants are unable to comply 
with ≥80% of the total prescribed doses of gepotidacin up to 48 hours (±4 hours), 
72 hours (±4 hours), and 96 hours (±4 hours). 
The additional secondary efficacy clinical questions of interest are to assess the 
following: 
• 
The improvement of clinical signs and symptoms without the need of any other 
systemic antimicrobials during the 5 days of treatment with gepotidacin in all 
participants regardless of compliance with study intervention before 48 hours 
(±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours). 
• 
The resolution of clinical signs and symptoms without the need of any other systemic 
antimicrobials during the 5 days of treatment with gepotidacin in all participants 
regardless of compliance with study intervention before 48 hours (±4 hours), 
72 hours (±4 hours), and 96 hours (±4 hours). 
The estimand attributes for the supplementary estimands for the secondary objectives are 
as follows: 
• 
The population is female participants aged ≥12 years with suspected uUTI. 
The efficacy endpoints are as follows: 
• 
Achieving clinical symptom improvement, defined as a decrease from Baseline of at 
least 1 point in the CSS total score at 48 hours (±4 hours), 72 hours (±4 hours), and 
96 hours (±4 hours), without the need for other systemic antimicrobials. 
• 
Achieving clinical symptom resolution, defined as a decrease from Baseline to a CSS 
total score of 0, at 48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours), 
without the need for other systemic antimicrobials. 
• 
The treatment condition is gepotidacin 1500 mg BID. 
• 
The ICEs and estimand strategies are as follows: 
• 
Participants unable to take ≥80% doses of gepotidacin up to 48 hours (±4 hours), 
72 hours (±4 hours), and 96 hours (±4 hours) (Treatment Policy Strategy). 
Interest lies in all participants regardless of compliance with study intervention. 
• 
A participant using other systemic antimicrobials (for uUTI or other infections) 
on or before 48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours) 
(Composite Strategy). This ICE is incorporated into the definition of the 
endpoint. 
• 
Study intervention discontinuation (due to any reason) (Treatment Policy 
Strategy). Interest lies in the treatment effect regardless of study intervention 
discontinuation. 
• 
The population-level summary to be estimated is percentage of participants who 
achieve clinical symptom improvement and its 95% Exact Binomial CI. 
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RATIONALE OF SUPPLEMENTARY ESTIMANDS FOR SECONDARY 
EFFICACY OBJECTIVES: 
• 
Interest lies in evaluating study intervention benefit through decrease in CSS total 
score in all participants, whether or not ≥80% compliant with study intervention. 
• 
Participants who take other antimicrobials for uUTI on or before 48 hours 
(±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours) indicate lack of treatment 
benefit and will not be able to achieve symptom improvement/resolution (i.e., 
treatment failures) at the respective time points. Participants who take other 
antimicrobials for other infections before 48 hours (±4 hours), 72 hours (±4 hours), 
and 96 hours (±4 hours) might confound the outcome of the 48 hours (±4 hours), 
72 hours (±4 hours), and 96 hours (±4 hours) by reducing the symptoms. Therefore, 
such participants are also set to treatment failures at the respective time points 
(Composite Strategy). 
• 
Interest lies in the treatment effect regardless of 5-day treatment completion, which 
reflects how participants may be treated in clinical practice. Hence, a treatment 
policy strategy is appropriate for treatment withdrawal before completing 5 days of 
treatment. 
Estimand for secondary safety objective: 
The estimand attributes for the secondary safety objectives are as follows: 
• 
The population is female participants aged ≥12 years with suspected uUTI. 
The safety endpoints are: 
• 
TEAEs  
• 
SAEs 
• 
AESIs 
• 
The treatment condition is gepotidacin 1500 mg BID. 
• 
The ICE and estimand strategy is as follows: 
• 
Study treatment discontinuation due to any reason (treatment policy). Interest 
lies in the group of participants irrespective of whether they completed the study 
intervention. 
• 
The population-level summary to be estimated are counts and percentages of 
participants who have experienced TEAEs, SAEs, and AESIs.  
• 
Rationale of estimand supporting secondary safety objectives: 
• 
The safety endpoints will be captured and reported postdose irrespective of 
whether or not the participant completed the study intervention. 

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4. 
STUDY DESIGN 
4.1. 
Overall design 
• 
Study 219575 is a Phase 3b, open-label, single-arm, multicenter study to evaluate 
clinical symptom improvement and the safety of gepotidacin during the treatment of 
uUTIs. 
• 
Female participants ≥12 years of age with 2 or more clinical symptoms of uUTI and 
nitrite or pyuria from a pretreatment clean-catch midstream urine sample will be 
offered enrollment into the study and consented/assented (Section 5.1). Participants 
who meet eligibility requirements will receive gepotidacin 1500 mg administered 
orally BID for 5 days. (Note: Each dose is to be taken after food consumption and 
with water to assist with tolerability.) 
• 
Appropriate clinical symptom and safety assessments will be conducted throughout 
the study. The total duration of study participation is approximately 28 days, with at 
least 1 planned onsite study visit and 6 telephone call study contacts (see Section 1.3 
and Section 8 for study visit details), with allowance for unscheduled visits, as 
follows: 
• 
Visit 1 (Baseline/Day 1): onsite 
• 
Visit 2 (24 hours ±4 hours), Visit 3 (48 hours ±4 hours), Visit 4 (72 hours 
±4 hours), and Visit 5 (96 hours ±4 hours): telephone 
• 
Visit 6 
): telephone 
• 
Visit 7 (Follow-up/Day 28): telephone 
• 
Unscheduled Visit: onsite or telephone 
o 
An additional onsite or telephone visit will be arranged if there are safety 
concerns, lack of response to study intervention, or early withdrawal. 
• 
Note: Each visit will be assessed over a 24-hour period, starting with the first 
dose of study intervention received for an individual participant. For example, 
participants who only receive 1 dose of study intervention on their first calendar 
day in the study due to a late afternoon/evening Baseline Visit will take the 
second dose on the following calendar day, which will complete Visit 1. This 
pattern will continue until all 10 doses are received; thus, the tenth/last dose will 
be taken prior to Visit 5 (96 hours ±4 hours) (may be 5 or 6 calendar days, 
depending on when the first dose is taken). 
• 
The study is outsourced and PPD will perform all study-related activities on behalf 
of GSK. PPD MedCom will perform activities completed by Virtual Research 
Coordination Center during the study. 
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• 
• 
Refer to Appendix Section 10.11 for details regarding allowed revisions to 
monitoring due to the coronavirus disease. 
• 
The primary uUTI symptom assessment will be the CSS (Appendix Section 10.1) at 
Visit 2 (24 hours ±4 hours). Participants must have taken a total of 2 doses of 
gepotidacin before the Visit 2 (24 hours ±4 hours) assessment of CSS. For the 
primary endpoint, clinical symptom improvement is defined as a decrease from 
Baseline of ≥1 point in the CSS total score 24 hours (±4 hours) after starting 
gepotidacin. 
• 
Other uUTI assessments will include the 
 
 (Appendix Section 10.2). 
 
 
A study design schematic is provided in Section 1.2. The SoA is provided in Section 1.3. 
Collection of study information via telemedicine during unexpected circumstances will 
be performed as local regulations permit. 
Participant safety will be monitored by the medical monitor, designated safety lead (or 
delegate), and a GSK SRT throughout the study (Section 8.3.6). 
4.2. 
Scientific rationale for study design 
uUTIs affect the quality of life of patients. Feedback from patients and medical providers 
has demonstrated the need to better assess the burden of UTIs in women and early 
clinical symptom improvement on a daily basis. 
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The Phase 3 gepotidacin studies conducted in uUTI (Section 2.2) were conducted based 
on the need to identify new and effective oral antibiotic treatment options for uUTI, as 
such therapies are becoming limited due to the increase of MDR uropathogens and 
ESBL-producing Enterobacterales uropathogens, which are impacting the efficacy of the 
currently available oral antibacterial treatment options. The studies focused on a primary 
therapeutic response composite endpoint of both clinical resolution and microbiological 
eradication, which were measured at specific time points, in line with regulatory guidance 
[DHHS, 2019]. 
However, the Phase 3 studies did not measure symptom improvement on a daily basis 
after the start of study intervention to characterize the time profile of change in clinical 
symptomatology improvement. The present study will align with the study design and 
treatment aspects of the gepotidacin Phase 3 studies [Perry, 2022]; however, it will focus 
primarily on clinical symptom improvement in participants with a uUTI by assessing the 
CSS on a daily basis after the start of and during gepotidacin treatment. This study data 
will provide additional clinical data for gepotidacin in uUTIs. 
4.3. 
Justification for dose 
The oral gepotidacin dose in this study is 1500 mg BID (total daily dose of 3000 mg) for 
5 days. This dosing regimen is the same as evaluated in a Phase 2 uUTI study and the 
Phase 3 uUTI studies conducted for gepotidacin (Section 2.2) [Perry, 2022]. This dose is 
justified because it supports the PK attainment targets for gepotidacin against uUTI 
uropathogens [Scangarella-Oman, 2022] and resulted in achieving noninferiority 
(Study 204989) and both noninferiority and superiority (Study 212390) results based on 
therapeutic response at the interim analysis when compared with the nitrofurantoin 
current first-line agent for efficacious antibacterial treatment of uUTI in women [Gupta, 
2011; NICE, 2019; EAU, 2019; Hall, 2023]. 
4.4. 
End-of-study definition 
A participant is considered to have completed study intervention if the participant has 
taken all doses of the study intervention (1500 mg BID taken as 2 × 750 mg tablets for a 
total of 10 doses). A participant is considered to have completed the study if the 
participant has completed all study visits including Visit 7 (Follow-up/Day 28). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 

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5.1. 
Inclusion criteria 
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 ICF/IAF and has a body 
weight ≥40 kg. 
Note: Although participants as young as 12 years of age may enroll in the study, 
study sites must follow their IRB guidelines. 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 symptoms of uUTI with onset 
<96 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain 
based on investigator assessment (see Appendix Section 10.1). 
3. The participant has nitrite or pyuria (presence of 3+/large leukocyte esterase) from a 
pretreatment clean-catch midstream urine sample per local laboratory procedures. 
Sex 
4. The participant is female. 
Contraceptive use is to be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
• 
A female participant is eligible to participate if she is a WOCBP who is not pregnant 
as confirmed by a high sensitivity urine pregnancy test predose at baseline regardless 
of current or prior contraception use or abstinence, is not breastfeeding, or is not a 
WOCBP as defined in Appendix Section 10.3.1.2. 
Note: Collection of pregnancy information, contraceptive guidance, and WOCBP 
definitions are provided in Appendix Section 10.3, and requirements for pregnancy 
testing during and after study intervention are located in Appendix Section 10.7. 
• 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed consent 
5. The participant is capable of giving documented informed consent/assent as 
described in Appendix Section 10.9.3, which includes compliance with the 
requirements and restrictions listed in the ICF/IAF and in this protocol. 

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5.2. 
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. 
3. The participant has a history of sensitivity to the study intervention, or components 
thereof, or a history of a drug or other allergy that, in the opinion of the investigator 
or medical monitor, contraindicates study 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 in the judgment of the investigator, 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 are to 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 
• 
Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study intervention 
(e.g., ileostomy or malabsorption syndrome). 
6. The participant, in the judgment of the investigator, would not be able or willing to 
comply with the protocol or complete study follow-up. 

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7. 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 
8. The participant has uUTI 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. 
9. The participant has symptoms known or suspected to be caused by another disease 
process, such as overactive bladder, chronic incontinence, or chronic interstitial 
cystitis, that may interfere with the clinical efficacy assessments or preclude 
complete resolution of uUTI symptoms. 
10. 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). 
11. The participant has an indwelling catheter, nephrostomy, ureter stent, or other 
foreign material in the urinary tract. 
12. The participant, 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. 
13. The participant has known anuria, oliguria, or significant impairment of renal 
function (creatinine clearance <30 mL/min or clinically significant elevated serum 
creatinine as determined by the investigator). 
14. The participant presents with vaginal discharge at Baseline (e.g., suspected sexually 
transmitted disease). 
Cardiac exclusions 
15. The participant has congenital long QT syndrome or known prolongation of the QTc 
interval. 
16. The participant has uncompensated heart failure. 
17. The participant has severe left ventricular hypertrophy. 
18. The participant has a family history of QT prolongation or sudden death. 
19. The participant has a recent history of vasovagal syncope or episodes of 
symptomatic bradycardia or brady arrhythmia within the last 12 months. 
20. The participant is taking QT-prolonging drugs or drugs known to increase the risk of 
TdP per the ww.crediblemeds.org. “Known Risk of TdP” category at the time of her 
Baseline Visit, which cannot be safely discontinued from the Baseline Visit (Day 1) 
through 7 days after the first dose of study intervention; or the participant is taking a 
strong CYP3A4 inhibitor or a strong P-gp inhibitor. 

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Cardiac electrocardiogram exclusions 
21. The participant has a mean triplicate QTc >450 msec or a mean triplicate QTc 
>480 msec for participants with bundle-branch block. 
Note: 
• 
The QTc is the QT interval corrected for heart rate according to QTcB, 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 is to 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. 
22. The participant has a documented or recent history of uncorrected hypokalemia 
within the past 3 months. 
Hepatic exclusions 
23. The participant has a known ALT value >2 × ULN. 
24. 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%). 
25. 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. 
Prior antibiotic/antifungal use exclusion 
26. The participant has received treatment with other systemic antimicrobials or 
systemic antifungals within 1 week before study entry. 
Concomitant medication use exclusion 
27. The participant plans to use any of the prohibited medications or nondrug therapies 
from the Baseline Visit through 7 days after the first dose of study intervention as 
detailed in Section 6.9. 
Prior/concurrent clinical study experience 
28. The participant has been previously enrolled in this study or has previously been 
treated with gepotidacin. 
29. 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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5.3. 
Lifestyle considerations 
• 
Participants will be requested to abstain from sexual activity from the Baseline Visit 
through 7 days after the first dose of study intervention to prevent possible re-
infection. 
5.3.1. 
Meals and dietary restrictions 
Study intervention is to be taken after food consumption (a meal or a snack) and with 
water (see Section 6.1). 
5.4. 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled. 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 publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, any protocol deviations, and any SAEs. 
Participants who are screen failures are allowed to be rescreened once 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. 
5.5. 
Criteria for temporarily delaying 
enrollment/randomization/administration of study 
intervention 
Not Applicable. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention (used interchangeably with study treatment) is defined as an 
investigational product intended to be administered to a participant. 
6.1. 
Study intervention administered 
All doses of study intervention are to be taken after food consumption and with water. 
Participants will receive oral study intervention (gepotidacin [2 × 750 mg tablets]) BID 
(approximately every 12 hours) for 5 days. Doses are to be taken approximately 12 hours 
apart, but the allowable window is 6 to 14 hours. There must be at least a 6-hour 
minimum window between doses. The first oral dose will be administered at the study 
site at Baseline; participants will self-administer subsequent doses as outpatients 
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Each treatment day will be assessed over a 24-hour period, starting with the first dose of 
study intervention received for an individual participant. For example, participants who 
only receive 1 dose of study intervention on their first calendar day in the study due to a 
late afternoon/evening Visit 1 will take the second dose on the following calendar day, 
which will complete Day 1. This pattern will continue until all 10 doses are received; 
thus, the tenth/last dose will be taken prior to Visit 5 (may be 5 or 6 calendar days, 
depending on when the first dose is taken). 
Gepotidacin tablets (750 mg) are not to be broken and must be swallowed whole. The 
dosage schedule must always encourage study intervention to be taken as close to 
12 hours apart as possible. 
Table 3 
Study intervention administered 
Intervention Name 
Gepotidacin 
Intervention Description 
Administer BID (every 12 hours) for 5 days: 
1500 mg as 2 × 750 mg tablets for a 3000 mg total daily dose 
Each dose is to be taken after food consumption and with water 
Type 
Drug 
Dose Formulation 
Tablets containing gepotidacin and inactive formulation excipients 
Unit Dose Strength 
750 mg tablets 
Dosage Level 
1500 mg BID  
Route of Administration 
Oral 
Use 
Investigational 
Sourcing 
Provided centrally by GSK
Packaging and Labeling 
Gepotidacin tablets will be provided in bottles with required labeling 
Manufacturer 
The supply and shipping of the study intervention will be supported by Xpress. 
6.2. 
Preparation, handling, storage, and accountability 
1. The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received and that any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention. 
3. All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
4. The investigator, institution, or head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
5. Further guidance and information for the final disposition of unused study 
intervention are provided in the pharmacy manual. 
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6. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. 
7. A Material Safety Data Sheet or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
6.3. 
Assignment to study intervention 
This is a nonrandomized, open-label study. All eligible participants will receive oral 
gepotidacin 1500 mg BID for 5 days. 
Study intervention will be dispensed at Baseline. 
Returned study intervention is not to be re-dispensed to other participants. 
6.4. 
Blinding 
This is an open-label study. 
6.5. 
Study intervention compliance 
• 
When participants are dosed at the study site during the Baseline Visit, they will take 
their study intervention 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 intervention 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 administration. 
• 
When participants self-administer study intervention as outpatients, compliance with 
gepotidacin will be assessed through querying the participant during the telephone 
On-treatment Visits (Visit 2 [24 hours ±4 hours], Visit 3 [48 hours ±4 hours], Visit 4 
[72 hours ±4 hours], and Visit 5 [96 hours ±4 hours]) and documented in the source 
documents and eCRF. In addition, a record of the number of gepotidacin tablets 
dispensed to and returned by each participant must be maintained and reconciled 
with study intervention and compliance records. Study intervention start and stop 
dates, including dates for intervention delays, will also be recorded in the eCRF. 
6.6. 
Dose modification 
The study design does not allow for modifications. 

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6.7. 
Continued access to study intervention after the end of the 
study 
Participants will not receive any additional treatment from GSK after they discontinue or 
complete the study. Participants experiencing symptoms suggestive of infection 
recurrence or relapse at Visit 7 (Follow-up/Day 28) will be assessed and treated per the 
investigator’s judgment. 
6.8. 
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 is to be instituted, as dictated by the participant’s clinical status. 
In the event of an overdose, the investigator is to: 
• 
Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study intervention will be interrupted. 
• 
Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 72 hours), as 
medically appropriate. 
• 
Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study intervention if requested by the medical monitor (determined on a 
case-by-case basis). 
• 
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
6.9. 
Prior and 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 is to be contacted if there are any questions regarding concomitant 
or prior therapy. 

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6.9.1. 
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 Section 10.4. 
Pain relief use as described in Appendix Section 10.4 is permitted throughout the study. 
In order to avoid potential masking of pain symptoms, these are permitted if unchanged 
from predose baseline (i.e., chronic medication). If needed, they are permitted for UTI 
pain; however, preferably not before Visit 5 (96 hours ±4 hours) to avoid masking. A list 
of permitted medications commonly used for nausea, vomiting, pain, and diarrhea per 
investigator discretion is provided in Appendix Section 10.4. Additionally, low dose 
acetylsalicylic acid (≤100 mg/day) is permitted for the prevention of CV disease events. 
A further detailed list of permitted medications is provided in Appendix Section 10.4. 
6.9.2. 
Prohibited medications and nondrug therapies 
At the time of enrollment and/or during the study from the Baseline Visit through 7 days 
after the first dose of study intervention, 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 7 days after the first dose of study intervention. 
• 
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 through 7 days after the first dose of 
study intervention. Details regarding website access and additional guidance are 
provided in Appendix Section 10.4. Of note, ondansetron is not allowed from the 
Baseline Visit through 7 days after the first dose of study intervention due to its 
known TdP risk. Alternative antiemetics that are permitted per investigator discretion 
are listed in Appendix Section 10.4. 
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. 

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• 
Strong CYP3A4 inhibitors (a list of strong CYP3A4 inhibitors is provided in 
Appendix Section 10.4). 
• 
St John’s wort or other strong CYP3A4 inducers are not permitted from 14 days 
before study entry through 7 days after the first dose of study intervention (a list is 
provided in Appendix Section 10.4). 
• 
Prescription, nonprescription, or supplements that may impact UTI clinical outcomes 
including, but not limited to, Uva ursi, D-mannose, cranberry tablets, 
phenazopyridine, NSAIDs including ibuprofen and cyclooxygenase-2 inhibitors, and 
uricosuric drugs (e.g., probenecid and sulfinpyrazone). As described in Appendix 
Section 10.4, acetylsalicylic acid (doses >100 mg/day) is not permitted. 
In addition, antacid preparations containing magnesium trisilicate are prohibited from the 
start of study intervention at the Baseline Visit throughout the completion of the dosing 
period (i.e., until all 10 doses of study intervention have been received). 
Due to gepotidacin’s property of acetylcholinesterase inhibition, the concomitant use of 
succinylcholine or other nondepolarizing paralytic agents is also prohibited. Caution is to 
be used in participants who have a condition requiring medication that may exacerbate 
the inhibition of acetylcholinesterase, or neuromuscular blocking agents. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Participants may voluntarily discontinue study intervention at any time. The investigator 
may also, at his or her discretion, discontinue the participant from study intervention at 
any time and initiate appropriate alternative therapy. 
The primary reason for premature discontinuation of study intervention will be 
documented in the eCRF based on the list below: 
• 
Adverse event 
• 
Protocol deviation 
• 
Termination of the study by GSK 
• 
Lost to follow-up 
• 
Investigator discretion 
• 
Lack of efficacy 
• 
Pregnancy 
• 
Study site terminated by sponsor 
• 
Withdrawal by participant 
• 
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• 
Other (specify) 
• 
Death 
Participants who discontinue study intervention for the reasons above will not be 
considered withdrawn from the study and should participate in all subsequent study visits 
(see Section 1.3). 
7.1.1. 
Liver chemistry stopping criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention 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 intervention discontinuation is in the 
best interest of the participant. 
Liver safety required actions and follow-up assessments can be found in Appendix 
Section 10.5. 
Figure 2 
Phase 3 liver chemistry stopping and increased monitoring 
algorithm 
 

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Figure 3 
Phase 3 liver chemistry increased monitoring algorithm with 
continued therapy for ALT 3 × ULN but <8 × ULN 
 
7.1.2. 
QTc stopping criteria 
If a clinically significant finding is identified (including, but not limited to, changes from 
Baseline in QT interval corrected using QTcB or QTcF) after enrollment, the investigator 
or qualified designee will determine if the participant can continue the study intervention 
and if any change in participant management is needed. This review of the ECG printed 
at the time of collection must be documented. Any new clinically relevant finding is to be 
reported as an AE. 
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 is to be considered: 
• 
A participant who meets the following bulleted criteria based on triplicate ECG 
readings will be withdrawn from study intervention: 
• 
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 
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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 are to 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 non-protocol-specified 
ECGs are an exception. 
• 
The QTc is to be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5- to 10-minute) recording period. 
7.1.3. 
Gastrointestinal evaluation criteria 
If a participant meets the criteria in Appendix Section 10.6, C. difficile toxin testing will 
be conducted and the specific eCRF page completed. CDAD is considered an AESI, as 
described in Section 8.4.4. 
7.2. 
Participant discontinuation/withdrawal from the study 
See the SoA (Section 1.3) for procedures to be performed at early withdrawal. 
A participant may withdraw from the study at any time at the participant’s own request or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 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, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
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The primary reason for participant discontinuation/withdrawal from the study will be 
documented in the eCRF based on the list below: 
• 
Participant lost to follow-up 
• 
Participant withdrew consent 
• 
Termination of the study by GSK 
• 
Investigator discretion 
• 
Other (specify) 
• 
Death 
Participants who are withdrawn from the study are to contact the study site and have their 
clinical symptoms assessed at the time of withdrawal (see the SoA in Section 1.3), if data 
permit, and return all unused study intervention. 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. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Appendix Section 10.8.5.5). 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
participate in 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 participate in a 
required study visit: 
• 
The study site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether 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, the participant will be considered 
to have withdrawn from the study. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3). 
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns are to be discussed with GSK/PPD immediately upon 
occurrence or awareness to determine if the participant will continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. Participants who have documented informed 
consent but are not eligible to proceed will be recorded in the eCRF with a status of 
“screen failure.” 
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA. 
• 
Prescreening activities may be conducted, including a prescreening informed consent 
and urine testing. The required baseline urine specimen may be collected as part of 
an optional prescreening process, if not already part of standard of care. This 
specimen can be used for the required baseline procedures of the diagnosis of 
presumptive uUTI and pregnancy testing. 
• 
In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution, 
and monitoring may be implemented by the sponsor or the investigator, as per local 
health authority/ethics requirements. 
• 
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 symptoms of uUTI. Participants will be assessed and 
treated per the investigator’s judgment. 
• 
Each visit will be assessed over 24 hours, starting with the first dose of study 
intervention. 
• 
The study will comprise the following 7 planned visits: 
• 
Visit 1 (Baseline/Day 1): Baseline will be performed onsite as Visit 1. Assessments 
will be performed as shown in the SoA (Section 1.3), including the following: 
• 
Participants will provide documented informed consent/assent before any 
clinical study procedures are performed. 

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• 
Demographic data such as year of birth, sex, race, and ethnicity will be recorded 
in the participant’s eCRF. The collection of sex, race, and ethnicity data is 
necessary to assess and monitor the diversity of the trial participants and to 
determine if the trial participants are truly representative of the impacted 
population. 
• 
The participant’s medical, uUTI, and surgical history will be obtained by 
interviewing the participant and/or the participant’s LAR and/or by review of 
the participant’s medical records. Any pre-existing conditions or symptoms 
present prior to the first dose of study intervention will be recorded in the eCRF. 
• 
Participants will provide a pretreatment, clean-catch, midstream urine sample 
for a urine dipstick test to determine eligibility, as defined in Section 5.1, using 
their local laboratory. 
• 
The CSS at Visit 1 will be conducted by VRCC via telephone call interview 
while the participant is onsite prior to the first dose of study intervention as per 
the SoA (Section 1.3) using the CSS and instructions in Section 8.2.1 and 
Appendix Section 10.1.The CSS will be reviewed (but not remeasured) by a 
study physician or otherwise appropriate medically trained staff from the study 
site onsite along with determination of whether other eligibility criteria are met 
before the first dose of study medication (Appendix Section 10.1). Only if 
VRCC cannot do the telephone call, then the study physician or otherwise 
appropriate medically trained staff from the study site will ask the CSS 
questions and complete the 
 
 before the first dose of study intervention, 
therefore only one CSS will be performed at baseline.  The same CSS  scorer 
will be used at all other assessment time points (i.e, Visit 1, 2, 3, 4 and 5) for 
each participant, on all occasions, whenever possible (Appendix Section 10.1). 
The CSS score will be used to programmatically determine the clinical outcome. 
• 
The 
 
 will be completed (Section 8.2.2 and Appendix Section 10.2) 
prior to the first dose of study intervention by an appropriately qualified health 
provider from VRCC. 
• 
Clinical laboratory tests will be conducted, vital signs will be measured, and a 
12-lead ECG and physical examination will be performed. 
• 
Following completion of all pretreatment assessments, participants who meet the 
inclusion and exclusion eligibility criteria will receive oral gepotidacin 1500 mg 
BID for 5 days. The first dose of study intervention will be administered at the 
study site under supervision. After dose administration, Visit 1 posttreatment 
assessments will be performed, as shown in the SoA (Section 1.3). Subsequent 
to administration of the first dose at the study site, participants will self-
administer doses as outpatients, beginning with the second dose. (Note: Each 
dose is to be taken after food consumption and with water.) 
• 
AEs, SAEs, and concomitant medication use will be recorded, and any AEs or 
clinically significant changes will be followed accordingly. 
• 
Visit 2 will be scheduled before the participant leaves the study site at Visit 1 (as 
indicated in Section 1.3). 
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• 
Visit 2 (On-treatment): telephone visit 24±4 h after the first dose 
• 
Participants must have taken a total of 2 doses of gepotidacin before the Visit 2 
assessment of CSS. This will be confirmed during the Visit 2 telephone call. 
• 
Clinical symptoms of uUTI will be recorded first based on a participant 
telephone interview performed by VRCC, who will determine the individual 
uUTI CSS. 
• 
The 
 will be completed by VRCC last. The same scorer will be used at 
all assessment time points for each participant, on all occasions, whenever 
possible. 
• 
Study intervention compliance will be recorded. 
• 
Participants will self-administer gepotidacin as an outpatient every 12 hours. 
Gepotidacin is to be taken after food consumption and with water to assist with 
tolerability. 
• 
AEs, SAEs, and concomitant medication use will be recorded, and any AEs or 
clinically significant changes reported to VRCC during the visit will be 
followed-up with the study site accordingly. 
• 
Remind participants of the at home pregnancy test that will be performed before 
the fifth dose of study intervention. 
• 
Visit 3 will be scheduled. 
• 
Visit 3 (On-treatment): telephone visit 48±4 h after the first dose 
• 
The CSS assessment will be completed first based on a participant telephone 
interview performed by VRCC. 
• 
• 
Study intervention compliance will be recorded. 
• 
Participants will self-administer gepotidacin as an outpatient every 12 hours. 
Gepotidacin is to be taken after food consumption and with water to assist with 
tolerability. 
• 
AEs, SAEs, and concomitant medication use will be recorded, and any AEs or 
clinically significant changes reported to VRCC during the visit will be 
followed-up with the study site accordingly. 
• 
Visit 4 will be scheduled. 
• 
Visit 4 (On-treatment): telephone visit 72±4 h after the first dose 
• 
The CSS assessment will be completed first based on a participant telephone 
interview performed by VRCC. 
• 
• 
Confirm the result of the at home pregnancy test. 
• 
Study intervention compliance will be recorded. 
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• 
Participants will self-administer gepotidacin as outpatient every 12 hours. 
Gepotidacin is to be taken after food consumption and with water to assist with 
tolerability. 
• 
AEs, SAEs, and concomitant medication use will be recorded, and any AEs or 
clinically significant changes reported to VRCC during the visit will be 
followed-up with the study site accordingly. 
• 
Visit 5 will be scheduled. 
• 
Visit 5 (On-treatment): telephone visit 96±4 h after the first dose 
• 
The CSS assessment will be completed first based on a participant telephone 
interview performed by VRCC. 
• 
The 
 
 will be completed by VRCC last. 
• 
Study intervention compliance will be recorded. 
• 
Participants will self-administer gepotidacin as an outpatient every 12 hours. 
Gepotidacin is to be taken after food consumption and with water to assist with 
tolerability. 
• 
AEs, SAEs, and concomitant medication use will be recorded, and any AEs or 
clinically significant changes reported to VRCC during the visit will be 
followed-up with the study site accordingly. 
• 
After the Visit 5 telephone call, participants will place all study intervention 
bottles in an envelope provided by the study site and send it back to the study 
site before Visit 7 (Follow-up/Day 28). 
• 
Visit 6 will be scheduled. 
• 
Visit 6: telephone visit 
 after the first dose 
• 
Visit 7 (Follow-up/Day 28) Visit: telephone visit 28±3 days after the first dose 
• 
The study site will perform this visit. Any AEs, SAEs, and concomitant 
medication use will be recorded. 
• 
Unscheduled Visit: 
• 
An onsite or telephone Unscheduled Visit may be arranged at any point during 
the study if there are safety concerns, lack of response to study intervention, or 
early withdrawal. An alternative antibiotic therapy may be 
prescribed/administered. 
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• 
Clinical symptoms of uUTI will be recorded based on a participant telephone 
interview performed by a study physician or otherwise appropriately medically 
trained staff who will determine the individual uUTI CSS. 
• 
The study site will perform this visit. Any AEs, SAEs, and concomitant 
medication use will be recorded, and any AEs or clinically significant changes 
will be followed accordingly. 
8.1. 
Administrative procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as date of birth, sex, race, and ethnicity in the 
participant’s eCRF. 
Collection of sex, race, and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2. 
Medical history 
Obtain the participant’s medical history by interviewing the participant/participant’s LAR 
and/or by reviewing the participant’s medical records. Record in the eCRF any 
pre-existing conditions and signs and/or symptoms present prior to the first dose of study 
intervention including urological or other data pertaining to symptoms which might 
confound interpretation of urinary symptoms. 
8.2. 
Efficacy assessments 
Planned time points for evaluation of clinical symptoms and the measure of clinical 
efficacy are provided in the SoA. 
8.2.1. 
Clinical symptom score (CSS) and clinical outcomes 
Clinical symptoms of uUTI will be recorded based on a participant interview at the time 
points in the SoA (Section 1.3) using the CSS and instructions in Appendix Section 10.1. 
At Baseline, the participant must present with at least 2 clinical symptoms of uUTI (i.e., a 
total CSS ≥2; Section 5.1). Symptom improvement is defined as a ≥1 point decrease in 
the CSS total score at 24±4 hours. 
During Visit 1, the CSS will be conducted by VRCC via telephone call interview while 
the participant is onsite prior to the first dose of study intervention as per the SoA 
(Section 1.3) using the CSS and instructions in Section 8.2.1 and Appendix Section 10.1. 
The CSS will be reviewed (but not remeasured) by a study physician or otherwise 
appropriate medically trained staff from the study site onsite along with determination of 
whether other eligibility criteria are met before the first dose of study medication 
(Appendix Section 10.1). Only if VRCC cannot do the telephone call, then the study site 
will ask the CSS questions and complete the 
 
 before the first dose of study 
intervention. Only one CSS is to be performed at baseline. The same CSS scorer will be 
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used at all other assessment time points (i.e, visits 2, 3, 4 and 5) for each participant, on 
all occasions, whenever possible. CSS at visit 6 will be performed by a study physician or 
otherwise appropriate medically trained staff from the study site (Appendix Section 
10.1). The CSS score will be used to programmatically determine the clinical outcome. 
Table 4 
Clinical improvement and resolution at 24 ±4 hours (Visit 2) 
Defining Criteria 
Outcome 
Resolution of clinical signs and symptoms of uUTI present at Baseline (i.e., 
reduction of total CSS to 0), without the participant receiving other systemic 
antimicrobials (not for current uUTI) prior to the 24 ±4 hours (Visit 2) assessment 
and without receiving other systemic antimicrobials for the current uUTI prior to or 
24 ±4 hours (Visit 2). 
Clinical 
resolution 
Clinical symptom improvement of at least one point at 24 ±4 hours (Visit 2) from 
Baseline, without the participant receiving other systemic antimicrobials (not for 
the current uUTI) prior to the 24 ±4 hours (Visit 2) assessment and without 
receiving other systemic antimicrobials for the current uUTI prior to or 24 ±4 
hours (Visit 2). 
Clinical 
improvement 
 
Table 5 
Clinical improvement and resolution at 48 ±4 hours (Visit 3), 72 ±4 
hours (Visit 4), 96 ±4 hours (Visit 5), and 
 (Visit 6) 
Defining Criteria 
Outcome 
Resolution of clinical signs and symptoms of uUTI present at Baseline (i.e., 
reduction of total CSS to 0), without the participant receiving other systemic 
antimicrobials (not for the current uUTI) prior to the assessment at each timepoint 
and without receiving other systemic antimicrobials for the current uUTI prior to or 
at each timepoint. 
Clinical 
resolution 
Clinical symptom improvement at least one point from Baseline, without the 
participant receiving other systemic antimicrobials (not for the current uUTI) prior 
to the assessment at each timepoint and without receiving other systemic 
antimicrobials for the current uUTI prior to or at each timepoint. 
Clinical 
improvement 
8.3. 
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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8.3.1. 
Physical examination 
• 
A physical examination will be performed at the Baseline Visit (Section 1.3). 
o 
The examination will include assessments of the respiratory, CV, abdominal, 
gastrointestinal, neurological, and urogenital systems. 
o 
Height and weight will be measured and BMI calculated and recorded prior to 
dosing only at the Baseline Visit. 
• 
Investigators are to pay special attention to clinical signs related to previous serious 
illnesses. 
• 
If an additional physical examination is performed (i.e., Unscheduled Visit), it may 
be symptom directed, and any clinically significant changes from Baseline or 
clinically significant new findings will be reported as AEs. 
8.3.2. 
Vital signs 
• 
Vital signs will be measured at the Baseline Visit (Section 1.3). 
• 
Temperature, systolic and diastolic blood pressure, respiratory rate, and pulse rate 
will be recorded (before blood collection for laboratory tests). 
• 
Vital signs will be measured in a semi-supine position after 5 minutes of rest. 
• 
If an additional vital sign measurements are obtained (i.e., Scheduled/Unscheduled 
Visit), clinically significant changes from Baseline will be reported as AEs. 
8.3.3. 
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 7.1.2 
for QTc stopping 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, study 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. 
• 
If an additional ECGs are performed (i.e., Scheduled/Unscheduled Visit), clinically 
significant parameter changes from Baseline will be reported as AEs. 

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8.3.4. 
Clinical safety laboratory tests 
• 
Safety laboratory assessments will be performed at PPD Global Clinical Laboratory. 
• 
Clinical safety laboratory tests will be performed at the Baseline Visit (Section 1.3). 
See Appendix Section 10.7 for the list of clinical laboratory tests to be performed. If 
additional clinical safety laboratory tests are performed (i.e., Unscheduled Visit), 
they may be symptom-directed. 
• 
The investigator must review the laboratory results, document this review, and 
record any clinically significant changes occurring post-treatment during the study as 
an AE. The laboratory results must be retained with source documents. 
• 
With the exception of the urine dipstick and pregnancy testing, a central laboratory 
will be used. Any baseline results received while participants are on-treatment that 
are exclusionary will be assessed by the medical monitor. The medical monitor will 
contact the investigator and advise on appropriate action with the study intervention. 
• 
Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study are to be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator or 
medical monitor. 
o 
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 
as an AE or SAE, if they meet the definition of an AE or SAE (Section 10.8.1 
and Section 10.8.2, respectively). 
o 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology will be identified and the sponsor 
notified. 
o 
If laboratory values from non-protocol-specified laboratory tests performed at 
the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (e.g., SAE or AE), then 
the results must be recorded. 
• 
All protocol-required laboratory assessments, as defined in Appendix Section 10.7, 
must be conducted in accordance with the laboratory manual. 
8.3.5. 
Pregnancy testing 
• 
Pregnancy testing will be performed at the time points listed in the SoA 
(Section 1.3). 
• 
Female participants of childbearing potential must perform a urine pregnancy test 
before the administration of any dose of study intervention (Appendix Section 10.7). 
Pregnancy testing must be done, even if the participant is menstruating at the time of 
the study visit. The study intervention may only be administered if the pregnancy test 
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• 
An additional pregnancy test using the urine test kit provided by the study site is 
required to be performed for WOCBP who have not used a highly effective 
contraception method (Appendix Section 10.3.2) or have not practiced abstinence 
from penile/vaginal intercourse for at least 14 days prior to the first dose of study 
intervention. The urine pregnancy kit will be provided to the participant to perform 
as an outpatient during the defined window (Appendix Section 10.7). A pregnancy 
test will be performed predose and just before taking the fifth dose. The pregnancy 
test just before taking the fifth dose will be done at home, with the result confirmed 
at Visit 4. For any participant with a positive pregnancy test result, study intervention 
must be immediately discontinued. 
• 
Refer to Appendix Section 10.3.3 for information on study continuation for 
participants who become pregnant during the study. 
8.3.6. 
Safety monitoring 
Participant safety will be monitored by the medical monitor, designated safety lead (or 
delegate), and a GSK SRT throughout the study. Pertinent findings and conclusions are 
shared with the product’s SRT for review of the overall benefit-risk profile of the 
product. For additional details, see Appendix Section 10.9.6. 
8.4. 
Adverse events (AEs), serious adverse events (SAEs), and 
other safety reporting 
For definitions relating to safety information, see Appendix Section 10.8. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or from 
the study (see Section 7). This includes events reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s LAR). 
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 
Section 10.8. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
All SAEs will be collected from the start of study intervention until Visit 7 
(Follow-up/Day 28) at the time points specified in the SoA. However, SAEs assessed as 
related to study participant (e.g., study intervention, protocol-mandated procedures, 
invasive tests, or changes in existing therapy) or related to a GSK procedure (non-IMP) 
will be recorded from the time a participant consents to participant in the study. 
All AEs will be collected from the start of study intervention until Visit 7 
(Follow-up/Day 28) at the time points specified in the SoA. 

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Medical occurrences that begin before the start of study intervention but after obtaining 
documented informed consent will be recorded as medical history/current medical 
conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance will this exceed 24 hours, as indicated in Appendix Section 10.8.5. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
A poststudy AE/SAE is defined as any event that occurs outside the AE/SAE reporting 
period defined in Section 8.4.1. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the investigator 
must record it in the medical records. If the investigator considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2. 
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 occurrences. 
8.4.3. 
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 AESIs (as defined in 
Section 8.4.4) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix Section 10.8.5.5. 
8.4.4. 
AESIs 
Predefined AESIs for this study are CV events, gastrointestinal events, CDAD events, 
and AEs related to AChE-I (see Section 2.3.1), which will be identified by a prespecified 
list of coded terms or determined by algorithm, as described in the SAP. 
For the CDAD testing procedure and algorithm, see Appendix Section 10.6. 
8.4.5. 
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 toward the safety of participants and the 
safety of a study intervention under clinical investigation are met. See Section 8.4.1 
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• 
For SAEs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in Appendix Section 10.8.5.3. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB, if appropriate 
according to local requirements. 
Table 6 
Timeframes for submitting SAE, pregnancy, and other events 
reports to GSK 
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 houra,b 
Electronic AEs Report 
24 houra 
Electronic AEs Report 
Pregnancies 
24 houra 
Electronic  pregnancy 
notification report 
24 houra 
Electronic pregnancy follow-up 
report 
a. 
Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
b. 
If EDC is unavailable, the site must complete and fax in the paper GSK SAE and Pregnancy Manual Report form. 
Paper AEs Report will be dated and signed by the investigator (or designee). For each SAE, the investigator(s) 
must document in the medical notes that they have reviewed the SAE and have provided an assessment of 
causality. 
8.4.6. 
Pregnancy 
Female participants who become pregnant after the first study intervention dose must not 
receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and through the follow-up period. 
If a pregnancy is reported, the investigator will inform GSK/PPD within 24 hours of 
learning of the pregnancy and will follow the procedures outlined in Appendix 
Section 10.3. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.4.7. 
Cardiovascular and death events 
For any CV events detailed in Appendix Section 10.8.3 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 MedDRA 
terms. The CV information will be recorded in the specific CV section of the eCRF 
within 1 week of receipt of a CV event data query prompting its completion. 

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The death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
8.4.8. 
Contact information for reporting SAEs and pregnancies 
SAEs and pregnancies must be reported to PPD PVG within 24 hours of learning of the 
event and to the local IRB/EC per their requirements. All available data must be entered 
and saved in the eCRF in EDC as soon as it is available within 24 hours of awareness, as 
it is the primary mechanism of reporting SAE and pregnancy data to GSK. Reference the 
eCRF Completion Guidelines for additional guidance on completion of the SAE and 
pregnancy eCRF. Updated SAE and pregnancy data must be submitted within 24 hours of 
the data being available. 
If EDC is unavailable, the site must complete and fax in the paper GSK SAE and 
Pregnancy Manual Report form to report the event or any follow-up information within 
24 hours. Please reference the GSK SAE and Pregnancy. Manual Report form and the 
investigator instructions that are included within the document. 
Table 7 
Contact information for reporting SAEs and pregnancies 
PPD SAE/Safety Hotline  
 
Telephone number:  
+1 800 201 8725 
SAE Fax number:  
+1 888 488 9697 
Email address:  
wilsafety@ppd.com 
8.5. 
Pharmacokinetics 
Pharmacokinetics are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamics are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity assessments 
This section is not applicable. 

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8.10. 
Medical resource utilization and health economics 
The 
 
 will be completed at the time points indicated in the SoA (Section 1.3). 
 
 
 
9. 
STATISTICAL CONSIDERATIONS 
Full details of all data handling conventions and statistical analyses conducted for this 
study will be provided in the SAP. 
This section is a summary of the planned statistical analyses of the most important 
endpoints, including primary and key secondary endpoints. 
9.1. 
Statistical hypothesis 
No formal hypothesis testing will be performed for the primary, secondary, and 
exploratory endpoints. 
9.1.1. 
Multiplicity adjustment 
No multiplicity adjustment will be performed for the primary, secondary, and exploratory 
endpoints. 
9.2. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
ITT 
All participants who enrolled in the study (i.e., 
excluding screen failures). 
• 
Study populations 
• 
 
• 
Supplementary estimand of the 
primary objective 
• 
Supplementary estimands of the 
secondary efficacy objectives 
(Clinical Improvement at 48 hours 
[±4 hours], 72 hours [±4 hours], 96 
hours [±4 hours] and Clinical 
Resolution at 24 hours [±4 hours], 
48 hours [±4 hours], 72 hours 
[±4 hours], 96 hours [±4 hours]). 
Primary Clinically 
Evaluable at 
24 hours (±4 hours) 
All participants in the ITT analysis set who 
were able to adhere to the 2 doses of 
treatment as prescribed before 24 hours 
(±4 hours). This is the Primary Analysis 
Population. 
• 
Estimand for secondary efficacy 
objectives (Clinical Resolution at 
24 hours (±4 hours)) 
Clinically Evaluable 
at 48 hours 
(±4 hours) 
All participants in the ITT analysis set who 
were able to adhere to at least 80% of 
planned doses of gepotidacin as prescribed 
up to 48 hours (±4 hours). 
• 
Estimands for secondary efficacy 
objectives (Clinical Improvement 
and Clinical Resolution at 48 hours 
[±4 hours]) 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Clinically Evaluable 
at 72 hours 
(±4 hours) 
All participants in the ITT analysis set who 
were able to adhere to at least 80% of 
planned doses of gepotidacin as prescribed 
up to 72 hours (±4 hours). 
Estimands for secondary efficacy 
objectives (Clinical Improvement and 
Clinical Resolution at 72 hours [±4 hours]) 
Clinically Evaluable 
at 96 hours 
(±4 hours) 
All participants in the ITT analysis set who 
were able to adhere to at least 80% of 
planned doses of gepotidacin as prescribed 
up to 96 hours (±4 hours). 
• 
Estimands for secondary efficacy 
objectives (Clinical Improvement 
and Clinical Resolution at 96 hours 
[±4 hours]) 
• 
 
 
 
Safety 
All enrolled participants who received at least 
1 dose of study intervention. 
• 
Estimand for secondary safety 
objective 
9.3. 
Statistical analyses 
9.3.1. 
General considerations/definitions 
This study aims to estimate the percentage of participants showing an improvement of the 
clinical symptoms with gepotidacin treatment in female participants with uUTI. 
9.3.2. 
Primary analysis 
The primary analysis will estimate the primary estimand using the Primary Clinically 
Evaluable at 24 hours (±4 hours) Set. 
9.3.2.1. 
Definition of main analytical approach 
Participants who are unable to complete the CSS assessment at 24 hours (±4 hours) will 
be considered treatment failures and included in the analysis as no improvers. The 
population-level summary to be estimated is the percentage of participants who achieve 
clinical symptom improvement along with the 95% Exact Binomial CI. 
9.3.2.2. 
Sensitivity analysis 
Participants who are unable to complete the CSS assessment at 24 hours (±4 hours) will 
be imputed using the MI method. Details of the MI method will be described in the SAP. 
9.3.2.3. 
Supplementary estimand analysis 
A supplementary estimand analysis (as described in Section 3) will be considered if
of participants in the ITT Set are unable to comply with the 2 doses of gepotidacin before 
24 hours (±4 hours). The supplementary estimand will be estimated using the ITT Set. 
Participants who are unable to complete the CSS assessment at 24 hours (±4 hours) will 
be considered treatment failures and included in the analysis as no improvers. The 
population-level summary to be estimated is the percentage of participants who achieve 
clinical symptom improvement along with 95% Exact Binomial CIs for the ITT Set. In 
the sensitivity analysis, participants who are unable to complete the CSS assessment at 
24 hours (±4 hours) will be imputed using the MI method. Details of MI method will be 
described in the SAP. 
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9.3.3. 
Secondary endpoints analyses 
Estimands of the secondary efficacy objectives will be estimated using the Clinically 
Evaluable Sets defined corresponding to each time point, i.e., 24 hours (±4 hours), 
48 hours (±4 hours), 72 hours (±4 hours), and 96 hours (±4 hours). The supplementary 
estimands for the secondary efficacy objectives will be estimated using the ITT Set. 
Participants who are unable to complete the CSS assessment at a specific time point will 
be considered treatment failures and included in the summary by time point as no 
improvers. 
The population-level summaries to be estimated are percentage of participants who 
achieve clinical symptom improvement and clinical symptom resolution at each time 
point, along with the 95% Exact Binomial CIs. 
In each sensitivity analysis, participants who are unable to complete the CSS assessment 
at a specific time point will be imputed using the MI method. Details of MI method will 
be described in the SAP.  
Safety analyses: 
All safety analyses will be performed on the Safety analysis set. 
The severity of TEAEs and treatment-emergent SAEs will be determined by the 
investigator according to the US National Institute of Allergy and Infectious Diseases 
DAIDS Table for grading the severity of adult and pediatric AEs (Appendix Section 
10.10). All reported TEAEs will be coded using MedDRA and summarized by system 
organ class and preferred terms. 
The safety endpoint will use a Treatment Policy Strategy for the ICE of study 
intervention discontinuation due to any reason, as safety will be assessed at all 
postbaseline assessments irrespective of whether the participant completed the study 
intervention. 
The number and percentage of TEAEs, study intervention-related AEs, deaths, SAEs, and 
AEs leading to study intervention or study withdrawal will be provided. 
TEAEs will also be summarized by severity. 
The severity of specified TEAEs will be graded according to the DAIDS Table. Data will 
be tabulated and reported by absolute grade for Grades 3 and higher and shift tables, as 
appropriate. 
AEs of special interest will include CV, gastrointestinal, and CDAD. In addition, TEAEs 
associated with AChE-I will also be considered special interest. 
Potential adverse reactions of gepotidacin will be identified using quantitative 
methodology if there is sufficient evidence of a causal association with the investigational 
product (gepotidacin) then qualitative evaluation of the potential adverse reactions will be 
determined. Further details about adverse reactions will be provided in SAP. 

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9.3.4. 
Exploratory endpoints analysis 
9.4. 
Interim analyses 
One or more interim analysis may be conducted to support business need and summarize 
accumulating data for primary, secondary, and exploratory endpoints as deemed 
appropriate. Further details will be described in the SAP. 
9.5. 
Sample size determination 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Clinical symptom score for uUTI 
Clinical symptoms of uUTI will be recorded as follows: 
Clinical Symptoms 
None 
 
Mild 
Symptom is easily 
tolerated, causing 
minimal discomfort 
and not interfering 
with everyday 
activities 
Moderate 
Symptom is 
sufficiently 
discomforting to 
interfere with normal 
everyday activities 
Severe 
Symptom prevents 
normal everyday 
activities 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Dysuriaa 
 
 
 
 
Frequency 
 
 
 
 
Urgency 
 
 
 
 
Lower abdominal or 
suprapubic pain 
 
 
 
 
a. 
Dysuria is defined as pain or burning when passing urine. 
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Please note the following clarification points for obtaining this information from 
participants and score determination during the telephone call interviews: 
• 
Responses to the score criteria will be obtained through direct conversation between 
the participant and a physician or otherwise appropriately medically trained staff  
from VRCC who will then determine the actual score based on the clinical symptoms 
described. 
• 
The CSS at Visit 1 will be conducted by VRCC via telephone call interview while 
the participant is onsite prior to the first dose of study intervention. The CSS will be 
reviewed (but not remeasured) by a study physician or otherwise appropriate 
medically trained staff from the study site onsite along with determination of 
whether other eligibility criteria are met before the first dose of study medication. 
Only if VRCC cannot do the telephone call, then the study site will ask the CSS 
questions and complete the 
 
 before the first dose of study intervention. 
Only one CSS assessment is to be performed at baseline. 
• 
The score criteria will be read out loud verbally to the participant (with verbatim 
translation into the participant’s own language where required). Particularly of note, 
each score will be specifically dependent and determined based on the participant’s 
normal everyday activities, lifestyle, and background information (e.g., daily fluid 
consumption, age, past pregnancy history). 
• 
Please ensure to take and record a detailed medical history, including non-uUTI 
urological symptoms. 
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10.3. 
Appendix 3: Contraceptive and barrier guidance 
10.3.1. 
Definitions 
10.3.1.1. 
Woman of childbearing potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
• 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective 
of the occurrence of menarche or following menarche. 
• 
From the time of menarche until becoming postmenopausal unless permanently 
sterile (see below). 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty, including breast development and 
pubic hair growth. 
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10.3.1.2. 
Woman of nonchildbearing potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenarchal: Tanner stage 1 (prepubertal) 
2. Permanently sterile due to one of the following procedures: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
• 
For permanently sterile individuals due to an alternate medical cause other than the 
above (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion will be applied to determining study entry. If reproductive 
status is questionable, additional evaluations are to be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more than 
one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
10.3.2. 
Contraception guidance 
• 
Refer to Appendix Section 10.7 regarding pregnancy testing for female participants 
at Visit 1 (Baseline) and associated pretreatment contraception and abstinence 
requirements. Female participants who enter the study using contraception must 
continue to do so through 7 days after the last dose of study intervention. 
• 
As described in Section 5.3, participants will be requested to abstain from sexual 
activity from Visit 1 (Baseline) through 7 days after the first dose of study 
intervention to prevent possible re-infection. 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of 
<1% per year when used consistently and correctly 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 

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• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method 
provided that the partner is the sole sexual partner of the WOCBP and the 
absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception will be used. Spermatogenesis cycle is approximately 
90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per 
year when used consistently and correctly 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant. 
a. 
Contraceptive use by men or women is to be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Male condom 
and female condom are not to be used together (due to risk of failure with friction). 
 
10.3.3. 
Collection of pregnancy information 
Female participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
• 
The initial information will be recorded on the appropriate form and submitted to 
GSK/PPD within 24 hours of learning of a participant’s pregnancy. 

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• 
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 AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
• 
Any SAE occurring as a result of a poststudy pregnancy that is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK/PPD as described in Appendix Section 10.8.5.7. 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 
intervention. 
10.4. Appendix 4: 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 top-line 
overview of how to use crediblemeds.org is also provided. 
List of concomitant medications permitted during the study: 
Generic Namea 
Common Therapeutic Use(s) 
Acetylsalicylic acid 
Only allowed for the prevention of cardiovascular disease events at 
a low dose of ≤100 mg/day 
Dolasetron 
Nausea, vomiting 
Granisetron 
Nausea, vomiting 
Metoclopramide 
Nausea, vomiting 
Palonosetron 
Nausea, vomiting 
Promethazine 
Nausea, vomiting 
Acetaminophen or paracetamolb 
Pain, fever 
Tramadolb 
Pain 
Hydrocodone ERb 
Pain, severe 
Oxycodoneb 
Pain, severe 
Loperamide 
Diarrhea 
Cetirizine 
Antihistamine (H1) 
Ebastine 
Antihistamine (H1) 
Fexofenadine 
Antihistamine (H1) 

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Generic Namea 
Common Therapeutic Use(s) 
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 
a. 
Check within each local country to assess if other generic names apply. 
b. 
See Section 6.9.1 for details regarding these medications. 
Note: See also Section 5.2 for other permitted medications. 
List of prohibited concomitant medications: 
Generic Name or Categorya 
Common Therapeutic Use(s) 
Ondansetron 
Nausea, vomiting 
Acetylsalicylic acid (doses >100 mg/day) 
Pain, other 
Celecoxib 
Pain 
Diclofenac 
Pain 
Diflunisal 
Pain 
Etodolac 
Pain 
Ibuprofen 
Pain, fever  
Indomethacin 
Pain 
Ketoprofen 
Pain 
Ketorolac 
Pain 
Nabumetone 
Pain 
Naproxen 
Pain 
Oxaprozin 
Pain 
Phenazopyridine 
Pain (urinary tract) 
Piroxicam 
Pain 
Rofecoxib 
Pain 
Salsalate 
Pain 
Sulindac 
Pain 
Tolmetin 
Pain 
Valdecoxib 
Pain 
Other investigational products 
Various 
Systemic antibiotics (e.g., ciprofloxacin, amoxicillin/clavulanate, cephalexin, 
doxycycline) 
Antibiotic – all systemic 
Systemic antifungals (e.g., itraconazole, fluconazole, terbinafine) 
Antifungal – all systemic 
Prednisolone or equivalent (refer to Section 6.9.2 for details) 
Immunosuppressive therapy 
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 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 6.9.2 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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List of strong CYP3A4 inhibitors: 
The list below is not exhaustive and is subject to regular updates as new knowledge 
emerges and new drugs are approved. 
Strong Inhibitors 
Amprenavir 
Ketoconazole 
Atazanavir 
Nefazodone 
Boceprevir 
Nelfinavir 
Clarithromycin 
Ritonavir 
Cobicistat 
Saquinavir 
Conivaptan 
Telaprevir 
Fosamprenavir 
Telithromycin 
Grapefruit juice 
Troleandomycin 
Indinavir 
Voriconazole 
Itraconazole 
 
 
List of strong CYP3A4 inducers: 
Rifampin 
Ivosidenib 
Mitotane 
Phenytoin 
Avasimibe 
Carbamazepine 
Rifapentine 
Enzalutamide 
Apalutamide 
St John’s wort extract 
Lumacaftor 
Phenobarbital 
 
List of prohibited antiretroviral medications: 
In general, protease inhibitors and non-nucleoside reverse transcriptase inhibitors used 
for treatment of HIV or hepatitis C are prohibited. 
Table of mechanism of antiretroviral-associated drug-drug-interactions: 
ARV by drug class 
P-glycoprotein 
CYP450 
inhibition 
CYP450 
induction 
Comments 
PK enhancers 
 
 
 
 
Cobicistat 
Inhibitor 
3A4 (2D6) 
 
Used as booster 
Ritonavir 
Inhibitor 
3A4 (2D6) 
 
Used as booster 
Protease inhibitors 
 
 
 
 
Atazanavir 
Inhibitor/inducer 
3A4  
 
 
Darunavir 
Inducer 
3A4 
 
 
Fosamprenavir 
Inhibitor 
3A4 
 
 
Indinavir 
 
3A4 
 
 
Lopinavir 
 
3A4 
 
 
Saquinavir 
Inhibitor 
3A4 
 
 
Tipranavir 
Inducer 
(2D6) 
3A4 
 
NNRTIs 
 
 
 
 
Efavirenz 
 
3A4 
3A4 
 
Etravirine 
 
 
3A4 
 
Nevirapine 
 
 
3A4 
 

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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 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 3 search options available. Choose the first option to 
search for 1 drug at a time. Free registration is required by the website. 
 
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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ePIP Flow Process 
 
 

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10.5. 
Appendix 5: Liver safety: suggested actions and follow-up 
assessments 
Phase 3 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
Phase 3 liver chemistry stopping criteria and required follow-up assessments 
Liver Chemistry Stopping Criteria 
ALT absolute 
ALT ≥8 × ULN 
ALT increase 
ALT ≥5 × ULN but <8 × ULN persists for ≥2 weeks 
ALT ≥3 × ULN but <5 × ULN persists for ≥4 weeks 
Bilirubina,b 
ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) 
INRb 
ALT ≥3 × ULN and INR >1.5 
Cannot 
monitor 
ALT ≥5 × ULN but <8 × ULN and cannot be monitored weekly for ≥2 weeks 
ALT ≥3 × ULN but <5 × ULN and cannot be monitored weekly for ≥4 weeks 
Symptomaticc 
ALT ≥3 × 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 intervention 
• 
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 intervention 
• 
If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
intervention and continue participant in the 
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 
• 
Viral hepatitis serologyd 
 
Only in those with underlying 
chronic hepatitis B at study entry 
(identified by positive hepatitis B 
surface antigen) and quantitative 
hepatitis B DNA 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminase values show downward 
trend 
• 
Obtain blood sample for PK analysis, 
within 24 hours after last dosee 
• 
Serum creatine phosphokinase and 
lactate dehydrogenase 
• 
Fractionate bilirubin, if total bilirubin 
2 × 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 

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• 
Monitor participant twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For all other criteria: 
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow-up assessments 
within 24 to 72 hours 
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
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 
a. 
Serum bilirubin fractionation is to be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3 × ULN and bilirubin 2 × 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 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’) must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving 
anticoagulants. 
c. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash, or 
eosinophilia). 
d. 
Includes: hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B core antibody; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); hepatitis E IgM antibody. In those with underlying chronic hepatitis B at study entry 
(identified by positive hepatitis B surface antigen) quantitative hepatitis B DNA and hepatitis delta antibody. If 
hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005]. 
e. 
PK sample will only be collected for an overdose. Record the date/time of the PK blood sample draw and the 
date/time of the last dose of study intervention 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 laboratory manual. 
 

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Phase 3 liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT 5 × ULN and <8 × ULN and 
bilirubin <2 × ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3 × ULN and <5 × ULN and 
bilirubin <2 × 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 intervention. 
• 
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 × ULN and 
<8 × ULN to ≥3 × ULN but <5 × ULN, continue to 
monitor liver chemistries weekly. 
• 
If, after 4 weeks of monitoring, ALT <3 × ULN 
and bilirubin <2 × ULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
 

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10.6. 
Appendix 6: CDAD testing procedure, algorithm, and 
process flow 
 
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 CDAD definition; consideration is to be given to diarrhea occurring in this 
early time frame to be suggestive of a cholinergic effect. 
Any specimens determined to be positive for toxigenic C. difficile: 
1. Participant presents/contacts study site with an AE of diarrhea. 
2. Symptoms are assessed for meeting C. difficile criteria stated above. 

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3. If symptoms meet the C. difficile criteria and the participant presents to the study site 
and a stool sample is collected and sent refrigerated to the local laboratory for C. 
difficile testing. 
4. If the participants present to an emergency room or other (e.g., 24/7 urgent care 
clinic), the local/reference laboratory will store the remaining sample frozen until 
advised to discard by the study site. 
5. Testing is conducted at the local laboratory for C. difficile or a reference laboratory 
according to their standard testing protocol. Upon completion of testing, the 
local/reference laboratory will store the remaining sample frozen until advised to 
discard by the study site. 
6. The C. difficile eCRF page will need to be completed with the local/reference 
laboratory C. difficile results. 
 

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10.7. 
Appendix 7: Clinical laboratory tests 
• 
The tests detailed in Table 9 will be performed by the central laboratory. 
• 
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for a response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same 
time. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Investigators must document their review of each laboratory safety report. 
Pregnancy testing 
• 
Refer to Section 5.1 for screening pregnancy criteria. 
• 
WOCBP will only be included after a confirmed menstrual period and a negative 
urine pregnancy test. 
• 
Pregnancy testing will be performed at Visit 1 (Baseline) before study intervention 
administration. The urine pregnancy test at Baseline will determine study 
contraception and abstinence requirements as follows: 
• 
Pregnancy testing at Visit 1 (Baseline) will 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. WOCBP are not required to be using 
contraception or to have practiced abstinence within 14 days prior to study entry 
if the high sensitivity urine pregnancy test results are negative at Visit 1 
(Baseline). 
• 
Note: ONLY if the study-specific pregnancy kit provided to the study site is 
unavailable, a standard urine pregnancy test with a sensitivity of 25 mIU/mL 
may be used as an exception. A participant with a negative urine pregnancy test 
result from the standard test may be included in the study only if the participant 
has used a highly effective contraception method as described in Section 10.3.2 
or has practiced abstinence from penile/vaginal intercourse for at least 14 days 
before receiving study intervention. 
• 
Before Dose 5, an additional pregnancy test using the urine test kit provided to the 
study site (FIRST RESPONSE Early Result Pregnancy Test with a sensitivity of 
≤6.3 mIU/mL) is required to be performed for WOCBP who have not used a highly 
effective contraception method (in Section 10.3.2) or have not practiced abstinence 
from penile/vaginal intercourse for at least 14 days prior to the first dose of study 
intervention. 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 intervention must be immediately discontinued. 

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• 
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 participant’s participation in the study. 
Table 9 
Protocol-required clinical safety laboratory tests 
Laboratory Tests 
Parameters 
Hematology 
• 
Platelet count 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC indices: 
o 
MCV 
o 
MCH 
• 
WBC Count With Differential: 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Eosinophils 
o 
Basophils 
Clinical chemistrya 
• 
Blood urea nitrogen/Urea 
• 
Potassium 
• 
Creatinine 
• 
Sodium 
• 
Calcium 
• 
Glucose (nonfasting) 
• 
Chloride 
• 
AST/SGOT 
• 
ALT/SGPT 
• 
Alkaline phosphatase 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total protein 
• 
Magnesium 
• 
Phosphorus 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, nitrite, leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
o 
Epithelial cells 
o 
RBC 
o 
WBC 
o 
Casts 
o 
Crystals 
Pregnancy testing 
• 
Highly sensitive urine hCG pregnancy test (as needed for WOCBP)b 
Other screening tests • 
Follicle-stimulating hormone and estradiol (as needed in WONCBP only) 
• 
Serum or urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines) 
NOTES: 
a. 
Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1 and 
Appendix Section 10.4. All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (> 35% direct bilirubin) or ALT 
≥3 × ULN and INR > 1.5 (if INR measured), which may indicate severe liver injury (possible Hy’s law), must be 
reported to sponsor in 24 hours (excluding studies of hepatic impairment or cirrhosis). 
b. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB. 

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10.8. 
Appendix 8: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.8.1. 
Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
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 intervention. 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, 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 condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses will be reported regardless of 
sequelae. 
• 
Events that occur as a result of protocol-mandated procedures (i.e., invasive 
procedures, modification of participant’s previous therapeutic regimen). 
• 
“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 an 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 that 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, admission for routine examination.). 
• 
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. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before documentation of the informed consent) that did not worsen from 
baseline. 
10.8.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 
one or more of the criteria listed: 
• 
Results in death. 
• 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (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 AEs. 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 is to be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity. 

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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) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
• 
Other situations: 
Possible Hy’s Law case: ALT ≥ 3 × ULN AND total bilirubin ≥ 2 × ULN (>35% direct 
bilirubin) or INR >1.5 must be reported as an SAE 
Medical or scientific judgment will be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events will usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.8.3. 
Definition of CV events and cases of CDAD 
CV definition: 
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following CV AEs and SAEs: 
• 
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 
Investigators will be required to fill out a specific CDAD eCRF for CDAD events. 

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10.8.4. 
Definition of TEAE 
TEAE definition: 
A TEAE is an event that emerges during treatment, having been absent pre-treatment, 
or worsens relative to the pre-treatment state. 
10.8.5. 
Recording, assessment, and follow-up of AEs and SAEs 
10.8.5.1. 
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 reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to 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. 
10.8.5.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate: 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
Additional information can be found in Appendix Section 10.10. 

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10.8.5.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• 
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. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes. 
• 
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 their 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. 
10.8.5.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious AEs recorded 
during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only) 
10.8.5.5. 
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. 

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• 
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 submitted documents. 
• 
The investigator will submit any updated SAE data to GSK/PPD within 24 hours of 
receipt of the information. 
• 
After the initial AE, SAE, or any other event of interest, the investigator is required 
to proactively follow each participant at subsequent visits/contacts. All SAEs and 
nonserious AESIs (as defined in Section 8.4.4) will be followed until the event is 
resolved, stabilized, or otherwise explained or until the participant is lost to 
follow-up. 
• 
Other nonserious AEs or AESIs must be followed until or until the participant is lost 
to follow-up. 
Follow-up during the study 
AEs and AESIs documented at a previous visit/contact and defined as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
Follow-up (Day 28) Visit. 
If a participant dies during their participation in the study or during a recognized 
follow-up period, GSK will be provided with any available postmortem findings, 
including histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the electronic pregnancy report and the 
AE report if applicable. Generally, the follow-up period does not need to be longer than 6 
to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it will always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in Section 8.4.6. 
10.8.5.6. 
Updating of SAEs, AESIs, and pregnancy information after removal of 
write access to the participant’s eCRF 
When additional SAE, AESI, or pregnancy information is received after write access to 
the participant’s eCRF is removed, new or updated information is to be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report is to be sent to the study contact for reporting SAEs or pregnancies (refer 
to Section 8.4.3). 

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10.8.5.7. 
Reporting of SAEs, AESIs, and pregnancies 
SAE, AESI and pregnancies Reporting to GSK/PPD via an Electronic Data 
Collection Tool 
• 
The primary mechanism for reporting an SAE, AESI and pregnancies to GSK/PPD 
will be the electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE, AESI 
and pregnancies data collection tool (see next section) to report the event within 24 
hours. 
• 
The site will enter the SAE, AESI and pregnancy data into the electronic system as 
soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE, AESI and pregnancy from a study 
participant or receives updated data on a previously reported SAE, AESI or 
pregnancy after the electronic data collection tool has been taken offline, then the 
site can report this information on a paper SAE, AESI or pregnancy forms (see next 
section) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any SAEs, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP, they will report 
these events to GSK or to the concerned competent authority via the national 
spontaneous reporting system. These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE, AESI and pregnancy reporting can be found in Section 8.4.8. 
SAE Reporting to GSK/PPD via Paper Data Collection Tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the GSK/PPD medical monitor. 
• 
In rare circumstances and in the absence of email/facsimile equipment, notification 
by telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.8. 

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10.9. 
Appendix 9: Regulatory, ethical, and study oversight 
considerations 
10.9.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS international ethical guidelines 
o 
Applicable ICH GCP guidelines 
o 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF/IAF/assent form (if applicable), IB, and 
other relevant documents (e.g., advertisements) must be submitted to an IRB by the 
investigator and reviewed and approved by the IRB before the study is initiated.* 
• 
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
Protocols and amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• 
The investigator will be responsible for the following, as applicable: 
o 
Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB* 
o 
Notifying the IRB of SAEs or other significant safety findings as required by 
IRB procedures* 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
*Note: In countries where the responsibility to perform these submissions and 
notifications resides with the sponsor rather than the investigator, GSK or their designee 
PPD (as described in the applicable powers of attorney) will take these responsibilities. 
10.9.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 

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10.9.3. 
Informed consent/assent process 
• 
The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants/participants’ LAR and 
answer all questions regarding the study. 
• 
Potential participants/participants’ LAR must be informed that their participation is 
voluntary. They or their LAR will be required to provide documentation of a 
statement of informed consent/assent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, privacy and data protection 
requirements, where applicable, and the IRB or study center. 
• 
The medical record must include a statement that physical/digital informed consent 
was obtained before the participant was enrolled in the study and the date the 
informed consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF/IAF during 
their participation in the study. 
• 
A copy of the informed consent must be provided to the participant and/or the 
participant’s LAR. 
• 
The investigator must obtain documented assent from the minor participant in 
addition to the consent provided by the participants’ LAR when a minor can assent 
to participate in a study. The investigator is also accountable for determining a 
minor's capacity to assent to participation in a research study according to the local 
laws and regulations. 
• 
In accordance with local laws and regulations, participants who become legally 
emancipated during the study, i.e., reach the legal age of consent, must be 
reconsented. The participant must provide consent by signing an ICF, which 
summarizes the study, includes a consent statement and provides documentation that 
the participant agrees to continue participating in the study. 
• 
As applicable, the IRB will be consulted before assent form development for 
guidance around age-appropriate groupings and any specific IRB requirements or 
local laws for conducting and documenting assent. 
Participants who are rescreened are required to sign a new ICF. 
In case of unexpected pregnancy, participants must be informed that personal identifiers 
such as the date of birth and sex of the baby will be collected as part of safety follow-up. 
Consent for the baby may be obtained from the participant and/or their partner as per 
local regulations. 
10.9.4. 
Study conduct materials and support 
Scout Clinical will provide patient reimbursement. 

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10.9.5. 
Data protection 
• 
Participants will be assigned a unique identifier. 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. 
• 
GSK will ensure protection of the personal data of the investigator and site staff that 
is collected within the framework of and for the purpose of the study. 
• 
The participant/participants’ LAR must be informed that their/the child’s 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/participants’/LAR, that their/their child’s data will be used as described in 
the informed consent. 
• 
The participant/participants’ LAR must be informed that their/the child’s medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB members, and by inspectors 
from regulatory authorities. 
10.9.6. 
Committees structure 
• 
A SRT is in place for each GSK product. It comprises a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT 
contribute to the continual assessment of incoming new efficacy and safety 
information. 
10.9.7. 
Dissemination of clinical study data 
• 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocol summaries 
prior to study start and target results summaries submission within 12 months of the 
primary/study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines. 
• 
Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• 
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities. 

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• 
GSK will provide the investigator with the participant-level line listings for their site 
only after completion of the full statistical analysis. 
• 
GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by study participants are used to maximum effect in the creation of 
knowledge and understanding. 
10.9.8. 
Data quality assurance 
• 
All participant data relating to the study will be recorded on 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 
signing the eCRF. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• 
The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source documents. 
• 
QTLs will be predefined in the study to identify systematic issues that can impact 
participant right, safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• 
Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
involvement of central reading mechanism) methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or onsite monitoring) are provided in the monitoring 
plan. 
• 
The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different 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. 
• 
When copies of source documents are shared externally for review by a central 
reader mechanism (e.g., endpoint adjudication committee, expert reader), documents 
are stored by the external body for 25 years. 
• 
The Electronic Data Capture system will be provided by Medidata Rave. 

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10.9.9. 
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 eCRF 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 and its origin can be found in the 
monitoring guidelines. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The sponsor or designee will perform monitoring to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Copies of documents are shared with external third parties contracted by GSK for 
review by a central reader mechanism (e.g., endpoint adjudication committee, expert 
reader). The non-exhaustive list of documents shared to inform the central reader 
may include discharge summaries, imaging reports, ECG reports, etc. Participant 
names or any information which would make the participant identifiable or is not 
essential for the central reader mechanism will be redacted by the investigator sites 
prior to transfer. Details of the list of documents and the redaction procedure are 
provided in the site manual or equivalent. These documents will be used by the third 
party solely for the purpose indicated within this protocol. 
10.9.10. 
Study and site start and closure 
Start of study and first act of recruitment 
The start of study and the first act of recruitment are defined as FPFV (first ICF/IAF 
signature date) at a country-level. 
Study/site termination 
GSK or 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. 

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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: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or temporary 
suspension, as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participant and is to assure appropriate participant therapy and/or 
follow-up. 
10.9.11. 
Publication policy 
The results of this study may be published in peer-reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
10.10. 
Appendix 10: Division of AIDS table for grading the severity 
of adult and pediatric AEs, version 2.1, July 2017 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events [DHHS, 2017] is a descriptive terminology which can be utilized for AE 
reporting. A grading (severity) scale is provided for each AE term. 
The DAIDS Table is available at this link: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as Grade 5. 

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Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
Threatening 
Clinical AE 
NOT identified 
elsewhere in the 
grading table  
Mild symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability to 
perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
10.11. 
 Appendix 11: COVID-19 protocol information specifically for 
data management and monitoring 
• 
If onsite 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 email 
approval can be accepted by replying to the relevant email that is sent by GSK/PPD. 

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11. 
REFERENCES 
Abadi ATB, Rizvanov AA, Haertlé T, et al. World Health Organization Report: current 
crisis of antibiotic resistance. BioNanoScience. 2019;9:778-88. 
Bax BD, Chan PF, Eggleston DS, et al. Type IIA topisomerase inhibition by a new class 
of antibacterial agents. Nature. 2010;466(7309):935-40. 
Biedenbach DJ, Bouchillon SK, Hackel M, et al. In vitro activity of gepotidacin, a novel 
triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of 
bacterial pathogens. Antimicrob Agents Chemother. 2016;60(3):1918-23. 
Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the 
United States; 2019. Updated 23 November 2021. Accessed 24 January 2023. 
https://stacks.cdc.gov/view/cdc/82532 
Department of Health and Human Services (DHHS), National Institutes of Health, 
National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1. July 2017. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
European Association of Urology (EAU). EAU guidelines. Edn. presented at the EAU 
Annual Congress Barcelona 2019. Accessed 26 Jul 2019. 
https://uroweb.org/guideline/urological-infections/ 
European Centre for Disease Prevention and Control (ECDC). Antimicrobial Resistance 
Surveillance (AMR) in Europe 2022. Annual Report of the European Antimicrobial 
Resistance Surveillance Network (EARS-Net). Copenhagen: WHO Regional Office for 
Europe; 2022. 
Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N 
Engl J Med. 2003;349(3):259-66. 
Flores-Mireles AL, Walker JN, Caparon M, et al. Urinary tract infections: epidemiology, 
mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-84. 
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. The epidemiology of urinary tract infection. Nat Rev Urol. 
2010;7(12):653-60. 
Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk 
factors, and disease burden. Infect Dis Clin North Am. 2014;28(1):1-13. 
Gibson EG, Bax B, Chan PF, et al. Mechanistic and structural basis for the actions of 
antibacterial gepotidacin against staphylococcus aureus gyrase. ACS Infect Dis. 
2019;5(4):570-81. 

CONFIDENTIAL 
219575 
Protocol Amendment 1 Final 
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101 
Grigoryan L, Mulgirigama A, Powell M, et al. The emotional impact of urinary tract 
infections in women: a qualitative analysis. BMC Womens Health. 2022;22:182. 
GSK. EAGLE-2 and EAGLE-3 phase III trials for gepotidacin stopped early for efficacy 
following pre-planned interim analysis by Independent Data Monitoring Committee. 
GlaxoSmithKline. Updated 2022. Accessed 21 February 2023. https://www.gsk.com/en-
gb/media/press-releases/gsk-announces-phase-iii-trials-for-gepotidacin/ 
GSK Study Report NCT04020341. Study 204989. 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). 2023. 
GSK Study Report NCT04187144. Study 212390. 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). 2023. 
Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the 
treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by 
the Infectious Diseases Society of America and the European Society for Microbiology 
and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-20. 
Hall L. Efficacy and safety of oral gepotidacin in the treatment of uUTI, poster 00326. 
2023. Abstract presented at the 33rd ECCMID, Copenhagen, Denmark. 
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(8):1779-84. 
Klimberg I, Shockey G, Ellison H, et al. Time to symptom relief for uncomplicated 
urinary tract infection treated with extended-release ciprofloxacin: a prospective, open-
label, uncontrolled primary care study. Curr Med Res Opin. 2005;(8):1241-50. 
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(5):2363-9. 
Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary 
tract infections. Ther Adv Urol. 2019;11:3-7. 
Mushtaq S, Vickers A, Sadouki Z, et al. In vitro activities of gepotidacin, a novel 
triazaacenaphthylene and topoisomerase IV DNA gyrase inhibitor, against 
Gram-negative bacteria and Staphylococcus saprophyticus, poster P1849. 2019. Abstract 
presented at the 29th ECCMID, Amsterdam, The Netherlands. 

CONFIDENTIAL 
219575 
Protocol Amendment 1 Final 
10 Sep 2024 
102 
National Institute for Health Care Excellence (NICE). Public Health England. Summary 
of antimicrobial prescribing guidance – managing common infections. February 2019. 
Accessed 19 June 2019. https://www.nice.org.uk/Media/Default/About/what-we-
do/NICE-guidance/antimicrobial%20guidance/summary-antimicrobial-prescribing-
guidance.pdf?UNLID=3157626232019111861 
Overcash JS, Tiffany CA, Scangarella-Oman NE, et al. Phase 2a pharmacokinetic, safety, 
and exploratory efficacy evaluation of oral gepotidacin (GSK2140944) in female 
participants with uncomplicated urinary tract infection (acute uncomplicated cystitis). 
Antimicrob Agents Chemother. 2020;64(7):e00199-20. 
Oviatt A, Huang J, Mattern K, et al. Biochemical and genetic evidence that gepotidacin 
demonstrates well-balanced dual targeting against DNA gyrase and topoisomerase IV in 
Escherichia coli, poster L0178. 2022. Abstract presented at the 32nd ECCMID, Lisbon, 
Portugal. 
Perry C, Hossain M, Powell M, et al. Design of two phase III, randomized, multicenter 
studies comparing gepotidacin with nitrofurantoin for the treatment of uncomplicated 
urinary tract infection in female participants. Infect Dis Ther. 2022;11(6):2297-310. 
Sanchez GV, Babiker A, Master RN, et al. Antibiotic resistance among urinary isolates 
from female outpatients in the United States in 2003 and 2012. Antimicrob Agents 
Chemother. 2016;60(5):2680-3. 
Scangarella-Oman NE, Hossain M, Hoover JL, et al. Dose selection for phase III clinical 
evaluation of gepotidacin (GSK2140944) in the treatment of uncomplicated urinary tract 
infections. Antimicrob Agents Chemother. 2022;66(3):e01492-21. 
Schmiemann G, Kniehl E, Gebhardt K, et al. The diagnosis of urinary tract infection: a 
systematic review. Dtsch Arztebl Int. 2010;107(21):361-7. 
Spellberg B, Doi Y. The rise of fluoroquinolone-resistant Escherichia coli in the 
community: scarier than we thought. J Infect Dis. 2015;212(12):1853-5. 
Suskind AM, Saigal CS, Hanley JM, et al. Incidence and management of uncomplicated 
recurrent urinary tract infections in a national sample of women in the United States. 
Urology. 2016;90:50-5. 
US Department of Health and Human Services (DHHS) Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Guidance for industry. 
Uncomplicated urinary tract infections: developing drugs for treatment. Updated August 
2019. Accessed 24 January 2023. https://www.fda.gov/media/129531/download. 
 
 
 
 
CCI

Signature Page for  219575 TMF-19896551 v1.0
Signature Page for TMF-19896551 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 10-Sep-2024 07:14:51 GMT+0000
PPD