Conditions: Urinary Tract Infections
Keywords: Acute cystitis Efficacy Gepotidacin Nitrofurantoin Urinary Tract Infection Japanese Female
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 380
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the consistency of therapeutic response of gepotidacin in female participants with acute uncomplicated cystitis with qualifying bacterial uropathogen(s) at baseline that all are susceptible to nitrofurantoin in Japan, with that from global studies (Studies 204989 \[NCT04020341\] and 212390 \[NCT04187144\]).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Gepotidacin intervention 2: Nitrofurantoin intervention 3: Placebo
Intervention descriptions: intervention 1: Gepotidacin will be administered. intervention 2: Nitrofurantoin will be administered. intervention 3: Placebo will be administered.

Protocol document:
Prot_000.pdf: 
TMF-15095845 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
214144
 
 
 
1 
Clinical Study Protocol template V16 dated 24-Jun-2021 
TITLE PAGE 
Protocol Title: A Phase III, Multicenter, Randomized, Active Reference, Double-
blind, Double-dummy Study in Japanese Female Participants to Evaluate the 
Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary 
Tract Infection (Acute Cystitis) 
 
Protocol Number: 214144/ amendment 02 
Compound 
Number: 
GSK2140944 
 
Brief Title: A study to investigate the efficacy and safety with gepotidacin in 
Japanese female participants with uncomplicated urinary tract infection (acute 
cystitis); Efficacy of Antibacterial Gepotidacin Evaluated in Japan (EAGLE-J) 
Study Phase: Phase III 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline K.K. (GSK) 
1-8-1, Akasaka, Minato-ku, Tokyo, 107-0052, Japan 
Study Director: Yasutoshi Okawa, Director, Clinical Development (Specialty) 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Sponsor Signatory 
Noritoshi Yoshii 
Head, Specialty Medical and Development 
Regulatory Agency Identifying Number(s): Not applicable 
Approval Date: 07-Nov-2022 
 
©2022 GSK group of companies or its licensor. All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


TMF-15095845 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
214144
 
 
 
2 
Clinical Study Protocol template V16 dated 24-Jun-2021 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 02 
07-NOV-2022 
TMF-15095845 
Amendment 01 
12-OCT-2022 
TMF-15039137 
Original Protocol (00) 
22-AUG-2022 
TMF-14785506 
 
Amendment 02 07-NOV-2022 
Overall Rationale for the Amendment: This amendment modified the requirement of 
high sensitivity urine pregnancy test kit provided to study sites based on the new 
nonclinical finding since the start of the Phase 3 program as the 12.5 mIU/mL urine 
pregnancy tests are more globally available than urine pregnancy tests with a sensitivity 
down to 6.3 mIU/mL. The name of ethical guidelines is modified. The description about 
a microbiology monitoring plan is deleted in Section 10.1.5. 
Section # and 
Name 
Description of Change 
Brief Rationale 
8.2.5. 
Pregnancy 
Testing 
Modified the requirement of high 
sensitivity urine pregnancy test kit 
provided to study sites from ≤6.3 
mIU/mL to ≤12.5 mIU/mL. 
To update the requirement of urine 
pregnancy test kit based on the new 
nonclinical finding since the start of the 
Phase 3 program as the 12.5 mIU/mL 
urine pregnancy tests are more globally 
available than urine pregnancy tests with 
a sensitivity down to 6.3 mIU/mL. 
8.6 Genetics 
Modified the name of ethical 
guidelines 
To apply the latest version of protocol 
template. 
10.1.5. 
Committees 
Structure 
Removed the description about a 
microbiology sample monitoring 
plan. 
The microbiology sample monitoring plan 
is not prepared for this study. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
3 
Clinical Study Protocol template V16 dated 24-Jun-2021 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 2 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1. 
Synopsis ....................................................................................................... 7 
1.2. 
Schema ...................................................................................................... 12 
1.3. 
Schedule of Activities (SoA) ........................................................................ 13 
2. 
INTRODUCTION .................................................................................................... 17 
2.1. 
Study Rationale .......................................................................................... 17 
2.2. 
Background ................................................................................................ 18 
2.2.1. 
Urinary Tract Infection.................................................................. 18 
2.2.2. 
Multidrug resistance in UTI .......................................................... 18 
2.2.3. 
Gepotidacin in acute uncomplicated cystitis treatment ................. 20 
2.3. 
Benefit/Risk Assessment ............................................................................ 20 
2.3.1. 
Risk Assessment ......................................................................... 21 
2.3.2. 
Benefit Assessment ..................................................................... 26 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 26 
3. 
OBJECTIVES AND ENDPOINTS AND/OR ESTIMANDS ....................................... 27 
4. 
STUDY DESIGN .................................................................................................... 38 
4.1. 
Overall Design ............................................................................................ 38 
4.1.1. 
Safety Review Team/Microbiology Review Team ........................ 39 
4.2. 
Scientific Rationale for Study Design .......................................................... 39 
4.2.1. 
Participant Input into Design ........................................................ 41 
4.3. 
Justification for Dose .................................................................................. 41 
4.4. 
End of Study Definition ............................................................................... 44 
5. 
STUDY POPULATION ........................................................................................... 44 
5.1. 
Inclusion Criteria ......................................................................................... 44 
5.2. 
Exclusion Criteria ........................................................................................ 45 
5.3. 
Lifestyle Considerations .............................................................................. 48 
5.3.1. 
Meals and Dietary Restrictions .................................................... 48 
5.4. 
Screen Failures........................................................................................... 48 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 49 
6.1. 
Study Intervention(s) Administered ............................................................. 49 
6.2. 
Preparation, Handling, Storage and Accountability ..................................... 51 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 52 
6.4. 
Study Intervention Compliance ................................................................... 53 
6.5. 
Dose Modification ....................................................................................... 53 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 53 
6.7. 
Treatment of Overdose ............................................................................... 54 
6.8. 
Concomitant Therapy.................................................................................. 54 
6.8.1. 
Permitted Medications and Nondrug Therapies ........................... 55 
6.8.2. 
Prohibited Medications and Nondrug Therapies........................... 55 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
4 
Clinical Study Protocol template V16 dated 24-Jun-2021 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 56 
7.1. 
Discontinuation of Study Intervention .......................................................... 56 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 57 
7.1.2. 
QTc Stopping Criteria .................................................................. 58 
7.1.3. 
Renal Stopping and Monitoring Criteria ....................................... 59 
7.1.4. 
Rechallenge ................................................................................. 60 
7.1.4.1. 
Study Intervention Restart or Rechallenge after 
liver stopping criteria met ............................................ 60 
7.1.5. 
Gastrointestinal Evaluation Criteria .............................................. 60 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 60 
7.3. 
Lost to Follow Up ........................................................................................ 61 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 61 
8.1. 
Efficacy Assessments ................................................................................. 64 
8.1.1. 
Therapeutic Response Evaluation ............................................... 64 
8.1.2. 
Bacteriology Samples .................................................................. 65 
8.1.2.1. 
Microbiological Outcome and Response ..................... 65 
8.1.3. 
Clinical Evaluation ....................................................................... 70 
8.1.3.1. 
Clinical Signs and Symptom Scores, Clinical 
Outcomes, and Clinical Response .............................. 70 
8.1.3.2. 
Investigator Assessment of Clinical Response ........... 74 
8.2. 
Safety Assessments ................................................................................... 74 
8.2.1. 
Physical Examinations ................................................................. 74 
8.2.2. 
Vital Signs .................................................................................... 74 
8.2.3. 
Electrocardiograms ...................................................................... 74 
8.2.4. 
Clinical Safety Laboratory Tests .................................................. 75 
8.2.5. 
Pregnancy Testing ....................................................................... 75 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 76 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 77 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 77 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 77 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 78 
8.3.5. 
Pregnancy ................................................................................... 78 
8.3.6. 
Cardiovascular and Death Events ................................................ 79 
8.3.7. 
Adverse Events of Special Interest .............................................. 79 
8.4. 
Pharmacokinetics ....................................................................................... 79 
8.5. 
Pharmacodynamics .................................................................................... 80 
8.6. 
Genetics ..................................................................................................... 80 
8.7. 
Biomarkers ................................................................................................. 80 
8.8. 
Immunogenicity Assessments ..................................................................... 80 
8.9. 
Medical Resource Utilization and Health Economics .................................. 80 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 81 
9.1. 
Statistical Hypotheses................................................................................. 81 
9.1.1. 
Multiplicity Adjustment ................................................................. 82 
9.2. 
Analysis Sets .............................................................................................. 82 
9.3. 
Statistical Analyses ..................................................................................... 83 
9.3.1. 
Primary Estimand Analysis .......................................................... 83 
9.3.2. 
Secondary Estimand(s) Analysis ................................................. 84 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
5 
Clinical Study Protocol template V16 dated 24-Jun-2021 
9.3.2.1. 
Therapeutic Response ............................................... 84 
9.3.2.2. 
Clinical Outcome and Response................................. 85 
9.3.2.3. 
Microbiological Outcome and Response ..................... 86 
9.3.2.4. 
Investigator Assessment of Clinical Response ........... 86 
9.3.3. 
Exploratory Endpoint(s) Analysis ................................................. 86 
9.3.4. 
Safety Analysis ............................................................................ 87 
9.3.5. 
PK and PK/PD analyses .............................................................. 87 
9.4. 
Interim Analysis .......................................................................................... 88 
9.5. 
Sample Size Determination ........................................................................ 88 
9.5.1. 
Gepotidacin Sample Size ............................................................. 88 
9.5.1.1. 
Sample Size Sensitivity .............................................. 88 
9.5.2. 
Nitrofurantoin Sample Size .......................................................... 89 
9.5.3. 
Proposed Sample Size ................................................................ 89 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 91 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 91 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 91 
10.1.2. 
Financial Disclosure ..................................................................... 92 
10.1.3. 
Informed Consent Process .......................................................... 92 
10.1.4. 
Data Protection ............................................................................ 93 
10.1.5. 
Committees Structure .................................................................. 93 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 93 
10.1.7. 
Data Quality Assurance ............................................................... 94 
10.1.8. 
Source Documents ...................................................................... 95 
10.1.9. 
Study and Site Start and Closure ................................................. 95 
10.1.10. Publication Policy ......................................................................... 96 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 97 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 99 
10.3.1. 
Definition of AE ............................................................................ 99 
10.3.2. 
Definition of SAE ........................................................................ 100 
10.3.3. 
Definition of Cardiovascular Events ........................................... 101 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 101 
10.3.5. 
Reporting of SAE to GSK ........................................................... 103 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 105 
10.4.1. 
Definitions: ................................................................................. 105 
10.4.2. 
Contraception Guidance: ........................................................... 106 
10.5. 
Appendix 5: Genetics ................................................................................ 108 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 109 
10.7. 
Appendix 7: Clostridioides Difficile Testing Procedure and Algorithm ........ 113 
10.8. 
Appendix 8: Algorithm for Determining Qualifying Uropathogens .............. 114 
10.9. 
Appendix 9: COVID-19 Protocol Information ............................................. 115 
10.9.1. 
Overall Rationale for this Appendix ............................................ 115 
10.9.2. 
Study Procedures During the COVID-19 Pandemic ................... 115 
10.10. Appendix 10: Clinical Signs and Symptoms Score for Acute Cystitis ........ 117 
10.11. Appendix 11: Investigator Assessment of Clinical Response 
Definitions ................................................................................................. 119 
10.12. Appendix 12: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment......................................... 120 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
6 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.13. Appendix 13: Abbreviations and Trademarks ............................................ 128 
10.14. Appendix 14: Protocol Amendment History ............................................... 131 
11. REFERENCES ..................................................................................................... 133 
 
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
7 
Clinical Study Protocol template V16 dated 24-Jun-2021 
1. 
PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase III, Multicenter, Randomized, Active Reference, Double-blind, 
Double-dummy Study in Japanese Female Participants to Evaluate the Efficacy and 
Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (Acute 
Cystitis) 
Brief Title: A study to investigate the efficacy and safety with gepotidacin in Japanese 
female participants with uncomplicated urinary tract infection (acute cystitis); Efficacy of 
Antibacterial Gepotidacin Evaluated in Japan (EAGLE-J) 
Rationale: 
Urinary tract infections (UTIs; acute cystitis) are very common, with approximately 11% 
of women (greater than 18 years of age) reporting at least 1 episode of acute 
uncomplicated cystitis per year. Of these, half will experience more than 1 recurrent 
episode over their lifetime [Foxman, 2000]. The peak incidence of acute cystitis occurs in 
young, sexually active women ages 18 to 29 years [Fihn, 2003]. The predominant 
uropathogen isolated in community-acquired UTIs is Escherichia coli (E. coli; 75% to 
90%) followed by Staphylococcus saprophyticus (5% to 15%). Multidrug resistance, 
which is typically associated with nosocomial infections, has emerged at the community 
level and has made treatment approaches for UTIs more difficult. Furthermore, extended 
spectrum β-Lactamase (ESBL)-producing Enterobacteriaceae (now recognized as 
Enterobacterales), which includes E. coli, is recognized as a serious threat. 
In Japan, published epidemiology studies reporting the incidence of UTIs are limited 
[Kusama, 2021; Sako, 2021], but the disease thought to be common infectious disease 
[Takahashi, 2022]. Most patients suffering from acute uncomplicated cystitis are sexually 
active women as shown in outside of Japan [Yamamoto, 2017]. The predominant 
uropathogens isolated from patients with acute uncomplicated cystitis are E coli 
(approximately 70%) followed by Klebsiella pneumoniae, Streptococcus agalactiae, S. 
saprophyticus, Enterococcus faecalis which are observed in only 3% to 5% [Wada, 
2021]. In Japan as well, the resistance rate of ESBL-producing bacteria has been 
increased [Hayami, 2013; Hayami, 2019; Wada, 2021], and similarly increasing global 
rates of MDR bacteria may elevate the likelihood of MDR associated UTI infections 
becoming more common [Arcilla, 2017; Hassing, 2015]. There is an unmet medical need 
for new therapeutic agents that exhibit strong antibacterial activity against such bacteria 
[Kusama, 2021; Nakagawa, 2021]. 
Gepotidacin is a first-in-class, novel triazaacenaphthylene bacterial type II topoisomerase 
inhibitor. The microbiological spectrum of activity of gepotidacin includes E. coli, S. 
saprophyticus, and E. faecalis. This Phase III study aims to assess the consistency of 
therapeutic response (combined per-participant microbiological and clinical response) of 
gepotidacin observed in this study with global studies (Studies 204989 and 212390). 
Objectives and Endpoints and Estimands: 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
8 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Objectives 
Endpoints 
Primary 
 
• 
To assess the consistency of 
therapeutic response of gepotidacin at 
the Test of cure (TOC) Visit (Day 10 to 
13) in female participants with acute 
uncomplicated cystitis with qualifying 
bacterial uropathogen(s) at Baseline 
that all are susceptible to nitrofurantoin 
in Japan, with that from global studies 
(Studies 204989 and 212390). 
• 
Therapeutic response (combined per-
participant microbiological and clinical 
response) at the TOC Visit 
Secondary 
 
• 
To assess the therapeutic response of 
gepotidacin compared to nitrofurantoin 
as an active reference descriptively, at 
the TOC Visit, in female participants 
with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
• 
Therapeutic response at the TOC Visit 
• 
To assess the clinical efficacy and 
microbiological efficacy of gepotidacin 
at the TOC Visit in female participants 
with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at 
Baseline that all are susceptible to 
nitrofurantoin 
• 
Clinical outcome and response at the 
TOC Visit 
• 
Microbiological outcome and response 
at the TOC Visit 
• 
To assess the therapeutic response, 
clinical efficacy and microbiological 
efficacy of gepotidacin at the TOC Visit 
in female participants with acute 
uncomplicated cystitis who have 
qualifying uropathogen(s) resistant to 
two or more specific classes of 
antimicrobials at Baseline 
• 
Therapeutic response at the TOC Visit 
• 
Clinical outcome and response at the 
TOC Visit 
• 
Microbiological outcome and response 
at the TOC Visit 
• 
To assess the clinical efficacy of 
gepotidacin at the TOC Visit in female 
participants with acute uncomplicated 
cystitis 
• 
Investigator assessment of clinical 
response at the TOC Visit 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
9 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
To assess the safety and tolerability of 
gepotidacin in female participants with 
acute uncomplicated cystitis 
• 
Occurrence of treatment-emergent 
adverse events (AEs), serious AEs 
(SAEs) and adverse events of special 
interest (AESIs) 
• 
Change from baseline in clinical 
laboratory tests 
• 
Change from baseline in 
electrocardiograms (ECGs) 
• 
Change from baseline in vital sign 
measurements 
• 
To determine the plasma and urine PK 
concentrations of gepotidacin in female 
participants with acute uncomplicated 
cystitis 
• 
Gepotidacin plasma and urine 
concentrations  
Please refer to Section 8.1.1, 8.1.2.1 and 8.1.3.1 for the definition of therapeutic response, microbiological 
outcome/response and clinical outcome/response 
Please refer to Section 10.8 for details of qualifying bacterial uropathogen(s) 
Note: Exploratory objectives are described in the main protocol text. 
 
Primary estimand 
The primary estimand is described by the following attributes: 
• 
Population: Japanese and non-Japanese (from Studies 204989 and 212390) female 
participants with acute uncomplicated cystitis who have qualifying uropathogen(s) at 
Baseline that all are susceptible to nitrofurantoin. 
• 
Treatment condition: Gepotidacin 1500 mg twice daily (BID) for 5 days in this study 
versus gepotidacin 1500 mg BID for 5 days in the global studies (Studies 204989 and 
212390) regardless of adherence. 
• 
Variable: Therapeutic response (combined per-participant microbiological and 
clinical response) at the TOC Visit. Microbiological success is defined as eradication 
(i.e. reduction) of all qualifying bacterial uropathogens recovered at baseline to <103 
colony-forming units/mL (CFU/mL) as observed on quantitative urine culture 
without the participant receiving other systemic antimicrobials. Clinical success is 
defined as resolution of signs and symptoms of acute cystitis present at Baseline (and 
no new signs and symptoms) without the participant receiving other systemic 
antimicrobials.  
• 
Summary measure: Comparison of the proportion of Japanese participants achieving 
therapeutic success in this study with 10%tile of the predicted distribution for the 
proportion of participants achieving therapeutic success in this study derived from 
the global studies (Studies 204989 and 212390) under the assumption of consistency 
• 
Intercurrent events (ICEs):  
• 
Study treatment discontinuation (due to any reason) – treatment policy strategy 
(interest is in the treatment effect regardless of study treatment discontinuation) 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
10 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• Use of systemic antimicrobials – composite strategy. This ICE is captured through 
the definitions of microbiological and clinical response (see Section 8.1.2.1 and 
8.1.3.1) 
The secondary estimands are provided in the Section 3.  
Overall Design: 
• Study 214144 is a Phase III randomized, multicentre, active reference, double-blind, 
double-dummy study in adolescent and adult Japanese female participants to evaluate 
the efficacy and safety of gepotidacin. The primary objective is to assess consistency 
of this study with global studies (Studies 204989 and 212390) for therapeutic 
response of gepotidacin. 
• The study duration will be approximately 28 days with 4 visits. 
• Participants will be stratified by age category (≤50 years, or >50 years) and acute 
uncomplicated cystitis recurrence (recurrent or nonrecurrent) and will be randomly 
assigned in a 3:1 ratio to receive either oral gepotidacin or oral nitrofurantoin (active 
reference). 
Brief Summary: 
The purpose of this study is to assess consistency of this study with global studies 
(Studies 204989 and 212390) for therapeutic response of gepotidacin at TOC Visit.  
Study details include: 
• Participants will receive treatment for 5 days according to their randomized treatment 
and assessed as follows: 
• Appropriate safety, clinical and microbiological assessments will be 
conducted at the Baseline (Day 1) Visit and repeated at the On-therapy (Day 2 
to 4), TOC (Day 10 to 13), and Follow-up (Day 28 ± 3) Visits. 
 
 
 
 
• For the primary efficacy endpoint of therapeutic response (combined per 
participant microbiological and clinical response), therapeutic success refers 
to participants who have been deemed both a microbiological success 
(reduction of all qualifying bacterial uropathogens [e.g., ≥105 colony-forming 
units/mL (CFU/mL)] recovered at Baseline to <103 CFU/mL as observed on 
quantitative urine culture without the participant receiving other systemic 
antimicrobials) and a clinical success (resolution of signs and symptoms of 
acute cystitis present at Baseline [and no new signs and symptoms] without 
the participant receiving other systemic antimicrobials) at the TOC Visit in the 
Microbiological Intent-to-Treat Nitrofurantoin-Susceptible (micro-ITT NTF-
S) Population defined in Section 8.1.3, regardless of treatment 
discontinuation. 
CCI


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
11 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• PK samples will be collected in all participants for analysis at the Baseline 
(postdose) and the On-therapy Visits (predose and postdose). 
Number of Participants: 
Approximately 300 participants will be enrolled to obtain approximately 108 Japanese 
females (adolescent and adults) ≥12 years meeting the eligibility criteria with qualifying 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin (micro-ITT NTF-S 
Population). Enrolment will continue until the approximate target number of participants 
in the micro-ITT NTF-S Population has been reached. This study will be conducted at 
multiple sites in Japan. 
Note: Enrolled means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any study activity after 
screening.  
Intervention Groups and Duration: 
Participants will be stratified by age category and acute uncomplicated cystitis recurrence 
(recurrent or nonrecurrent). Recurrence is defined as a confirmed infection [not including 
the current infection in the calculation] with at least 1 prior episode within the past 3 
months, at least 2 prior episodes within the past 6 months, or at least 3 prior episodes 
within the past 12 months before study entry). Participants will be randomly assigned in a 
3:1 ratio to receive either oral gepotidacin or oral nitrofurantoin as follows: 
• Gepotidacin: 1500 mg administered orally BID for 5 days 
• Nitrofurantoin: 100 mg administered orally BID for 5 days 
Note: each dose of gepotidacin and nitrofurantoin should be taken after food consumption 
and with water. 
The duration of study participation is approximately 28 days with 4 planned study visits: 
• Baseline (Day 1) Visit 
• On-therapy (Day 2 to 4) Visit 
• TOC (Day 10 to 13) Visit 
• Follow-up (Day 28±3) Visit 
 
Data Monitoring/ Other Committee: A GlaxoSmithKline Safety Review Team will 
monitor blinded safety data, while a Microbiology Review Team will monitor blinded 
microbiological data instream. 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
12 
Clinical Study Protocol template V16 dated 24-Jun-2021 
1.2. Schema 
Figure 1 
Study Design Schematic 
 
BID=twice daily; HPF=high-power field; TOC=Test-of-Cure; WBC=white blood cell. 
a. 
There will be central randomization with stratification by age category (≤50 years, or >50 years) and acute uncomplicated cystitis recurrence 
(nonrecurrent infection or recurrent infection, defined as a confirmed infection [not including the current infection in the calculation] with at least 1 
prior episode within the past 3 months, at least 2 prior episodes within the past 6 months, or at least 3 prior episodes within the past 12 months before 
study entry). 
b. 
Study treatment will be administered under double-blind, double-dummy conditions. Each dose should be taken after food consumption and 
with water. 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
13 
Clinical Study Protocol template V16 dated 24-Jun-2021 
1.3. Schedule of Activities (SoA) 
Visit 
Baseline 
On-
Therapya TOCb Follow-
up 
Early 
Withdraw
al 
Notes 
Study Day 
1 
2 to 4 
10 to 
13 
28±3 
NA 
 
Procedure 
Pre-
dose 
Post-
dose 
Written informed consent/assent 
X 
 
 
 
 
 
 
IRT – Screening module 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
Participant demography 
X 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
IRT – Randomization module 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Schedule next visit 
X 
 
X 
X 
X 
 
• On Day 1, the planned return day/time for the On-therapy, TOC, 
and Follow-up Visits should be scheduled before the participant 
leaves the study site. 
• Pre-visit reminder: Study site staff will contact the participant 
24±4 hours before the scheduled On-therapy, TOC, and Follow-
up Visits. 
Assessments 
Physical examination (including 
height and weight at Baseline only) 
X 
 
 
X 
 
 
At the TOC Visit, the physical examination may be symptom 
directed and is only required if indicated for a specific participant. 
12-lead ECG 
X 
X 
X 
X 
 
 
• See Section 5.2 for ECG exclusion criterion for participants aged 
≥12 to <18 years. For additional details see Section 7.1.2 and 
Section 8.2.3. 
• For postdose on Day 1 and On-Therapy Visit, ECGs will be 
collected at approximately 2 hours postdose (i.e., expected time of 
maximum concentration; ECG collection should ideally be within 
approximately 1.5 hours postdose to 4 hours postdose). 
Electrocardiograms will be reviewed locally by the investigator 
for safety purposes. 
Vital sign measurements 
X 
 
X 
X 
 
 
Take measurement of temperature, blood pressure, and pulse rate. 
Record 
acute 
cystitis 
sign 
and 
symptoms 
X 
 
X 
X 
X 
X 
Individual clinical signs and symptoms scores of acute cystitis will 
be recorded by a study physician or otherwise appropriately 
medically trained staff based on participant interview and using 
the scoring system in 10.10. The same scorer will be used at all 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
14 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Visit 
Baseline 
On-
Therapya TOCb Follow-
up 
Early 
Withdraw
al 
Notes 
Study Day 
1 
2 to 4 
10 to 
13 
28±3 
NA 
 
Procedure 
Pre-
dose 
Post-
dose 
assessment time points for each participant, on all occasions, 
whenever possible. 
Investigator assessment of clinical 
response 
 
 
 
X 
X 
X 
The investigator will provide an assessment of clinical response 
(clinical success, clinical failure, or indeterminate, per the 
definitions in Section 10.11) for each participant at the TOC and 
Follow-up Visits, and at early withdrawal (if applicable). This 
assessment should be completed after the clinical signs and 
symptoms score is determined by the same study physician or 
otherwise appropriately medically trained staff who performed the 
clinical scoring assessment. 
Labs & blood/urine sampling 
Bacteriology samples 
X 
 
X 
X 
X 
X 
• Participants will provide a clean-catch midstream urine sample 
at each visit for Gram stain, quantitative bacteriology culture, 
and in vitro antimicrobial susceptibility testing by a designated 
central laboratory(ies). Refer to the laboratory manual. 
• A predose bacteriology urine sample will be collected at the On-
therapy Visit. 
Hematology, chemistry, and 
urinalysis 
X 
 
X 
X 
 
 
 
Diagnosis of presumptive acute 
uncomplicated cystitis 
X 
 
 
 
 
 
Based on confirmation of nitrite or pyuria (>15 WBC/HPF or the 
presence of 3+/large leukocyte esterase) from a pretreatment clean-
catch midstream urine sample per local laboratory procedures. 
Urine pregnancy test 
X 
 
X 
X 
 
X 
For women of childbearing potential, a negative high sensitivity 
urine pregnancy test is sufficient for eligibility. See Section 8.2.5 
for Baseline urine test sensitivity requirements and 10.4 for 
associated contraception requirements. Pregnancy testing should 
CCI


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
15 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Visit 
Baseline 
On-
Therapya TOCb Follow-
up 
Early 
Withdraw
al 
Notes 
Study Day 
1 
2 to 4 
10 to 
13 
28±3 
NA 
 
Procedure 
Pre-
dose 
Post-
dose 
be performed after Dose 4 and before Dose 8, as specified in 
Section 8.2.5. 
Serology (hepatitis B and C and HIV) 
X 
 
 
 
 
 
If serology testing was performed within 3 months prior to the first 
dose of study treatment and the results were positive, testing at 
Baseline is not required. If testing was performed within 3 months 
and any result was negative, testing at Baseline is required. 
Drug and alcohol screen 
X 
 
 
 
 
 
 
Genetic sample 
X 
 
 
 
 
 
Collect sample only if the participant has a signed consent/assent 
specific for this purpose. The Baseline Visit is the recommended 
time to collect the sample, but it can be collected at any time 
during the study. 
PK blood sample 
 
X 
X 
 
 
 
Sparse PK blood samples will be collected.  
• At the Baseline Visit, the PK blood samples will be collected at 1-
2 hours post-dose as peak concentration. 
• At the On-therapy Visit, the PK blood samples will be collected 
at pre-dose as trough concentration (i.e., 12 hours post-dose, 
which is at the end of the dosing interval from the previous dose) 
and at 1-2 hours-post dose as peak concentration. 
(Further detailed information will be provided in the SRM.) 
PK urine sample 
 
X 
X 
 
 
 
• At the Baseline Visit, samples will be collected from pre-dose to 
approximately 2 hours (1 to 3 hours) post-dose as pooled urine. 
• At the On-therapy Visit, samples will be collected at pre-dose 
(i.e., 12 hours postdose as spot urine, which is at the end of the 
dosing interval from the previous dose) and from pre-dose to 
approximately 2 hours (1 to 3 hours) post-dose as pooled urine. 
(Further detailed information will be provided in the SRM.) 
Study treatment 
Administer 
oral 
dose 
of 
study 
treatment 
 
X 
X 
 
 
 
• Participants will receive oral study treatment BID for 5 days 
under double-blind, double-dummy conditions. The first oral dose 
will be administered at the study site during the Baseline Visit; 
participants will self-administer as outpatients thereafter, 
beginning with the second dose, excluding the day of On-therapy 
Visit (i.e., taking morning dose at study site). Each dose should 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
16 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Visit 
Baseline 
On-
Therapya TOCb Follow-
up 
Early 
Withdraw
al 
Notes 
Study Day 
1 
2 to 4 
10 to 
13 
28±3 
NA 
 
Procedure 
Pre-
dose 
Post-
dose 
be taken after food consumption and with water. The date and 
time of each dose administered at the study site will be recorded 
in the source documents. 
• At the On-therapy Visit, whenever it is possible, the participant 
will have the pregnancy test performed at the study site. If the 
visit coincides with the 8th dose, the participant will take their 
next dose of study treatment at the study site after negative 
pregnancy test results are confirmed. Note: The On-therapy Visit 
should be scheduled to support completion of the postdose ECG 
within the protocol-defined window. Also, in a woman of 
childbearing potential, the high sensitivity pregnancy test must 
be performed and show negative results at the latest before Dose 
8 of study treatment is taken. 
Study treatment compliance 
 
 
X 
X 
 
 
Determine study treatment compliance by performing pill count. 
Safety reviews 
Serious adverse events 
XC 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
Record adverse events from the time of the first dose of study 
treatment. 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
 
BID = twice daily; ECG =electrocardiogram; HIV=human immunodeficiency virus; HPF=high-power field; IRT=interactive response technology; NA=not 
applicable; PK=pharmacokinetic; TOC=Test-of-Cure; UTI=urinary tract infection; WBC=white blood cell. 
a. 
For the On-therapy (Day 2 to 4) Visit: Participants will be instructed to return to the study site within 1 to 3 days postrandomization. Each treatment 
day will be assessed over 24 hours starting with the first dose of study treatment, as further detailed in the Study Reference Manual. 
b. 
For the TOC (Day 10 to 13) Visit: Participants will be instructed to return to the study site 5 to 8 days after completion of study treatment. 
c. 
SAEs must be collected from signing of Informed Consent if considered related to study procedures or GSK concomitant medication. 
 
 
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
17 
Clinical Study Protocol template V16 dated 24-Jun-2021 
2. 
INTRODUCTION 
Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial type II 
topoisomerase inhibitor, is being developed for the treatment of uncomplicated urinary 
tract infections (UTIs; acute cystitis). Gepotidacin has activity versus key pathogens, 
including drug-resistant strains associated with a range of conventional and biothreat 
infections. The microbiological spectrum of activity of gepotidacin includes Escherichia 
coli, the key causative pathogen of acute uncomplicated cystitis, Staphylococcus 
saprophyticus, and Enterococcus faecalis.  
Gepotidacin selectively inhibits bacterial DNA replication by interacting in a unique way 
on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial 
topoisomerase IV. This interaction appears to be highly specific to bacterial 
topoisomerases as evidenced by weak in vitro inhibition of human topoisomerase IIα, 
supporting the selective activity of gepotidacin against the bacterial target. The novel 
mode of action of this new class antibacterial affords in vitro activity against most target 
pathogens resistant to established antibacterials, including fluoroquinolones. 
2.1. Study Rationale 
This study is being conducted based on the need to establish new and effective oral 
antimicrobial treatment options for acute uncomplicated cystitis, as such therapies are 
becoming limited due to the increase of multidrug-resistant (MDR) pathogens and 
extended-spectrum β-lactamase (ESBL) producing Enterobacterales pathogens, which 
are impacting the efficacy of currently available oral antibacterial treatment options (see 
Section 2.2).  
Two Phase II studies were conducted and the results demonstrated that gepotidacin was 
effective in the treatment of uncomplicated urogenital gonorrhea and acute bacterial skin 
and skin structure infections (ABSSSIs) (see investigator’s brochure [IB] for details). In 
addition, a Phase IIa pharmacokinetic (PK) study (206899) was conducted in 22 female 
participants with acute uncomplicated cystitis that also included exploratory clinical and 
microbiological efficacy objectives. All 22 participants were evaluated for PK and 
clinical efficacy analysis. Of the 22 participants, 19 participants (86%) and 18 
participants (82%) achieved symptom resolution at the Test-of-Cure (TOC) and Follow-
up Visits, respectively. Eight of 22 participants (36%) who received at least 1 dose of 
gepotidacin had a qualifying baseline uropathogen (5 with E. coli isolates, 1 with a S. 
saprophyticus isolate, 1 with a Klebsiella pneumoniae isolate, and 1 with a Citrobacter 
koseri isolate). Of these 8 participants, 7 participants (88%) and 6 participants (75%) had 
a microbiological response of microbiological success (<103 colony-forming units/mL 
[CFU/mL]) at the TOC and Follow-up Visits, respectively. Furthermore, of these 8 
participants, 6 participants (75%) and 5 participants (63%) had a therapeutic response 
(combined per-participant microbiological and clinical response) of success at the TOC 
and Follow-up Visits, respectively. Refer to the IB for PK, safety, and additional efficacy 
results. 
Global Phase III studies (204989 and 212390) are being conducted aiming to evaluate the 
therapeutic response (combined microbiological and clinical efficacy per participant) of 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
18 
Clinical Study Protocol template V16 dated 24-Jun-2021 
oral gepotidacin compared to oral Nitrofurantoin for acute uncomplicated cystitis in 
adolescent and adult female participants.  
The purpose of this Phase III study (214144) is to assess the consistency of therapeutic 
response (combined per-participant microbiological and clinical response) of gepotidacin 
observed in this study with global studies (Studies 204989 and 212390). 
2.2. Background 
2.2.1. 
Urinary Tract Infection 
Urinary tract infections (UTIs) are very common, with approximately 11% of women 
>18 years of age experiencing at least 1 episode of acute uncomplicated cystitis per year 
[Foxman, 2000]. Of these, half will experience more than 1 recurrent episode over their 
lifetime [Foxman, 2000]. The peak incidence of acute uncomplicated cystitis occurs in 
young, sexually active women ages 18 to 29 years [Fihn, 2003]. The predominant 
uropathogens isolated in community-acquired UTIs are E. coli (75% to 90%) followed by 
S. saprophyticus (5% to 15%) [Stamm, 1993; Talan, 2000; Foxman, 2010]. Klebsiella, 
Enterobacter, Proteus species, and enterococci are observed in only 5% to 10% of acute 
uncomplicated cystitis [Stamm, 1993; Talan, 2000; Foxman, 2010]. 
In Japan, published epidemiology studies reporting the incidence of UTIs are limited 
[Kusama, 2021; Sako, 2021], but the disease thought to be common infectious disease 
[Takahashi, 2022]. Most patients suffering from acute uncomplicated cystitis are sexually 
active women as shown in overseas [Yamamoto, 2017]. The predominant uropathogens 
isolated from patients with acute uncomplicated cystitis are E. coli (approximately 70%) 
followed by Klebsiella pneumoniae, Streptococcus agalactiae, S. saprophyticus, 
Enterococcus faecalis which are observed in only 3% to 5% [Wada, 2021]. 
2.2.2. 
Multidrug resistance in UTI 
Multidrug resistance, which is typically associated with nosocomial infections, has now 
emerged at the community level and has made treatment approaches for UTIs more 
difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. This has led to increasing patient 
morbidity, increasing costs due to reassessment and retreatment, higher rates of 
hospitalization, and increased use of broad-spectrum antimicrobials [Foxman, 2002; 
Gupta, 2011a; Hooton, 2012]. Furthermore, ESBL-producing Enterobacteriaceae (now 
recognized as Enterobacterales), which includes E. coli, is recognized as a serious threat 
by the Centers for Disease Control and Prevention (CDC) [CDC, 2019] and drug-
resistant Enterobacteriaceae is a critical priority pathogen for the World Health 
Organization (WHO) [WHO, 2017]. The availability of oral antimicrobials that are 
effective against ESBL producers is limited and, for some outpatient infections, no oral 
options remain. 
An in vitro evaluation of antimicrobial resistance of urinary E. coli isolates 
(n=12,253,679) among US outpatients between 2000 and 2010 was conducted using The 
Surveillance Network and found significant increases in the percentage of E. coli that 
were resistant to ciprofloxacin (3% to 17.1%) and trimethoprim-sulfamethoxazole (TMP-
SXT) (17.9% to 24.2%), whereas there were minimal changes in the percentage of 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
19 
Clinical Study Protocol template V16 dated 24-Jun-2021 
resistance to nitrofurantoin (0.8% to 1.6%) and ceftriaxone (0.2% to 2.3%) over time 
[Sanchez, 2012]. Another surveillance study, which looked at US susceptibility patterns 
and ESBL rates of E. coli from UTIs, showed an increase in ESBL rates from 7.8% to 
18.3% (p<0.0001) from 2010 to 2014 [Lob, 2016]. The expansion of ESBL-producing E. 
coli, which are usually co-resistant to TMP-SXT and fluoroquinolones, is of urgent 
concern globally as well [Oteo, 2010]. Recent global surveillance data of E. coli showed 
high resistance rates to third-generation cephalosporins and fluoroquinolones in all 6 
WHO regions [WHO, 2014]. An evaluation of the prevalence and susceptibility of acute 
uncomplicated cystitis pathogens in 9 European countries and Brazil from 2003 to 2006 
showed that >10% of E. coli strains were MDR and 1.7% were ESBL producers [Schito, 
2009]. A separate study in Brazil reported the prevalence of 7.6% ESBL-producing 
Enterobacterales among pathogens from community-acquired UTIs [Abreu, 2013]. In 
China, the prevalence of ESBLs in urinary E. coli in women ranged from 5% to 10.6% 
depending on the age group [Ho, 2007]. 
Based on these resistant pathogen trends, guidelines for acute uncomplicated cystitis now 
recommend first-line antimicrobial treatment with nitrofurantoin, TMP-SXT, fosfomycin, 
or pivmecillinam, assuming the drug is available, and the patient does not have a 
concerning allergy history or tolerance issues [Gupta, 2011b]. Trimethoprim-
sulfamethoxazole should not be used as a first-line treatment if the prevalence of 
resistance exceeds the 20% threshold or if TMP-SXT was used for the treatment of a UTI 
in the previous 3 months. If any of these are concerns for a patient, then fluoroquinolones 
or β-lactams are recommended. 
In Japan, fluoroquinolone-resistant bacteria and ESBL-producing bacteria have been 
paying attention as well. In early 2000, quinolone-resistant strains were rarely isolated in 
acute uncomplicated cystitis, but gradually increased, and the resistance rate of E. coli 
was reported to be 15.6% in a recent study [Wada, 2021]. ESBL-producing bacteria were 
originally regarded as one of the pathogens of nosocomial infections, and were rarely a 
problem in pathological conditions such as acute uncomplicated cystitis previously, 
however in recent years, ESBL-producing E. coli could be detected at approximately 
9.5% [Wada, 2021]. 
In Japan, the treatment recommendations of antimicrobials for acute uncomplicated 
cystitis differ between premenopausal and postmenopausal women. This is because the 
frequency of isolation of Gram-positive cocci is low and isolated E. coli shows a high 
rate of fluoroquinolone resistance in postmenopausal women, compared with 
premenopausal women. The Japanese therapeutic guideline recommends that 
fluoroquinolones should be used as the first-line treatment for acute uncomplicated 
cystitis in premenopausal women if tested positive by urinalysis for Gram-positive cocci, 
but should not be used if tested positive for Gram-negative rods [Yamamoto, 2017]. For 
these women, the guideline recommends using cephalosporins, or penicillins with β-
Lactamase inhibitor (BLI). For postmenopausal women, on the other hand, the guideline 
recommends selecting cephalosporins or penicillins with BLI as the first-line treatment 
because of a high proportion of fluoroquinolone-resistant isolates for the major 
uropathogen E. coli in acute uncomplicated cystitis. However, when Gram-positive cocci 
have been detected in a urine test, fluoroquinolones are recommended. Since ESBL-
producing strains are frequently resistant to fluoroquinolones, fosfomycin and faropenem 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
 
 
 
 
20 
Clinical Study Protocol template V16 dated 24-Jun-2021 
are recommended in both premenopausal and postmenopausal women if their 
uropathogen(s) are ESBL-producing strains [Yamamoto, 2017]. 
ESBL-producing E. coli has been spreading rapidly and worldwide, with extremely high 
detection rates in some areas [Doi, 2013; Flamm, 2014]. In current global society, there 
are no borders in the transmission of bacteria, and anyone can be a carrier of ESBL-
producing bacteria and MDR bacteria [Arcilla, 2017; Hassing, 2015]. In fact, the 
resistance rate of ESBL-producing E. coli has been gradually increased in Japan 
[Hayami, 2013; Hayami, 2019; Wada, 2021], and similarly increasing global rates of 
MDR bacteria may elevate the likelihood of MDR associated UTI infections becoming 
more common in Japan. In addition, National action plan on Antimicrobial Resistance 
was established [The Government of Japan, 2016]. There is an unmet medical need for 
new therapeutic agents that exhibit strong antibacterial activity against such bacteria 
[Kusama, 2021; Nakagawa, 2021]. 
2.2.3. 
Gepotidacin in acute uncomplicated cystitis treatment 
Gepotidacin is a first-in-class, novel triazaacenaphthylene antibacterial compound that 
has demonstrated in vitro activity against uropathogens including E. coli (see the IB for 
details) and provides high and sustained urine concentrations for the treatment of UTIs. 
With its unique ability to selectively inhibit bacterial DNA replication by a means not 
utilized by any currently approved human therapeutic agent, gepotidacin warrants further 
study as a potential opportunity to address an unmet medical need by providing a new 
and effective oral treatment option for acute uncomplicated cystitis. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the IB.  
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of gepotidacin may be found in the IB. 
And those of nitorofrantoin may be found in the package insert. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
21 
Clinical Study Protocol template V16 dated 24-Jun-2021 
2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Gepotidacin (GSK2140944) 
Cardiovascular Effects 
Based on nonclinical data, cardiovascular effects 
were reversible increase in heart rate and blood 
pressure (dog and monkey); reversible 10 to 21 
msec (4% to 9%) increase in QTc (monkey); and at 
the highest dose, a reversible 2 to 3 msec (6% to 
8%) increase in QRS (monkey). 
Based on a thorough QTc clinical study, gepotidacin 
may cause mild, reversible heart rate effects and QT 
prolongation. 
In a thorough QTc study, infusion of gepotidacin at 
doses of 1000 and 1800 mg over 2 hours caused a 
mild increased heart rate effect of approximately 6 to 
10 bpm and QT prolongation measured as ∆∆QTcF 
of 12 to 22 msec. The QT prolongation evolved 
during the infusion and was quickly reversed over 2 
hours after the end of the infusion (see the IB for 
details). 
In Phase I studies, concentration-dependent QT 
prolongation has been observed during clinical trials 
with gepotidacin; however, this increase has not 
translated into clinically significant QTc values or 
changes from baseline (change from baseline 
>60 msec or QTcF >500 msec) or cardiovascular 
AEs.  
In Phase I and II studies, gepotidacin did not have a 
clinically relevant effect on cardiac conduction (PR 
and QRS intervals). 
Although there appears to be a trend to higher 
gepotidacin systemic exposure in healthy Japanese 
compared to Western subjects, the higher systemic 
exposure of gepotidacin observed in Japanese 
subjects is currently considered to be within the 
tolerable range and not associated with any 
cardiovascular safety concerns. 
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 6.8.2). 
See also the Renal and Hepatic sections within this 
table below. 
Gastrointestinal Effects 
Based on nonclinical data, gastrointestinal effects 
were mild ulceration of the nonglandular mucosa 
and minimal erosion and/or mural inflammation of 
See also the Acetylcholinesterase Inhibition section 
within this table below. 
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.  


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
22 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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. 
Clostridioides difficile and C. difficile-associated 
diarrhea has been observed in clinical trials with 
gepotidacin. 
Suspected C. difficile infection will be managed 
according to a prespecified algorithm provided in 
10.7. 
Acetylcholinesterase Inhibition 
In vitro testing showed gepotidacin to be a rapidly 
reversible inhibitor of acetylcholinesterase in the 
clinical plasma concentration range. 
 
Based on clinical data, caution should be used in 
participants who have a condition requiring 
treatment with anticholinergic medications or who 
have certain medical conditions that may be 
exacerbated by the acetylcholinesterase inhibition 
activity of gepotidacin. 
Increased cholinergic effects can potentially be 
associated with more severe symptoms including 
atrioventricular block, seizure/convulsions, 
bronchospasm, and vasovagal syncope. No causal 
relationship between these events and the use of 
gepotidacin has been established during clinical 
trials to date. 
 
Adverse events consistent with acetylcholinesterase 
inhibition, including diarrhea, nausea, vomiting, 
gastrointestinal cramping and pain, dyspnea, 
bradycardia, lacrimation, salivation, dysarthria, and 
diaphoresis/sweating have been reported during 
clinical trials with gepotidacin.  
Mild and transient non-gastrointestinal AEs have 
been associated with Cmax levels higher than this 
dosing regimen. 
Participants who have medical conditions or require 
medications that may be impacted by inhibition of 
acetylcholinesterase will be excluded from 
participation in this study. See Section 5.2 for 
excluded medical conditions and Section 6.8.2, 
Prohibited Medications and Nondrug Therapies, for 
prohibited medications. 
Close monitoring of clinical parameters and AEs will 
be conducted to assess effects potentially related to 
acetylcholinesterase inhibition (Section 1.3). 
Hepatic Effects 
In preclinical studies, increases in ALT, GLDH, 
alkaline phosphatase, and total bilirubin were 
observed in some rat studies of varying exposure. 
Elevations in ALT have occurred in a few 
participants with pre-existing hepatitis C infection, 
but none were felt related to study treatment. The 
type and pattern of elevation in liver transaminases 
observed has not been suggestive of an adverse 
effect of gepotidacin and none were considered 
related to study treatment. 
Participants with severe hepatic impairment are 
excluded from Phase III trials. See Section 5.2 for 
excluded medical conditions. Monitoring and 
stopping criteria liver events have been 
implemented. 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
23 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in volunteer 
participants with severe hepatic impairment. 
Renal Effects 
In preclinical trials, mild to moderate tubular 
degeneration was noted in the rat and proteinuria in 
the dog. Proteinuria was also observed in humans. 
No clinical evidence of renal toxicity has been seen 
in clinical trials to date. 
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in severe renal 
impairment/ESRD participants not on hemodialysis 
and in ESRD participants requiring hemodialysis 
(note: gepotidacin may have been administered at 
any time other than when receiving dialysis). 
Participants with severe renal impairment/ESRD 
(including those who may require dialysis) are 
excluded from Phase III trials. See Section 5.2 for 
excluded medical conditions. Monitoring criteria 
have been implemented. 
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 exposure (65 µg.h/mL in rat and 
35µg.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 10.4 for contraceptive measures and Section 
8.2.5 for required pregnancy testing. 
Other 
Nitrofurantoin 
The most frequent AEs possibly or probably related 
to oral nitrofurantoin treatment are nausea (8%), 
Close monitoring of clinical parameters and AEs 
(Section 1.3) will be conducted, and treatment 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
24 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
headache (6%), and flatulence (1.5%). As with 
gepotidacin, there is also a need to monitor for C. 
difficile-associated diarrhea during nitrofurantoin 
treatment.  
Nitrofurantoin is contraindicated for patients with 
anuria, oliguria, or significant impairment of renal 
function; pregnant patients at term (38 to 42 weeks’ 
gestation), during labor and delivery, or when the 
onset of labor is imminent; neonates under 1 month 
of age; and patients with a previous history of 
cholestatic jaundice/hepatic dysfunction associated 
with nitrofurantoin. 
Rare adverse reactions that generally occur in 
patients receiving treatment for 6 months or longer 
are acute, subacute, or chronic pulmonary reactions, 
with potential insidious development of chronic 
pulmonary reactions (diffuse interstitial pneumonitis 
or pulmonary fibrosis, or both).  
Peripheral neuropathy has occurred, which may be 
enhanced for patients with renal impairment, 
anemia, diabetes mellitus, electrolyte imbalance, 
vitamin B deficiency, and debilitating disease. 
Nitrofurantoin has induced the occurrence of 
hemolytic anemia of the primaquine sensitivity type, 
which appear to be linked to a glucose-6-phosphate 
dehydrogenase deficiency in the red blood cells of 
the affected patients.  
monitoring and evaluation criteria (Section 7.1.1) will 
be utilized to mitigate hepatic effects. 
Because planned treatment in this study is only 5 
days, the probability for adverse reactions 
associated with long-term use is low. 
The exclusion criteria for this study include 
contraindications to nitrofurantoin use and exclude 
participants at risk for nitrofurantoin adverse 
reactions, including acute porphyria as an example 
of a rare genetic risk (see Section 5.2).  
Participants with a history of sensitivity to 
nitrofurantoin, or components thereof, will not be 
allowed to enroll in the study (Section 5.2). 
Participant’s medical history will be carefully 
evaluated for history of hypersensitivity. 
Participants must agree not to use antacid 
preparations containing magnesium trisilicate or 
uricosuric drugs during study treatment (see Section 
5.2). 
Suspected C. difficile infection will be managed 
according to a prespecified algorithm provided in 
10.7. 
Precautions related to nitrofurantoin are summarized 
in detail in the Study Reference Manual. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
25 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Hepatic reactions, including hepatitis, cholestatic 
jaundice, chronic active hepatitis, and hepatic 
necrosis, occur rarely. 
Concomitant administration of nitrofurantoin with 
antacids containing magnesium trisilicate reduces 
both the rate and extent of absorption, and 
uricosuric drugs, such as probenecid and 
sulfinpyrazone, can inhibit renal tubular secretion of 
nitrofurantoin. 
Participants with a known glucose-6-phosphate 
dehydrogenase deficiency will not be allowed to 
enroll in the study (Section 5.2) 
bpm=beats per minute; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AUC=area under the drug concentration-curve; 
Cmax=maximum concentration; CYP3A4=cytochrome P450 enzyme 3A4; ESRD=end-stage renal disease; GLDH=glutamate dehydrogenase; IB=investigator’s 
brochure; IV=intravenous; ΔΔQTcF=placebo-corrected change from-baseline in corrected QT interval using the Fridericia formula; QTc=corrected QT interval; 
QTcF=interval corrected for heart rate according to Fridericia’s formula. 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
26 
Clinical Study Protocol template V16 dated 24-Jun-2021 
2.3.2. 
Benefit Assessment 
Acute uncomplicated cystitis is among the most common indications for which 
antimicrobials are prescribed for otherwise healthy women [Gupta, 2011b]. The increase 
in antimicrobial resistance among pathogens causing community-acquired UTIs over the 
past 2 decades has made treatment approaches for UTIs more difficult. Rising incidences 
of Anti-microbial Resistance and MDR represent a pressing and growing public health 
issue in both Japan and the rest of the world. There are limited options currently available 
for treating infections with MDR organisms. Merely a few antimicrobials with new 
mechanisms and no cross resistance to other antimicrobials are in clinical development at 
this time. 
Gepotidacin is active in vitro and in vivo against the key causative pathogen in acute 
uncomplicated cystitis, E. coli, including most isolates resistant to other antibacterial 
treatments. Given gepotidacin’s spectrum of activity against E. coli, S. saprophyticus, and 
E. faecalis, as well as human safety data and the PK profile, it is anticipated that 
gepotidacin will benefit participants with acute uncomplicated cystitis. 
The active reference in this study is nitrofurantoin, a marketed antimicrobial in several 
global markets including the US and EU for the treatment of acute uncomplicated UTIs 
(acute cystitis) caused by susceptible strains of E. coli or S. saprophyticus as a first-line 
therapy with high efficacy and good tolerability dosed for 5 days or longer. Although 
nitrofurantoin is not approved in Japan, it was a marketed antimicrobial in Japan until 
1990 and has shown efficacy in Japanese patients with acute uncomplicated cystitis and 
had no clinically significant safety issues [Tsunoda, 1970; Ookita, 1970; Tofukuji,1970]. 
Participants randomly assigned to this treatment group are also expected to experience 
treatment benefits.  
Overall, all participants in this study will not only receive routine medical monitoring 
appropriate for acute uncomplicated cystitis, but they will also receive heightened 
monitoring to minimize safety risks when participating in a clinical study. 
 
2.3.3. 
Overall Benefit: Risk Conclusion 
Antimicrobial resistance among uropathogens causing acute uncomplicated cystitis has 
increased in the past decades [Gupta, 2011b; Sanchez, 2016]. However, despite of 
increasing drug resistance to existing agents, few new antimicrobials with novel 
mechanisms of action are being developed. Gepotidacin selectively inhibits bacterial 
DNA replication by a means not utilized by any currently approved human therapeutic 
agent. Based on the known preclinical data for gepotidacin against E. coli, S. 
saprophyticus, and E. faecalis, the Phase II results showing the effective treatment of 
uncomplicated urogenital gonorrhea and ABSSSIs, Phase IIa results indicating efficacy 
in acute uncomplicated cystitis, and the cumulative safety results from Phase I and Phase 
II studies with oral gepotidacin treatment, this study will assess the consistency of this 
study with global studies (Studies 204989 and 212390) for the therapeutic response 
(combined microbiological and clinical efficacy per participant) of oral gepotidacin. 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
27 
Clinical Study Protocol template V16 dated 24-Jun-2021 
None of the potential or identified risks seen to date in participants dosed with 
gepotidacin preclude further clinical development. Mitigation strategies have been 
implemented to promptly identify and appropriately address risks to protect participant 
safety and to better characterize the safety profile of the study treatments (Section 2.3.1). 
Furthermore, a GlaxoSmithKline (GSK) Safety Review Team (SRT) will monitor 
blinded safety data in stream (see 10.1). Careful safety monitoring should also identify 
any emerging safety issues for gepotidacin and nitrofurantoin.  
The investigator may also, at his or her discretion, discontinue the participant from study 
treatment at any time and initiate appropriate alternative therapy. 
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with gepotidacin and nitrofurantoin 
are justified by the anticipated benefits that may be afforded to participants with acute 
uncomplicated cystitis. 
 
3. OBJECTIVES AND ENDPOINTS AND/OR ESTIMANDS 
Objectives 
Endpoints 
Primary 
 
• 
To assess the consistency of therapeutic 
response of gepotidacin at the Test of cure 
(TOC) Visit (Day 10 to 13) in female 
participants with acute uncomplicated 
cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are 
susceptible to nitrofurantoin in Japan, with 
that from global studies (Studies 204989 
and 212390). 
• 
Therapeutic response (combined per-
participant microbiological and clinical 
response) at the TOC Visit 
Secondary 
 
• 
To assess the therapeutic response of 
gepotidacin compared to nitrofurantoin as 
an active reference descriptively, at the 
TOC Visit, in female participants with acute 
uncomplicated cystitis with qualifying 
bacterial uropathogen(s) at Baseline that 
all are susceptible to nitrofurantoin 
• 
Therapeutic response at the TOC Visit 
• 
To assess the clinical efficacy and 
microbiological efficacy of gepotidacin at 
the TOC Visit in female participants with 
acute uncomplicated cystitis with qualifying 
• 
Clinical outcome and response at the TOC 
Visit 
• 
Microbiological outcome and response at 
the TOC Visit 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
28 
Clinical Study Protocol template V16 dated 24-Jun-2021 
bacterial uropathogen(s) at Baseline that 
all are susceptible to nitrofurantoin 
• 
To assess the therapeutic response, 
clinical efficacy and microbiological 
efficacy of gepotidacin at the TOC Visit in 
female participants with acute 
uncomplicated cystitis who have qualifying 
uropathogen(s) resistant to two or more 
specific classes of antimicrobials at 
Baseline 
• 
Therapeutic response at the TOC Visit 
• 
Clinical outcome and response at the TOC 
Visit 
• 
Microbiological outcome and response at 
the TOC Visit 
• 
To assess the clinical efficacy of 
gepotidacin at the TOC Visit in female 
participants with acute uncomplicated 
cystitis 
• 
Investigator assessment of clinical 
response at the TOC Visit 
• 
To assess the safety and tolerability of 
gepotidacin in female participants with 
acute uncomplicated cystitis 
• 
Occurrence of treatment-emergent 
adverse events (AEs), serious AEs 
(SAEs) and adverse events of special 
interest (AESIs) 
• 
Change from baseline in clinical laboratory 
tests 
• 
Change from baseline in 
electrocardiograms (ECGs) 
• 
Change from baseline in vital sign 
measurements 
• 
To determine the plasma and urine PK 
concentrations of gepotidacin in female 
participants with acute uncomplicated 
cystitis 
• 
Gepotidacin plasma and urine 
concentrations  
Exploratory 
 
CCI


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
29 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Please refer to Section 8.1.1, 8.1.2.1 and 8.1.3.1 for the definition of therapeutic response, microbiological 
outcome/response and clinical outcome/response 
Please refer to Section 10.8 for details of “qualify bacterial uropathogen(s) 
Primary estimand 
The primary clinical question of interest is: Whether the therapeutic response at the TOC 
visit in female participants with acute uncomplicated cystitis who have qualified 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin in this study is 
consistent with that from the global studies, regardless of intervention discontinuation for 
any reason. Receipt of systemic antimicrobials will impact the endpoint definition (see 
Section 8.1.2.1 and 8.1.3.1).  
The estimand is described by the following attributes: 
• 
Population: Japanese and non-Japanese (from Studies 204989 and 212390) female 
participants with acute uncomplicated cystitis who have qualifying uropathogen(s) at 
Baseline that all are susceptible to nitrofurantoin. 
• 
Treatment condition: Gepotidacin 1500 mg BID for 5 days in this study versus 
gepotidacin 1500 mg BID for 5 days in the global studies (Studies 204989 and 
212390) regardless of adherence. 
• 
Variable: Therapeutic response (combined per-participant microbiological and 
clinical response) at the TOC Visit. Microbiological success is defined as eradication 
(i.e. reduction) of all qualifying bacterial uropathogens recovered at baseline to <103 
CCI


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
30 
Clinical Study Protocol template V16 dated 24-Jun-2021 
colony-forming units/mL (CFU/mL) as observed on quantitative urine culture 
without the participant receiving other systemic antimicrobials. Clinical success is 
defined as resolution of signs and symptoms of acute cystitis present at Baseline (and 
no new signs and symptoms) without the participant receiving other systemic 
antimicrobials.  
• 
Summary measure: Comparison of the proportion of Japanese participants achieving 
therapeutic success in this study with 10%tile of the predicted distribution for the 
proportion of participants achieving therapeutic success in this study derived from 
the global studies (Studies 204989 and 212390) under the assumption of consistency.  
• 
Intercurrent events (ICEs):  
• 
Study treatment discontinuation (due to any reason) – treatment policy strategy 
(interest is in the treatment effect regardless of study treatment discontinuation) 
• 
Use of systemic antimicrobials – composite strategy. This ICE is captured 
through the definitions of microbiological and clinical response (see Section 
8.1.2.1 and 8.1.3.1 
Rationale for estimand:  
Interest in this study lies in whether the efficacy of this study is consistent with the global 
studies.  
The clinical question of interest in this study and the global studies (Studies 204989 and 
212390) lies in the treatment effect regardless of whether the full course of 5 days of 
treatment was taken or not, which reflects how patients may be treated in clinical 
practice. Hence, a treatment policy strategy is appropriate for treatment withdrawal 
before completing 5 days of treatment. Use of other systemic antimicrobials may 
confound the bacterial culture results; thus, the microbiological response will be 
considered failure. For clinical data, the use of a systemic antimicrobial for acute 
uncomplicated cystitis is a sign of treatment failure and use of a systemic antimicrobial 
for another infection cannot be considered a success as it confounds the assessment of 
efficacy. Therefore, the definition of a successful therapeutic response precludes the use 
of other systemic antimicrobials.  
 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
31 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 1 
Estimand for the Other Secondary Endpoints 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
To assess the 
therapeutic response of 
gepotidacin compared 
to nitrofurantoin as an 
active reference 
descriptively, at the 
TOC Visit, in female 
participants with acute 
uncomplicated cystitis 
with qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Japanese female 
participants with acute 
uncomplicated cystitis 
with qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days versus 
nitrofurantoin 100 mg 
BID for 5 days, 
regardless of adherence 
Therapeutic response at 
the TOC Visit 
Difference in proportions 
of participants achieving 
therapeutic success in 
the gepotidacin and 
nitrofurantoin treatment 
groups 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 
To assess the clinical 
efficacy and 
microbiological efficacy 
of gepotidacin at the 
TOC Visit in female 
participants with acute 
uncomplicated cystitis 
with qualifying bacterial 
uropathogen(s) at 
Japanese female 
participants with acute 
uncomplicated cystitis 
with qualifying bacterial 
uropathogen(s) at 
Baseline that all are 
susceptible to 
nitrofurantoin 
Gepotidacin 1500 mg 
BID for 5 days, 
regardless of adherence 
Clinical response at the 
TOC Visit 
Proportion of 
participants achieving 
clinical success in the 
gepotidacin group 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
32 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Baseline that all are 
susceptible to 
nitrofurantoin 
Clinical outcome at the 
TOC Visit 
Proportion of 
participants in each 
outcome category in the 
gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 
Microbiological 
response at TOC Visit 
Proportion of 
participants achieving 
microbioglocal success 
in the gepotidacin group 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
33 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Microbiological outcome 
at TOC Visit 
Proportion of 
participants in each 
outcome category in the 
gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 
To assess therapeutic 
response, clinical 
efficacy and 
microbiological efficacy 
of gepotidacin at the 
TOC Visit in female 
participants with acute 
uncomplicated cystitis 
who have qualifying 
Japanese female 
participants with acute 
uncomplicated cystitis 
who have qualifying 
uropathogen(s) 
resistance to two or 
more specific classes of 
antimicrobials at 
Baseline 
Gepotidacin 1500 mg 
BID for 5 days 
Therapeutic response 
(combined per-
participant 
microbiological and 
clinical response) at the 
TOC Visit 
Proportion of 
participants achieving 
therapeutic success in 
the gepotidacin group 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
34 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
uropathogen(s) resistant 
to two or more specific 
classes of antimicrobials 
at Baseline 
Clinical response at the 
TOC Visit 
Proportion of 
participants achieving 
clinical success in the 
gepotidacin group 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 
Clinical outcome at the 
TOC Visit 
Proportion of 
participants in each 
outcome category in the 
gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
35 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Microbiological 
response at the TOC 
Visit 
Proportion of 
participants achieving 
microbiological success 
in the gepotidacin group 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest   – composite 
strategy 
Microbiological outcome 
at the TOC Visit 
Proportion of 
participants in each 
outcome category in the 
gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
36 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
To assess the clinical 
efficacy of gepotidacin 
at the TOC Visit in 
female participants with 
acute uncomplicated 
cystitis 
Japanese female 
participants with acute 
uncomplicated cystitis 
Gepotidacin 1500 mg 
BID for 5 days, 
regardless of adherence 
Investigator assessment 
of clinical response at 
the TOC Visit 
Proportion of 
participants with 
investigator assessed 
clinical response of 
success, failure and 
indeterminate/missing 
on the gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 
Use of systemic 
antimicrobials on or 
prior to the visit of 
interest – composite 
strategy 
To assess the safety 
and tolerability of 
gepotidacin in female 
participants with acute 
uncomplicated cystitis 
Japanese female 
participants with acute 
uncomplicated cystitis 
Gepotidacin 1500 mg 
BID for 5 days, 
regardless of adherence 
TEAEs, AESI, SAEs, as 
well as change from 
baseline results for 
clinical laboratory tests, 
electrocardiograms 
(ECGs) and vital sign 
measurements 
Summary statistics in 
the gepotidacin arm  
Incident rate for TEAE, 
AESI and SAE 
Mean change from 
baseline for clinical 
laboratory tests, ECGs 
and vital sign 
measurements.  
Study treatment 
discontinuation (due to 
any reason) – treatment 
policy 


TMF-15095845 
CONFIDENTIAL 
 
 
 
214144 
37 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Secondary objective 
Population 
Treatment Condition 
Variable 
Summary Measure 
Intercurrent Event 
Pharmacokinetic 
Japanese female 
participants with acute 
uncomplicated cystitis  
Gepotidacin 1500 mg 
BID for 5 days 
Gepotidacin plasma and 
urine concentrations 
Summary statistics 
(appropriate for each 
type of endpoint) in the 
gepotidacin arm 
Study treatment 
discontinuation (due to 
any reason) – while on 
treatment strategy 
(treatment phase 
defined as from first 
dose to On-therapy 
Visit) 
 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
38 
Clinical Study Protocol template V16 dated 24-Jun-2021 
4. 
STUDY DESIGN 
4.1. Overall Design 
• 
Study 214144 is a Phase III, randomized, multicenter, active reference, parallel-
group, double-blind, double-dummy study in adolescent and adult female 
participants to assess consistency of therapeutic response of gepotidacin at the TOC 
Visit in female participants with acute uncomplicated cystitis observed in this study 
with global studies (Studies 204989 and 212390). In addition, the efficacy 
(therapeutic response) of gepotidacin compared to active reference (nitrofurantoin) 
descriptively will also be evaluated for therapeutic response at the TOC Visit. 
Participants will be stratified by age category (≤50 years, or >50 years) and acute 
uncomplicated cystitis recurrence (nonrecurrent infection or recurrent infection, 
defined as a confirmed infection [not including the current infection in the 
calculation] with at least 1 prior episode within the past 3 months, at least 2 prior 
episodes within the past 6 months, or at least 3 prior episodes within the past 12 
months before study entry) and will be randomly assigned in a 3:1 ratio to receive 1 
of the following study treatments: 
• 
Gepotidacin: 1500 mg administered orally twice daily (BID) for 5 days 
• 
Nitrofurantoin: 100 mg administered orally BID for 5 days 
Note: Each dose of gepotidacin or nitrofurantoin should be taken after food 
consumption and with water. 
• 
Appropriate safety, clinical and microbiological assessments will be conducted at the 
Baseline (Day 1) Visit and repeated at the On-therapy (Day 2 to 4), TOC (Day 10 to 
13), and Follow-up (Day 28±3) Visits. 
 
 
 Each treatment day will be assessed over 24 
hours starting with the first dose of study treatment, as further detailed in the Study 
Reference Manual (SRM). 
• 
For the primary efficacy endpoint of therapeutic response (combined per-participant 
microbiological and clinical response), therapeutic success refers to participants who 
have been deemed both a microbiological success (reduction of all qualifying 
bacterial uropathogens [e.g., ≥105 CFU/mL; defined in 10.8] recovered at Baseline to 
<103 CFU/mL as observed on quantitative urine culture without the participant 
receiving other systemic antimicrobials) and a clinical success (resolution of signs 
and symptoms of acute cystitis present at Baseline [and no new signs and symptoms] 
without the participant receiving other systemic antimicrobials) at the TOC Visit in 
the Microbiological Intent-to-Treat Nitrofurantoin-Susceptible (micro ITT NTF-S) 
Population, regardless of treatment discontinuation. 
• 
PK samples will be collected in all participants for analysis at the Baseline (postdose) 
and the On-therapy Visits (predose and postdose). 
• 
Participants may return to the study site at any time due to AEs or if they are 
experiencing new or continuing signs and symptoms of acute uncomplicated cystitis. 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
39 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Participants will be assessed and treated per the investigator’s judgement. If a 
participant is switched to a different antimicrobial before or during the TOC Visit, all 
TOC procedures should be completed before the other antimicrobial is started. 
• 
Participants with a concomitant fungal infection can only be treated with topical 
antifungals per local standard of care. 
• 
Participants will return to the study site on Day 28 (±3) for a Follow-up Visit. 
Participants experiencing signs and symptoms suggestive of infection recurrence or 
relapse will be assessed and treated per the investigator’s judgement.  
• 
The study duration is approximately 28 days with 4 planned study visits (see Section 
8 for study visit details): 
• 
Baseline (Day 1) Visit 
• 
On-therapy (Day 2 to 4) Visit 
• 
TOC (Day 10 to 13) Visit 
• 
Follow-up (Day 28±3) Visit 
A study design schematic is depicted in Figure 1. The Schedule of Activities (SoA) is 
provided in Section 1.3. 
Refer to 10.9 for details regarding allowed revisions to study conduct and/or monitoring 
due to coronavirus disease (COVID-19). For all study visits, to minimize the amount of 
time that participants spend at the clinic, eConsent may be utilized and remote collection 
of study-related data may be obtained as described in the SRM. Thus, some visit data 
may be collected through a combination of telemedicine and on-site visits. Collection of 
information via telemedicine will be performed only where local regulations permit. 
Of note, to reduce participant on-site visits or if unforeseen issues impact clinic visits, 
and participants are unable to attend a site visit, home healthcare (home visits and 
telemedicine visits) may be used to conduct procedures as detailed in the Study 
Reference Manual. Home healthcare will only be utilized where applicable country and 
local regulations and infrastructure allow. 
4.1.1. 
Safety Review Team/Microbiology Review Team 
There will be a GlaxoSmithKline Safety Review Team to monitor blinded safety data, 
and a Microbiology Review Team to monitor blinded microbiological data instream (see 
Section 10.1.5). 
4.2. Scientific Rationale for Study Design 
The study design of global Phase III studies (Studies 204989 and 212390) was based on 
the Food and Drug Administration (FDA) guidance for industry for developing drug 
treatments for uncomplicated and complicated UTIs [DHHS, 2019; DHHS, 2018], the 
European Medicines Agency (EMA) addendum to the guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections [EMA, 2013], and 
feedback from the FDA and EMA. This study is designed in consideration of bridging to 
assess the consistency between this study and the global Phase III studies based on the 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
40 
Clinical Study Protocol template V16 dated 24-Jun-2021 
feedback from the Pharmaceuticals and Medical Devices Agency (PMDA) at the 
consultation meeting. 
The primary efficacy endpoint will be the therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC Visit in participants who have a 
qualifying bacterial uropathogen at Baseline that all are susceptible to nitrofurantoin. 
Although the guidance differs in their criteria for defining qualifying uropathogens, this 
study has been designed with the qualifying uropathogen criteria defined in 10.8 and 
microbiological success defined as reduction of all qualifying bacterial uropathogens 
recovered at Baseline to <103 CFU/mL as observed on quantitative urine culture without 
the participant receiving other systemic antimicrobials. Clinical success at the TOC Visit 
is defined as the resolution of signs and symptoms of acute cystitis present at Baseline 
(and no new signs and symptoms) without the participant receiving other systemic 
antimicrobials. Therapeutic success refers to participants who have been deemed both a 
microbiological success and a clinical success (i.e., responders). The primary objective of 
this study is to assess consistency of this study with global studies (Studies 204989 and 
212390) for therapeutic response of gepotidacin at the TOC Visit.  
Nitrofurantoin has been selected as the active reference in this study. Nitrofurantoin is 
globally available as the indication for the treatment of acute uncomplicated UTI (acute 
cystitis) caused by susceptible strains of E. coli or S. saprophyticus in most regions 
except for Japan and is a recommended oral first-line treatment for acute uncomplicated 
cystitis per current US and European Association of Urology guidelines [Gupta, 2011b; 
EAU, 2019]. Although nitrofurantoin is not approved in Japan, nitrofurantoin was a 
marketed antimicrobial in Japan until 1990 and showed efficacy in Japanese patients with 
acute uncomplicated cystitis and had no clinically significant safety issues [Tsunoda, 
1970; Ookita, 1970; Tofukuji, 1970]. Both gepotidacin and nitrofurantoin will be 
administered BID for a treatment duration of 5 days. As described in Section 4.3, the 
dose of each study treatment and the 5-day duration were selected to provide efficacious 
treatment for acute uncomplicated cystitis. Having the same dose regimen will also 
support double-blind dose administration. 
Both adult and adolescent (≥12 to <18 years of age) eligible female participants will be 
enrolled in this double-blinded study. The study is restricted to female participants since 
this study is conducted as bridging-like study to assess the consistency between this study 
and the global studies, which was planned per FDA guidance [DHHS, 2019]. Adolescent 
participants will only be enrolled at study sites where investigators have experience in 
this population and if allowed per the study site’s institutional ethics committees and 
enrollment will be contingent upon such approvals. Adolescent assent forms and adult 
consent forms will be developed with oversight from local governing institutional review 
boards (IRBs)/independent ethics committees (IECs) (see 10.1). There is no upper age 
limit for study participants; however, participants are excluded if they reside in a nursing 
home or dependent care type-facility, or if they have any comorbidities associated with 
complicated UTI. Thus, any participants >75 years of age will only be eligible for the 
study if they are residing independently. 
In order to maximize the efficiency of this study while minimizing discomfort and 
inconvenience to participants consenting to this protocol, a GSK SRT will monitor 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
41 
Clinical Study Protocol template V16 dated 24-Jun-2021 
blinded safety data in stream, while a Microbiology Review Team will monitor blinded 
uropathogen identification and susceptibility data in stream, including the enrollment rate 
of participants with a qualifying bacterial uropathogen at Baseline and the resistance 
profile of uropathogens. For details on these review teams, refer to 10.1. 
4.2.1. 
Participant Input into Design 
Interview of patients with acute uncomplicated cystitis was conducted during the design 
of this protocol. The findings confirmed that the study design is acceptable. A record of 
insights from the patients into the design and implementation is maintained in the Trial 
Master File. 
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. A 5-day dosing duration is in alignment with current treatment guidelines for 
efficacious antibacterial treatment of acute uncomplicated cystitis in women, which 
typically ranges from 3 to 7 days [Gupta, 2011b;; EAU, 2019;Yamamoto, 2017]. The 
safety and tolerability at this oral dose and duration have been evaluated in Phase I 
studies and in Phase II studies (BTZ116704 and 206899) (see IB for details). 
Furthermore, high urine concentrations of gepotidacin are expected in this study based on 
a healthy volunteer Phase I study (BTZ117351) and a Phase IIa study in participants with 
acute uncomplicated cystitis (206899). In BTZ117351, approximately 287 mg of 
unchanged gepotidacin was excreted in urine after a single oral 1500-mg (2 × 750-mg 
tablets) dose of gepotidacin (minimum urine area under drug concentration-time curve 
over 12 hours [AUC12h]=807 µg.h/mL). In the Phase IIa study, 206899, in participants 
with acute uncomplicated cystitis, approximately 460 mg of unchanged gepotidacin was 
excreted in urine over the steady-state dosing interval of 12 hours after repeat BID oral 
dosing of 1500 mg (2 × 750-mg tablets) gepotidacin (minimum steady-state urine 
AUC12h=2256 µg.h/mL). 
For the global phase III studies (Studies 204989 and 212390), the gepotidacin dose and 
duration were selected based on in vitro and in vivo studies including experimental 
animal pyelonephritis studies that simulated human PK exposures of gepotidacin to 
determine the efficacy of gepotidacin against isolates of E. coli, including MDR strains 
(see the IB for further details). Based on GSK assessment of the limitations of the current 
acute cystitis efficacy model in rodents, the pyelonephritis model is considered to allow 
evaluation of antibacterial efficacy in a more robust UTI. 
Additionally, an in vitro study to determine the PK/pharmacodynamic (PD) 
characteristics of gepotidacin against E. coli (dose-fractionation and dose ranging studies) 
indicate that AUC/minimum inhibitory concentration (MIC) is the primary PK/PD index 
predictive of gepotidacin efficacy against E. coli. The magnitude of the ratio of free-drug 
AUC to MIC over 24 hours (fAUC/MIC) required to achieve net bacterial stasis as well 
as 1- and 2-log reductions in bacterial burden from Baseline across multiple E. coli 
isolates with gepotidacin MIC values ranging from 1 to 4 µg/mL, were 34.5, 41.3, and 
49.7, respectively.  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
42 
Clinical Study Protocol template V16 dated 24-Jun-2021 
A set of duplicate 10-day hollow fiber infection model studies was also completed using 
E. coli isolate NCTC 13441 to determine the fAUC/MIC exposure of gepotidacin 
required to prevent the amplification of a resistant subpopulation. An inverted-U shaped 
function described the relationship between drug resistance amplification and fAUC, with 
fAUC values ≥549 preventing resistance amplification to gepotidacin for E. coli in the 
hollow fiber infection model for 10 days. This equates to an fAUC/MIC value ≥275 when 
applying the gepotidacin broth microdilution MIC of 2 µg/mL for E. coli NCTC 13441.  
When taking the fAUC/MIC target of 275 for resistance suppression into consideration 
with the concentrations of gepotidacin in human urine measured in BTZ117351 
(minimum urine AUC12h=807 µg.h/mL; thus, minimum urine AUC over 24 hours [AUC 
24 h]=1614 µg.h/mL) and applying an MIC value of 4 µg/mL, the minimum human urine 
AUC/MIC achieved for the 1500 mg oral BID dose exceeds the fAUC/MIC resistance 
suppression target of 275 by approximately 1.5-fold and 100% target attainment for a 
urine AUC/MIC target of 275 would be expected for participants with E. coli isolates 
with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing.  
When applying the higher concentrations of gepotidacin in human urine measured in the 
Phase IIa study (206899; minimum urine AUC 12 h=2256 µg.h/mL; thus, AUC 24 
h=4512 µg.h/mL) and applying a MIC value of 4 µg/mL, the minimum human urine 
AUC/MIC achieved for the 1500 mg oral BID dose further exceeds the fAUC/MIC 
resistance suppression target of 275 by approximately 4 fold and 100% target attainment 
for a urine AUC/MIC target of 275 would also be expected for participants with E. coli 
isolates with gepotidacin MICs ≤4 µg/mL following 1500 mg BID oral dosing. 
Additionally, in the Phase IIa study (206899), for 4 participants with available urine 
AUC24h steady-state PK parameters and qualifying Enterobacterales uropathogens who 
were microbiological successes at TOC, the plasma fAUC24h/MIC values ranged from 7 
to 90.5 and urine AUC24h/MIC ratios ranged from 1292 to 121,698. The participant with 
the lowest plasma fAUC/MIC (7.0) and urine AUC/MIC (1292) had a K. pneumoniae 
uropathogen with a gepotidacin MIC of 4 µg/mL. No participants had an outcome of 
microbiological persistence at TOC. 
Based on results from Phase I study (213678), following a 1500 mg single gepotidacin 
dose and twice 3000 mg gepotidacin doses under fed conditions, there was a trend to 
higher geometric mean gepotidacin Cmax (7% to 30%) in Japanese participants 
compared to Western Caucasian participants, while total plasma exposures (AUC) were 
generally similar. Following the administration of 1500 mg single dose of gepotidacin to 
Japanese participants in the fed state, the mean trough concentration in the urine obtained 
in the 8- to 12-hour window was 53.7 μg/mL, which exceeds the gepotidacin MIC90 of 4 
μg/mL for drug-resistant subsets of E. coli. Geometric mean gepotidacin urine AUC (0-
24) and AUC (0-τ) was slightly lower in Japanese participants compared to Western 
(Caucasian) participants.  
To investigate the possibility that the dosage and administration of gepotidacin (1500 mg 
orally BID for 5 days) specified in global phase III studies (Studies 204989 and 212390) 
may affect the dosage regimen in Japanese patients, a PK-PD study was conducted from 
the viewpoints of efficacy evaluation and safety evaluation. From the viewpoint of 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
43 
Clinical Study Protocol template V16 dated 24-Jun-2021 
efficacy evaluation, the overall probability of target attainment in Japanese subjects 
considering the percentage of actual MICs is as high as 99.9% for fAUC0-24hr/MIC = 
41.3 in urine and 96.1% for fAUC0-24hr/MIC = 275 in urine (related to resistance 
suppression), which is also expected to be effective in Japanese subjects. From the 
viewpoint of safety evaluation, the predicted plasma concentration after twice-daily 
administration of gepotidacin 1500 mg to Japanese subjects is below the concentration 
associated with mild transient adverse events (such as salivation, blurred vision, and 
slurred speech) in previous studies, and the predicted ∆∆∆ QTcF in the Japanese 
population is below the value observed in previous intravenous and oral studies in which 
clinically relevant QTc changes were reported. Therefore, it is considered safe in 
Japanese subjects. Based on the above, it is appropriate to apply the dosage and 
administration of gepotidacin (1500 mg orally BID for 5 days) used in global phase III 
studies (Studies 204989 and 212390) to the Japanese study (Study 214144). 
In conclusion, minimum urine levels of gepotidacin are anticipated to be in excess of the 
fAUC/MIC target necessary for both efficacy and resistance suppression for E. coli as 
determined from the in vitro PK/PD models. Given that the bladder is the primary site of 
infection in cystitis, the use of gepotidacin urine PK data, coupled with the robust in vivo 
efficacy demonstrated in the Phase IIa acute uncomplicated cystitis study and human 
simulated PK pyelonephritis model, is appropriate for selecting the gepotidacin 1500 mg 
BID oral dose for 5 days for study in the treatment of participants with acute 
uncomplicated cystitis.  
In addition, a PK evaluation (Study 209611) in healthy adult and adolescent participants 
has been completed (see the IB for further details). Overall, plasma Cmax values were 
27% higher in adolescents; however, the range of Cmax values were similar, and AUC(0-
∞) values were similar for adults and adolescents following a 1500-mg single 
gepotidacin dose. Following the first of two 3000 mg gepotidacin doses 6 hours apart, 
Cmax values were 29% higher in adolescents; however, the ranges of Cmax values were 
similar, and following the second dose for adults and adolescents Cmax values were 
similar. The AUC(0-τ) was approximately 35% higher in adolescents following both 
doses compared to adults. The total amount of gepotidacin excreted in urine was similar 
in adult and adolescent participants following a 1500-mg single gepotidacin dose. 
Following two 3000 mg gepotidacin doses given 6 hours apart, the total amount excreted 
was approximately 35% higher in adolescents compared to adults. The maximum dose of 
gepotidacin evaluated in adolescents was 3000 mg given as 2 doses 6 hours apart. Across 
the age groups, the safety-risk profile was similar. 
The oral nitrofurantoin dose in this study is 100 mg BID (total daily dose of 200 mg) for 
5 days. Nitrofurantoin is commonly available as 2 formulations (macrocrystals and a 
monohydrate) and the most common commercial products globally are nitrofurantoin 
monohydrate/macrocrystals (Macrobid) and nitrofurantoin macrocrystals (Macrodantin, 
Furandantin) [Gupta, 2011b]. Adequate clinical response and safety profiles have been 
reported with nitrofurantoin treatment in acute uncomplicated cystitis and similar PK, 
safety, and efficacy profiles were reported between the 2 formulations: 100 mg BID 
nitrofurantoin monohydrate/macrocrystals and 50 mg QID nitrofurantoin macrocrystals 
[Pelletier, 1992; Ten Doesschate, 2019; Wijma, 2020; Macrobid, 2020]. The previously 
recommended dosing of nitrofurantoin (macrocrystals) in Japan was 100 mg, QID (total 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
44 
Clinical Study Protocol template V16 dated 24-Jun-2021 
daily dose of 400 mg). The oral dose, duration, and formulation of nitrofurantoin 
(monohydrate/macrocrystals) in this study is within the prescribed recommendations 
globally, which is 100 mg BID for up to 7 days for adults and paediatric patients over 12 
years of age [Gupta, 2011b]. In this study, the monohydrate/macrocrystal nitrofurantoin 
formulation (Macrobid) is used, which is same formulation used in the global Phase III 
studies (Studies 204989 and 212390). The labeled 7 days dosing duration of 
nitrofurantoin was based on clinical registration studies from several decades ago. More 
recently, a 5-day dosing duration of nitrofurantoin was shown to be efficacious for the 
treatment of acute uncomplicated cystitis in women [Gupta, 2007] and a treatment 
duration of <7 days for nitrofurantoin is in alignment with current treatment guidelines 
[Gupta, 2011b; EAU, 2019]. 
4.4. End of Study Definition 
A participant is considered to have completed study treatment if she has taken all doses 
of the randomly assigned study treatment and completed the TOC Visit. The end of the 
study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if she has completed all periods 
of the study including Follow-up Visit. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Otherwise healthy Japanese participants are eligible to be included in the study only if all 
of the following criteria apply: 
Age 
1. The participant must be ≥12 years of age inclusive, at the time of signing the 
informed consent/assent and has a body weight ≥40 kg. 
Note: Although participants as young as 12 years may enrol in the study, study sites 
must follow their institutional ethics committee and enrollment will be contingent 
upon such approvals regarding the allowed lower age limit for clinical study 
participants. 
Type of Participant and Disease Characteristics 
2. The participant has 2 or more of the following clinical signs and symptoms of acute 
cystitis with onset <96 hours prior to study entry: dysuria, frequency, urgency, or 
lower abdominal pain (see Section 10.10). 
3. The participant has nitrite or pyuria (>15 WBC/HPF or the presence of 3+/large 
leukocyte esterase) from a pretreatment clean-catch midstream urine sample based 
on local laboratory procedures. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
45 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Sex and Contraceptive/Barrier Requirements 
4. The participant is female 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
• 
A female participant is eligible to participate if she is a woman of childbearing 
potential (WOCBP) who is not pregnant as confirmed by a high sensitivity urine 
pregnancy test at Baseline (Day 1) regardless of current or prior contraception use or 
abstinence, is not breastfeeding, or is not a WOCBP.  
Note:  Pregnancy testing requirements, contraceptive guidance, and WOCBP 
definitions are provided in Section 10.4 and requirements for pregnancy testing 
during and after study treatment are located in Section 8.2.5. 
• 
Additional requirements for pregnancy testing during and after study treatment are 
located in in section 8.2.5. 
• 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
5. The participant is capable of giving signed informed consent/assent as described in 
Section 10.1 which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF) /assent form and in this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. The participant resides in a nursing home or dependent care type facility. 
2. The participant has a body mass index ≥40.0 kg/m2 or a body mass index 
≥35.0 kg/m2 and is experiencing obesity-related health conditions such as 
uncontrolled high blood pressure or uncontrolled diabetes. 
3. The participant is immunocompromised or has altered immune defenses that may 
predispose the participant to a higher risk of treatment failure and/or complications 
(e.g., uncontrolled diabetes, renal transplant recipients, participants with clinically 
significant persistent granulocytopenia [absolute neutrophil count <1000/µL], and 
participants receiving immunosuppressive therapy, including corticosteroid therapy 
[>40 mg/day prednisolone or equivalent for >1 week, ≥20 mg/day prednisolone or 
equivalent for >2 weeks, or prednisolone or equivalent ≥10 mg/day for >6 weeks]). 
Participants with a known CD4 count of <200 cells/mm3 should not be enrolled. 
4. The participant has any of the following: 
• 
Medical condition that requires medication that may be impacted by inhibition 
of acetylcholinesterase, such as: 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
46 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
Poorly controlled asthma or chronic obstructive pulmonary disease at 
Baseline and, in the opinion of the investigator, not stable on current therapy 
• 
Acute severe pain, uncontrolled with conventional medical management 
• 
Active peptic ulcer disease 
• 
Parkinson disease 
• 
Myasthenia gravis 
• 
A history of seizure disorder requiring medications for control (this does not 
include a history of childhood febrile seizures) 
OR 
• 
Known acute porphyria 
• 
Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study treatment 
(e.g., ileostomy or malabsorption syndrome) 
5. The participant has a known glucose-6-phosphate dehydrogenase deficiency. 
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. 
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. 
8. The participant has acute uncomplicated cystitis that is known or suspected to be due 
to fungal, parasitic, or viral pathogens; or known or suspected to be due to 
Pseudomonas aeruginosa or Enterobacterales (other than E. coli) as the contributing 
pathogen. 
9. The participant has symptoms known or suspected to be caused by another disease 
process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, 
or chronic interstitial cystitis, that may interfere with the clinical efficacy 
assessments or preclude complete resolution of acute cystitis symptoms. 
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 who, in the opinion of the investigator, has an otherwise complicated 
UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptom onset 
≥96 hours before study entry, or a temperature ≥38°C, flank pain, chills, or any other 
manifestations suggestive of upper UTI. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
47 
Clinical Study Protocol template V16 dated 24-Jun-2021 
13. The participant has known anuria, oliguria, or significant impairment of renal 
function (creatinine clearance <60 mL/min or clinically significant elevated serum 
creatinine as determined by the investigator). 
14. The participant presents with vaginal discharge at Baseline (e.g., suspected sexually 
transmitted disease). 
15. The participant has congenital long QT syndrome or known prolongation of the 
corrected QT (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 
torsades de pointes (TdP) per the www.crediblemeds.org. “Known Risk of TdP” 
category at the time of her Baseline Visit, which cannot be safely discontinued from 
the Baseline Visit to the TOC Visit; or the participant is taking a strong cytochrome 
P450 enzyme 3A4 (CYP3A4) inhibitor. 
21. For any participant ≥12 to <18 years of age, the participant has an abnormal ECG 
reading at Baseline. 
22. The participant has a QTc >450 msec or a QTc >480 msec for participants with 
bundle branch block. 
Note: 
• 
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), or Fridericia’s (QTcF) formula, and/or another method. It is 
either machine read or manually overread. 
• 
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In 
other words, several different formulas cannot be used to calculate the QTc for 
an individual participant and then the lowest QTc value used to include or 
discontinue the participant from the trial. 
23. The participant has a documented or recent history of uncorrected hypokalemia 
within the past 3 months. 
24. The participant has a known alanine aminotransferase (ALT) value >2 × upper limit 
of normal (ULN). 
25. The participant has a known total bilirubin value >1.5 × ULN (isolated bilirubin >1.5 
× ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
26. The participant has cirrhosis or current unstable liver or biliary disease per 
investigator assessment defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
48 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Note: Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome, 
asymptomatic gallstones, and chronic stable hepatitis B or C [e.g., presence of 
hepatitis B surface antigen or positive hepatitis C antibody test result]) is acceptable 
if the participant otherwise meets entry criteria. 
27. The participant has a previous history of cholestatic jaundice/hepatic dysfunction 
associated with nitrofurantoin. 
Prior/Concomitant Therapy 
28. The participant has received treatment with other systemic antimicrobials or 
systemic antifungals within 1 week before study entry. 
29. The participant who are expected to be non-compliant with restrictions on 
medications or nondrug therapies prior to the study or during the study as detailed in 
Section 6.8.2. 
Prior/Concurrent Clinical Study Experience 
30. The participant has been previously enrolled in this study or has previously been 
treated with gepotidacin. 
31. The participant has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer. 
Diagnostic Assessments 
32. The participant has a positive human immunodeficiency virus (HIV) antibody test 
Other Exclusions 
33. Current drug or alcohol abuse or dependence, or history of drug or alcohol abuse or 
dependence within 12 months prior to randomisation 
34. The participant has a history of sensitivity to any of the study interventions, or 
components thereof, or drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates participation in the study. 
 
5.3. Lifestyle Considerations 
Participants must abstain from sexual activity from the Baseline Visit through the TOC 
Visit to prevent possible re-infection. 
5.3.1. 
Meals and Dietary Restrictions 
Study treatment should be taken after food consumption (a meal or a snack) and with 
water (see Section 6.1). 
5.4. Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical 
study is not subsequently randomized. A minimal set of screen failure information is 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
49 
Clinical Study Protocol template V16 dated 24-Jun-2021 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 
Participants who are screen failures are allowed to be rescreened once with the agreement 
of the Medical Monitor for the same infection episode or a subsequent infection episode 
and participate in the study if they meet all the inclusion and do not meet all the exclusion 
criteria. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. Study Intervention(s) Administered 
• 
All doses of study treatment should always be taken after food consumption and with 
water. Participants will receive oral study treatment (gepotidacin [2 tablets] + 
nitrofurantoin matching placebo [1 capsule] or nitrofurantoin [1 capsule] + 
gepotidacin matching placebo [2 tablets]) BID (approximately every 12 hours) for 5 
days. 
• 
The first oral dose will be administered at the study site during the Baseline Visit; 
participants will self-administer subsequent doses as outpatients thereafter, excluding 
the day of On-therapy Visit. 
• 
At the On-therapy Visit, participants will go to the study site before taking the 
morning dose, have the PK sample collection performed, and then take the morning 
dose, while aiming to keep the time of dosing as close as possible to 12 hours after 
the previous evening dose was taken. 
• 
At the On-therapy Visit, whenever it is possible, the participant will have the 
pregnancy test performed at the study site. If the visit coincides with the 8th dose, the 
participant will take their next dose of study treatment at the study site after negative 
pregnancy test results are confirmed. 
• 
Before the On-therapy Visit, if the requirement for the single pregnancy test to be 
done between dose 4 and dose 8 cannot be done at the study site due to availability of 
open clinic hours and the investigator considers the participant reliable to accurately 
perform the study-provided pregnancy test at home will be instructed to do so. If the 
pregnancy test is negative, those participants will be instructed to take their next dose 
of study treatment at home via text or by study site staff before going to the study site 
for their On-therapy Visit. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
50 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Note: The On-therapy Visit should be scheduled to support completion of the 
postdose PK sample collection and ECG within the protocol-defined window. Also, 
in WOCBP, the high sensitivity pregnancy test must be performed and show negative 
results at the latest before Dose 8 of study treatment is taken. 
 
Table 2 
Study Intervention(s) Administered 
Intervention Label 
Gepotidacin 
Placebo 
(Matched to 
Nitrofurantoin) 
Nitrofurantoin 
Placebo 
(Matched to 
Gepotidacin) 
Intervention on 
Label 
Gepotidacin 
(GSK2140944) 
Placebo 
(Matched to 
Nitrofurantoin) 
Nitrofurantoin 
Placebo 
(Matched to 
Gepotidacin) 
Intervention 
Description 
Tablet for BID 
dosing 
Capsule for BID 
dosing 
Capsule for BID 
dosing 
Tablet for BID 
dosing 
Type  
Drug 
Drug 
Drug 
Drug 
Dose Formulation  
Tablets containing 
gepotidacin and 
inactive formulation 
excipients 
Over-encapsulated 
unit-dose 
nitrofurantoin 
placebo to match 
capsule 
Over-encapsulated 
capsules containing 
nitrofurantoin (25 mg 
nitrofurantoin 
macrocrystals and 
75 mg nitrofurantoin 
monohydrate) and 
inactive formulation 
excipients 
Unit-dose 
gepotidacin 
placebo-to-match 
tablet 
Unit Dose 
Strength(s)  
2 x 750-mg tablets 
Not applicable 
1 x 100-mg capsule 
Not applicable 
Dosage Level(s) 
1500 mg, BID 
BID 
100 mg, BID 
BID 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo matched to 
Nitrofurantoin for 
blinding 
Active reference 
Placebo matched to 
Gepotidacin for 
blinding 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Dosing 
Instructions 
Administer BID for 5 
days: 
1500 mg – 2 tablets  
Administer BID for 5 
days: 
1 capsule  
Administer BID for 5 
days: 
100 mg – 1 capsule  
Administer BID for 5 
days: 
2 tablets  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
51 
Clinical Study Protocol template V16 dated 24-Jun-2021 
(3000 mg total daily 
dose) 
Each dose should 
be taken after food 
consumption and 
with water. 
Each dose should 
be taken after food 
consumption and 
with water. 
(200 mg total daily 
dose) 
Each dose should 
be taken after food 
consumption and 
with water. 
Each dose should 
be taken after food 
consumption and 
with water. 
Packaging and 
Labeling 
 
Gepotidacin tablets 
will be provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Placebo-to-match 
nitrofurantoin 
capsules will be 
over-encapsulated 
and provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Nitrofurantoin 
capsules will be 
over-encapsulated 
and provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
Placebo-to-match 
gepotidacin tablets 
will be provided in 
bottles. Each bottle 
will be labeled as 
required per country 
requirement. 
 
Table 3 
Study Arm(s) 
Arm Title 
Gepotidacin 
Nitrofurantoin 
Arm Type 
Experimental 
Active reference 
Arm Description 
Participants will receive Gepotidacin 
1500 mg (with placebo matched to 
Nitrofurantoin) BID for 5 days 
Participants will receive Nitrofurantoin 
100 mg (with placebo matched to 
Gepotidacin) BID for 5 days 
Associated Intervention 
Labels 
Gepotidacin tablets and Placebo-to-
match nitrofurantoin capsules will be 
provided in bottles. Each bottle will be 
labeled as required per country 
requirement. 
Nitrofurantoin capsules and Placebo-to-
match gepotidacin tablets will be 
provided in bottles. Each bottle will be 
labeled as required per country 
requirement. 
 
6.2. Preparation, Handling, Storage and Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and 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 or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
52 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK. 
6.3. Measures to Minimize Bias: Randomization and Blinding 
Participants will be stratified by age category (≤50 years, or >50 years) and acute 
uncomplicated cystitis recurrence (nonrecurrent infection or recurrent infection, defined 
as a confirmed infection [not including the current infection in the calculation] with at 
least 1 prior episode within the past 3 months, at least 2 prior episodes within the past 6 
months, or at least 3 prior episodes within the past 12 months before study entry). 
Participants will be centrally randomized in a 3:1 ratio to either gepotidacin + matching 
nitrofurantoin placebo or nitrofurantoin + matching gepotidacin placebo. All participants 
will be centrally randomized using interactive response technology (IRT). Before the 
study is initiated, information and directions for the IRT will be provided to each study 
site. 
Study treatment will be dispensed at the study visits summarized in Section 1.3. 
Returned study treatment should not be re-dispensed to other participants. 
This is a double-blind, double-dummy study. The study treatment taken during the study 
will be double-blind. Neither the participant nor study personnel (i.e., investigators, GSK) 
will know which study treatment the participant is receiving. In order to maintain study 
treatment blinding, participants will receive, in addition to their randomized active 
treatment (gepotidacin or nitrofurantoin), a matching placebo form of the active treatment 
to which they were not assigned. The matching placebos will look identical to the active 
form.  
Designated independent representative(s), that is a few selected GSK CP-M&S, SDTM 
Unblinding Programmer, Biostatistics and appropriate service provider (when it is 
possible) members, may be unblinded for performing population PK and PKPD dataset 
preparation and draft PK and PKPD model development using scrambled (random 
reassignment of subject identification numbers) PK and PKPD unblinded datasets, 
including baseline demographic characteristics.   
The IRT will be programmed with blind-breaking instructions. In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact GSK prior to 
unblinding a participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is unblinded GSK 
must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and electronic case 
report form (eCRF), as applicable. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
53 
Clinical Study Protocol template V16 dated 24-Jun-2021 
A participant may continue in the study if that participant’s treatment is unblinded 
provided that there are no safety concerns for the participant per the investigator’s 
judgement. 
The GSK SRT, which will monitor safety data in stream, will remain blinded to 
participant treatment assignment throughout the study (see Section 10.3). A Microbiology 
Review Team will monitor blinded pathogen identification and susceptibility data in 
stream as well as the number of participants eligible for the micro ITT Population. 
Blinded monitoring of pathogens will be conducted, to determine whether end-of-study 
targets are likely to be achieved.  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
6.4. Study Intervention Compliance 
• 
When participants are dosed at the site during the Baseline and On-therapy Visits, 
they will take their study intervention when directed by the investigator or designee, 
under medical supervision. The date and time of each dose administered in 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 intervention. 
• 
When participants self-administer study intervention(s) at home, compliance with 
gepotidacin, nitrofurantoin placebo, nitrofurantoin, and gepotidacin placebo will be 
assessed by direct questioning during the site visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be 
recorded. 
• 
A record of the quantity of gepotidacin and gepotidacin placebo tablets and 
nitrofurantoin and nitrofurantoin placebo capsules dispensed to and returned by each 
participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays will also be recorded. 
6.5. Dose Modification 
The study design does not allow for dose modifications. 
6.6. 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 (i.e., after the Follow-up Visit). Participants experiencing signs and 
symptoms suggestive of infection recurrence or relapse at the Follow-up Visit will be 
assessed and treated per the investigator’s judgement. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
54 
Clinical Study Protocol template V16 dated 24-Jun-2021 
6.7. Treatment of Overdose 
For this study, any dose of Gepotidacin or Nitrofurantoin greater than 3000 mg or 200 mg 
within a 24-hour time period, respectively, will be considered an overdose, as further 
detailed in the SRM. 
There is no specific antidote for overdose with a bacterial topoisomerase inhibitor. In the 
event of a suspected overdose, it is recommended that the appropriate supportive clinical 
care should be instituted, as dictated by the participant’s clinical status. 
Occasional incidents of acute overdosage of nitrofurantoin have not resulted in any 
specific symptoms other than vomiting (refer to the package insert). Induction of emesis 
is recommended. There is no specific antidote, but a high fluid intake should be 
maintained to promote urinary excretion of the drug. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 72 hours). 
3. Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study intervention if requested by the medical monitor (determined on a 
case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions will be made by the investigator in consultation 
with the Medical Monitor based on the clinical evaluation of the participant. 
6.8. 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 antimicrobial use within 6 months prior to the Baseline Visit or during the 
study must be recorded in the eCRF. The concomitant therapy name must be recorded in 
the eCRF along with the following: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
55 
Clinical Study Protocol template V16 dated 24-Jun-2021 
6.8.1. 
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, fradiomycin or polymyxin) and topical, 
nonsystemic antifungals (e.g., topical clotrimazole, tolnaftate, or ketoconazole) is allowed 
throughout the study. 
Acetaminophen use is permitted throughout the study as it does not mask symptoms of 
the disease under study. Low-dose aspirin (≤100 mg/day) is permitted for the prevention 
of cardiovascular (CV) disease events.  
6.8.2. 
Prohibited Medications and Nondrug Therapies 
At the time of enrollment and/or during the study from the Baseline Visit through the 
Follow-up Visit, the participant is prohibited from use of the following medications. 
• 
Treatment with other systemic antimicrobials (e.g., oral ciprofloxacin, 
amoxicillin/clavulanate, cephalexin, or doxycycline) within 1 week before study 
entry, unless other systemic antimicrobials are needed as additional therapy for the 
infection under study (acute uncomplicated cystitis), including recurrence of the 
infection or new infection. 
At the time of enrollment and/or during the study from the Baseline Visit through the 
TOC Visit, the participant is prohibited from use of the following medications and 
nondrug therapies: 
• 
An investigational product within 30 days or 5 half-lives, whichever is longer, of the 
Baseline Visit. 
• 
Treatment with systemic antifungals (e.g., oral fluconazole, itraconazole, or 
terbinafine) within 1 week before study entry.  
• 
Immunosuppressive therapy, including corticosteroid therapy (>40 mg/day 
prednisolone or equivalent for >1 week, ≥20 mg/day prednisolone or equivalent for 
>2 weeks, or prednisolone or equivalent ≥10 mg/day for >6 weeks). 
• 
QT-prolonging drugs or drugs with known TdP risk, per the www.crediblemeds.org 
“Known Risk of TdP” category, at the time of their Baseline Visit, which cannot be 
safely discontinued from the Baseline Visit to the TOC Visit. Details regarding 
website access are provided in the SRM. Of note, ondansetron is not allowed from 
the Baseline Visit to the TOC Visit due to its known TdP risk.  
Note: Crediblemeds.org categorizes drugs into 4 categories. The only category for 
exclusion in this study is the “Known Risk of TdP” category; participants taking 
drugs that meet criteria of other categories are NOT excluded from participation. 
• 
Strong CYP3A4 inhibitors. 
• 
St John’s wort or other strong CYP3A4 inducers are not permitted from 14 days 
before study entry through the TOC Visit. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
56 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
Prescription, nonprescription, or supplements that may impact UTI clinical or 
microbiological efficacy outcomes including, but not limited to, Uva ursi, D-
mannose, cranberry tablets, nonsteroidal anti-inflammatory drugs including 
ibuprofen and cyclooxygenase-2 inhibitors, and uricosuric drugs (e.g., probenecid). 
Aspirin (doses >100 mg/day) is not permitted. 
In addition, antacid preparations containing magnesium trisilicate are prohibited from the 
start of study treatment at the Baseline Visit throughout the completion of the dosing 
period (i.e., until all 10 doses of study treatment have been received). 
Due to the gepotidacin’s property of acetylcholinesterase inhibition, the concomitant use 
of succinylcholine or nondepolarizing paralytic agents is also prohibited. Caution should 
be used in participants who have a condition requiring medication that may exacerbate 
the inhibition of acetylcholinesterase, or neuromuscular blocking agents. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1. 
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety and efficacy. See the SoA (Section 1.3) for 
data to be collected at the time of discontinuation of study intervention and follow-up and 
for any further evaluations that need to be completed. 
Participants may voluntarily discontinue study treatment at any time. The investigator 
may also, at his or her discretion, discontinue the participant from study treatment at any 
time and initiate appropriate alternative therapy. 
Reasons for study treatment discontinuation may include the following: 
• 
Adverse event 
• 
Protocol deviation 
• 
Termination of the study by GSK 
• 
Investigator discretion 
• 
Lack of efficacy 
Note: Pathogen identification or in vitro resistance of recovered uropathogens is not 
a reason for study treatment discontinuation. 
The reason for study treatment discontinuation will be recorded in the eCRF. Participants 
who discontinue study treatment for the reasons above will not be considered withdrawn 
from the study and should attend all subsequent study visits (see Section 1.3). 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
57 
Clinical Study Protocol template V16 dated 24-Jun-2021 
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 Algorithm A or Algorithm B 
or  
• 
in the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, if the investigator believes that it is in the best interest of the 
participant.  
 
Algorithm A: Phase 3 Liver Chemistry Stopping Criteria and Increased Monitoring 
Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal 
Refer to Section 10.6 for required Liver Safety Actions and Follow up Assessments.  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
58 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Algorithm B：Phase 3 Liver Chemistry Increased Monitoring Algorithm with 
Continued Study Intervention for Participants with ALT ³3xULN but <8xULN 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal, Tbili = Total bilirubin. 
Refer to Section 10.6 for required Liver Safety Actions and Follow up Assessments. 
7.1.2. 
QTc Stopping Criteria 
Adult Participant 
• 
If a clinically significant finding is identified (including, but not limited to changes 
from baseline in QT interval corrected using Bazett’s formula [QTcB] or Fridericia’s 
formula [QTcF]) after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study 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 should be reported as an AE. 
• 
A participant who meets the bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study intervention: 
• 
QTc > 500 msec OR Uncorrected QT > 600 msec 
• 
Change from baseline of QTc > 60 msec 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
59 
Clinical Study Protocol template V16 dated 24-Jun-2021 
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below: 
Baseline QTc with Bundle Branch 
Block 
Discontinuation QTc with Bundle 
Branch Block 
< 450 msec 
> 500 msec 
450 – 480 msec 
≥ 530 msec 
 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled. (Note: Ideally, all 
ECGs for a participant should be performed with the same ECG machine.) 
• 
For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well. 
• 
Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Other nonprotocol-specified ECGs are an 
exception. 
• 
The QTc should be based on the average of triplicate ECG readings obtained over a 
brief (e.g., 5- to 10-minute) recording period. 
Participant ≥12 to <18 years of age 
For any participant ≥12 to <18 years of age, if the participant has an abnormal ECG 
reading during the study treatment, the investigator or qualified designee will determine 
if the participant can continue in the study and if any change in participant management 
is needed. 
7.1.3. 
Renal Stopping and Monitoring Criteria 
• 
If baseline creatinine clearance (CrCl) <45 ml/min, stop study treatment immediately 
and ensure prompt clinical assessment including repeat labs 
• 
If baseline CrCl 45 to < 60 ml/min, advise that the On Therapy visit is expedited so 
that participants undergo prompt clinical assessment. Evaluation should include on 
therapy labs and an assessment of clinical response and adverse effects to treatment 
to weigh the potential benefits and concerns with continuing or discontinuing 
treatment. If the patient is clinically well, study treatment can be continued or if there 
are concerns, study treatment can be discontinued at investigator’s discretion when 
this is felt to be in the best interest of the participant. The following factors should be 
considered: 
• 
All patients to remain in the study for safety follow-up 
• 
All patients to have labs including CrCl repeated at the TOC visit as per study 
protocol 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
60 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
7.1.4. 
Rechallenge 
7.1.4.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study are not allowed. 
7.1.5. 
Gastrointestinal Evaluation Criteria 
If a participant meets the criteria in 10.7, Clostridioides difficile toxin testing should be 
conducted and the specific eCRF page completed, then reported as AE if positive for the 
testing. Clostridioides difficile infection or colitis is considered an AE of special interest 
(Section 8.3.7). 
7.2. Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• 
Reasons for study withdrawal include: 
• 
Participant lost to follow-up 
• 
Participant withdrew consent 
• 
Termination of the study by GSK 
• 
Investigator discretion 
• 
At the time of discontinuing from the study, if possible, an early withdrawal visit 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
The reason for participant withdrawal will be recorded in the eCRF. Participants who are 
withdrawn from the study should return to the study site and have the microbiological 
and clinical outcomes assessed at the time of withdrawal (see the SoA in Section 1.3), if 
data permit, and return all unused study treatment. Data from these participants will be 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
61 
Clinical Study Protocol template V16 dated 24-Jun-2021 
considered evaluable up to the point at which they are withdrawn, using the same criteria 
for evaluability as for participants who complete the study. 
7.3. Lost to Follow Up 
A participant will be considered lost to follow-up if she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The 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, she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
10.1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the timeframe defined in the SoA. 
• 
Prescreening activities may be conducted, including a prescreening informed consent 
and urine testing, as further detailed in the SRM. The required baseline urine 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
62 
Clinical Study Protocol template V16 dated 24-Jun-2021 
specimen may be collected as part of an optional prescreening process, if not already 
part of standard of care, and is further detailed in the SRM. This specimen can be 
used for the required baseline procedures of the diagnosis of presumptive acute 
uncomplicated cystitis and pregnancy testing. 
• 
Laboratory results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 
• 
The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
200 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
• 
Participants may return to the study site at any time due to AEs or if they are 
experiencing new or continuing signs and symptoms of acute cystitis. Participants 
will be assessed and treated per the investigator’s judgement. If a participant is 
switched to a different antimicrobial before or during the TOC Visit, all TOC 
procedures should be completed before the other antimicrobial is started. 
• 
Each treatment day will be assessed over 24 hours starting with the first dose of 
study treatment, as further detailed in the SRM. 
The study will comprise the following 4 planned study visits: 
Note: For all study visits, to minimize the amount of time that participants spend at 
the clinic, eConsent may be utilized and remote collection of study-related data may 
be obtained as described in the SRM. Thus, some visit data may be collected through a 
combination of telemedicine and on-site visits. Collection of information via 
telemedicine will be performed only where local regulations permit. 
• 
Baseline (Day 1) Visit: The Baseline Visit will be performed before dosing on Day 
1. Assessments will be performed as shown in the SoA (Section 1.3), including the 
following: 
• 
Pretreatment baseline specimens for microbiological testing will be collected, as 
described in Section 8.1.2 Clinical signs and symptoms of acute cystitis will be 
recorded, as described in Section 8.1.3.1 and 10.10. 
 
. 
• 
Following completion of all pretreatment assessments, eligible participants will 
be randomly assigned to a study treatment, as described in Section 6.3. 
• 
The first dose of randomly assigned oral study treatment will be administered at 
the study site. Participants will remain at the study site approximately 2 hours 
(1.5 to 4 hours) after dosing, during which time all Day 1 posttreatment 
assessments will be performed (i.e., triplicate ECG and postdose plasma and 
pooled urine PK sample collection), as shown in Section 1.3. Any AEs or 
clinically significant changes should be followed accordingly. Subsequent to 
administration of the first dose at the study site, participants will self-administer 
doses as outpatients thereafter, beginning with the second dose, excluding the 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
63 
Clinical Study Protocol template V16 dated 24-Jun-2021 
day of On-therapy Visit. (Note: Each dose should be taken after food 
consumption and with water.) 
• 
The On-therapy, TOC, and Follow-up Visits should be scheduled before the 
participant leaves the study site on Day 1 (as per the Schedule of Activities 
Table in Section 1.3); the planned return day/time should be at the convenience 
of the participant and also the availability of the study site staff. 
• 
On-therapy (Day 2 to 4) Visit: Participants will be instructed to return to the study 
site 1 to 3 days following study treatment administration at Baseline in order to 
complete the On-therapy Visit. Assessments will be performed as shown in the SoA 
(Section 1.3), including the following: 
• 
The On-therapy Visit will be preceded by a documented reminder contact from 
the study site to the participant 24 ± 4 hours before the scheduled appointment 
time per the method (e.g., text message, telephone call, e-mail) confirmed with 
the study site staff prior to departing the study site on Day 1. 
• 
At the On-therapy Visit should be scheduled to support completion of the 
predose plasma & spot urine and postdose plasma & pooled urine PK samples 
collection, if at all possible: 
• 
Participants will go to the study site before taking the morning dose, have 
the PK sample collection performed, and then take the morning dose, while 
aiming to keep the time of dosing as close as possible to 12 hours after the 
previous evening dose was taken. 
• 
Participants will remain at the study site until approximately 2 hours (1.5 to 
4 hours) after dosing, during which time all Day 1 posttreatment 
assessments will be performed (i.e., triplicate ECG and postdose PK sample 
collection), as shown in Section 1.3. 
• 
At the On-therapy Visit, whenever it is possible, the participant will have the 
pregnancy test performed at the study site. If the visit coincides with the 8th 
dose, the participant will take their next dose of study treatment at the study site 
after negative pregnancy test results are confirmed. 
• 
Before the On-therapy Visit, if the requirement for the single pregnancy test to 
be done between dose 4 and dose 8 cannot be done at the study site due to 
availability of open clinic hours and the investigator considers the participant 
reliable to accurately perform the study-provided pregnancy test at home will be 
instructed to do so. If the pregnancy test is negative, those participants will be 
instructed to take their next dose of study treatment at home via text or by study 
site staff before going to the study site for their On-therapy Visit. 
Note: The On-therapy Visit should be scheduled to support completion of the 
postdose PK sample collection and ECG within the protocol-defined window. 
Also, in WOCBP, the high sensitivity pregnancy test must be performed and 
show negative results at the latest before Dose 8 of study treatment is taken. 
• 
Specimens for microbiological testing will be collected, as described in Section 
8.1. Clinical signs and symptoms of acute cystitis will be recorded, as described 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
64 
Clinical Study Protocol template V16 dated 24-Jun-2021 
in Section 8.1.3.1 and 10.10. 
 
 
• 
Pregnancy testing, as required, after Dose 4 and before Dose 8. Refer to Section 
8.2.5 for details. 
• 
TOC (Day 10 to 13) Visit: Participants will be instructed to return to the study site 5 
to 8 days after completion of study treatment in order to complete the TOC Visit. 
Assessments will be performed as shown in the SoA (Section 1.3), including the 
following: 
• 
The TOC Visit will be preceded by a documented reminder contact from the 
study site to the participant 24 ± 4 hours before the scheduled appointment time 
per the method (e.g., text message, telephone call, e-mail) confirmed with the 
study site staff prior to departing the study site on Day 1. 
• 
Specimens for microbiological testing will be collected, as described in Section 
8.1. Clinical signs and symptoms of acute cystitis will be recorded, as described 
in Section 8.1.3.1 and 10.10. Investigator assessment of clinical response will be 
documented per the definitions described in Section 8.1.3.2and 10.11. 
 
 
• 
Follow-up (Day 28±3) Visit: Participants will be instructed to return to the study site 
on Day 28 (±3) in order to complete the Follow-up Visit. Assessments will be 
performed as shown in Section 1.3, including the following: 
• 
The Follow-up Visit will be preceded by a documented reminder contact from 
the study site to the participant 24 ±4 hours before the scheduled appointment 
time per the method (e.g., text message, telephone call, e-mail) confirmed with 
the study site staff prior to departing the study site on Day 1. 
• 
Specimens for microbiological testing will be collected, as described in Section 
8.1. Clinical signs and symptoms of acute cystitis will be recorded, as described 
in Section 8.1.3.1 and 10.10. Investigator assessment of clinical response will be 
documented per the definitions described in Section 8.1.3.2 and 10.11.
 
 
• 
Participants experiencing signs and symptoms suggestive of infection recurrence 
or relapse will be assessed and treated per the investigator’s judgement. 
8.1. Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1. 
Therapeutic Response Evaluation 
Therapeutic response (success/failure) is a measure of the overall efficacy response. A 
therapeutic success refers to participants who have been deemed both a “microbiological 
success” (see Section 8.1.2.1) and a “clinical success” (see Section 8.1.3.1). All other 
combinations (other than clinical success + microbiological success) will be deemed 
failures for therapeutic response. 
CCI
CCI
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
65 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Therapeutic response will be determined by statistical programming for the TOC and 
Follow-up Visits. 
Therapeutic response at TOC is the primary efficacy endpoint. 
8.1.2. 
Bacteriology Samples 
At the Baseline Visit, a pretreatment, clean-catch midstream urine sample must be 
obtained from all randomized participants for Gram stain, quantitative bacteriological 
culture, and in vitro antimicrobial susceptibility testing at a designated central 
laboratory(ies). For inclusion in the micro-ITT Population, a baseline qualifying bacterial 
uropathogen is required as defined in Section 10.8; for inclusion in the micro-ITT NTF-S 
Population, the baseline qualifying uropathogen must also be susceptible to 
nitrofurantoin. At the On-therapy, TOC, and Follow-up Visits, a clean-catch midstream 
urine sample will be obtained and sent to a designated central laboratory(ies) for Gram 
stain, quantitative bacteriological culture, and in vitro antimicrobial susceptibility testing. 
Identification and susceptibility testing of isolates recovered from urine specimens at all 
visits will also be conducted at a designated central laboratory(ies). Additional tests, as 
needed, to further characterize recovered isolates will also be performed by a designated 
central laboratory(ies). Instructions for sample collection, processing, and shipment are 
provided in the SRM and the laboratory manual. The study site should follow the 
Microbiology Procedures section of the laboratory manual to minimize potential 
contamination of the specimens. 
8.1.2.1. 
Microbiological Outcome and Response 
Only those participants who have a qualifying bacterial uropathogen (defined in Section 
10.8) identified at Baseline will be evaluated for microbiological outcome and response 
by baseline qualifying uropathogen for the primary efficacy endpoint. The 
microbiological outcome and response to study treatment will be determined 
programmatically for each participant/uropathogen prior to breaking of the study blind. 
The microbiological outcome by baseline qualifying uropathogen is determined by 
comparing the baseline culture results to the culture results at each subsequent visit (see 
Table 4, Table 5, and Table 6 for baseline qualifying uropathogen outcomes). The 
corresponding microbiological response (success or failure) “by uropathogen” is then 
assigned, as shown in Table 5 and Table 6. Participant-level microbiological response is a 
measure of the combined “by uropathogen” response(s). Participant-level microbiological 
success refers to participants who have been deemed a “microbiological success” for all 
of their “by uropathogen” microbiological responses. All other combinations (other than 
all “microbiological successes”) are deemed failures for participant-level microbiological 
response. The participant-level microbiological outcome and response definitions are 
provided in Table 7. 
Microbiological outcome criteria for new qualifying uropathogens (i.e., uropathogens not 
identified at Baseline) are defined by visit in  
Table 8, Table 9, and Table 10. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
66 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 4 
Microbiological Outcome by Baseline Qualifying Uropathogen at the 
On-Therapy Visit 
Defining Criteria 
Outcome 
A quantitative urine culture taken at the 
On-therapy Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline is 
reduced to <103 CFU/mL, without the 
participant receiving other systemic 
antimicrobials before the On-therapy Visit 
Microbiological eradication 
A quantitative urine culture taken at the 
On-therapy Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, without the participant 
receiving other systemic antimicrobials before 
the On-therapy Visit 
Microbiological persistence 
The On-therapy urine culture result is missing, 
or  
The participant received other systemic 
antimicrobials before the Ontherapy Visit 
Unable to determine 
CFU=colony-forming units. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
67 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 5 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Test-of-Cure Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit. 
A quantitative urine culture taken at the TOC 
Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline 
to <103 CFU/mL, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit 
Microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to persist or unable to 
determine at the On-therapy Visit, grows 
≥103 CFU/mL, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit  
Microbiological 
persistence 
Microbiological failure 
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to be eradicated at 
the On-therapy Visit, grows ≥103 CFU/mL, 
without the participant receiving other 
systemic antimicrobials before the TOC Visit 
Microbiological 
recurrence 
Microbiological failure 
The TOC urine culture result is missing, or 
The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to determine 
Microbiological failure 
CFU=colony-forming units; TOC=Test-of-Cure. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
68 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 6 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Follow-Up Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit. 
A quantitative urine culture taken at the 
Follow-up Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline to 
<103 CFU/mL, following microbiological 
eradication at the TOC Visit, without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Sustained 
microbiological 
eradication 
Microbiological 
success 
A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, following microbiological 
eradication at the TOC Visit, without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Microbiological 
recurrence 
Microbiological 
failure 
A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL, and also did not achieve 
an outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other 
systemic antimicrobials before the Follow-up 
Visit 
Microbiological 
persistence 
Microbiological 
failure 
A quantitative urine culture taken at the 
Follow-up Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline to 
<103 CFU/mL, and also did not achieve an 
outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other 
systemic antimicrobials before the Follow-up 
Visit 
Delayed  
microbiological  
eradication 
Microbiological 
failure 
The Follow-up urine culture result is missing, or 
The participant received other systemic 
antimicrobials before the Follow-up Visit 
Unable to determine 
Microbiological 
failure 
CFU=colony-forming units; TOC=Test-of-Cure. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
69 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 7 
Participant-Level Microbiological Outcome and Response 
Definitions per Study Visit 
Defining Criteria at the On-Therapy Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of eradication at On-therapy 
Microbiological 
eradication 
NA 
At least one qualifying baseline uropathogen has an 
outcome of persistence at On-therapy 
Microbiological 
persistence 
NA 
All qualifying baseline uropathogen outcomes are unable to 
determine at On-therapy  
Unable to determine 
NA 
 
Defining Criteria at the TOC Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of eradication at TOC 
Microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an 
outcome of persistence at TOC 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of recurrence and none have an outcome of 
persistence at TOC 
Microbiological 
recurrence 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at TOC 
Unable to determine 
Microbiological 
failure 
 
Defining Criteria at the Follow-up Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological 
outcome of sustained eradication at Follow-up 
Sustained 
microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an 
outcome of recurrence and none have an outcome of 
persistence at Follow-up 
Microbiological 
recurrence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of persistence at Follow-up 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an 
outcome of delayed eradication and none have an outcome 
of persistence or recurrence at Follow-up 
Delayed 
microbiological 
eradication 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at Follow-up 
Unable to determine 
Microbiological 
failure 
NA=Not applicable; TOC=Test-of-Cure. 
 
Table 8 
Microbiological Outcome by New Qualifying Uropathogen at the 
On-Therapy Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the On-therapy 
Visit 
New uropathogen 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
70 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 9 
Microbiological Outcome by New Qualifying Uropathogen at the 
Test-of-Cure Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Test-of-Cure 
Visit in a participant who did not achieve a 
clinical outcome of clinical resolution at the 
Test-of-Cure Visit 
New infection 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Test-of-Cure 
Visit in a participant who did achieve a clinical 
outcome of clinical resolution at the 
Test-of-Cure Visit 
Colonization 
 
Table 10 
Microbiological Outcome by New Qualifying Uropathogen at the 
Follow-up Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who did not achieve a clinical 
resolution at the Follow-up Visit 
New infection 
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who did achieve a clinical 
resolution at the Follow-up Visit 
Colonization 
 
8.1.3. 
Clinical Evaluation 
8.1.3.1. 
Clinical Signs and Symptom Scores, Clinical Outcomes, and Clinical 
Response 
Clinical signs and symptoms of acute cystitis will be recorded based on participant 
interview per the SoA (Section 1.3) using the scoring system and instructions in 10.10. At 
Baseline, the participant must present with at least 2 signs and symptoms and have a total 
cumulative symptom score ≥2. At TOC, success is defined as normal presentation of 
signs and symptoms with a total cumulative symptom score of zero and no new signs and 
symptoms of the infection under study. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
71 
Clinical Study Protocol template V16 dated 24-Jun-2021 
A study physician or otherwise appropriately medically trained staff will determine the 
individual clinical signs and symptoms scores for acute cystitis (10.10) at the On-therapy, 
TOC, and Follow up Visits. The same scorer will be used at all assessment time points 
for each participant, on all occasions, whenever possible. The score will be used to 
programmatically determine the clinical outcome at the On-therapy Visit (Table 11) and 
the clinical outcome and response (success or failure) at the TOC Visit (Table 12) and the 
Follow-up Visit (Table 13). 
Table 11 
Clinical Outcome at the On-Therapy Visit 
Defining Criteria 
Outcomea 
Resolution of signs and symptoms of acute 
cystitis present at Baseline (and no new signs 
and symptoms), without the participant 
receiving other systemic antimicrobials before 
the On-therapy Visit 
Clinical resolution 
Improvement in total symptom scores from 
Baseline, but not complete resolution, without 
the participant receiving other systemic 
antimicrobials before the On-therapy Visit 
Clinical improvement 
Worsening or no change in total symptom 
scores from Baseline or the participant 
received other systemic antimicrobials for the 
current infection prior to or on the date of the 
On-therapy Visit 
Clinical worsening 
The Baseline score is missing, or 
The On-therapy assessment is missing, or 
The participant received other systemic 
antimicrobials not for the current infection prior 
to the assessment (unless clinical worsening 
outcome criteria were met) 
Unable to determine 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (10.10), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
72 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 12 
Clinical Outcome and Response at the Test-of-Cure Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of 
acute cystitis present at Baseline (and no 
new signs or symptoms), without the 
participant receiving other systemic 
antimicrobials before the TOC Visit 
Clinical resolution 
Clinical success 
Improvement in total symptom scores 
from Baseline, but not complete 
resolution, without the participant 
receiving other systemic antimicrobials 
before the TOC Visit 
Clinical improvement  
Clinical failure 
Worsening or no change in total symptom 
scores from Baseline or the participant 
received other systemic antimicrobials for 
the current infection before or on the date 
of the TOC Visit 
Clinical worsening 
Clinical failure 
The Baseline score is missing, or 
The TOC assessment is missing, or 
The participant received other systemic 
antimicrobials not for the current infection 
prior to the assessment (unless clinical 
worsening criteria were met) 
Unable to determine 
Clinical failure 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (10.10), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
73 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Table 13 
Clinical Outcome and Response at the Follow-up Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of 
acute cystitis demonstrated at the TOC 
Visit persist at the Follow-up Visit (and no 
new signs and symptoms), without the 
participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Sustained clinical resolution 
Clinical success 
Resolution of signs and symptoms of 
acute cystitis present at Baseline (and no 
new signs or symptoms), after clinical 
failure at TOC, without the participant 
receiving other systemic antimicrobials 
before the Follow-up Visit 
Delayed clinical resolution 
Clinical failure 
Improvement in total symptom scores 
from Baseline, but not complete 
resolution, without the participant 
receiving other systemic antimicrobials 
before the Follow-up Visit 
Clinical improvement 
Clinical failure 
Worsening or no change in total symptom 
scores at Follow-up compared to Baseline 
after clinical failure at TOC, or the 
participant received other systemic 
antimicrobials for the current infection 
before or on the date of the Follow-up 
Visit 
Clinical worsening 
Clinical failure 
Signs and symptoms of acute cystitis 
reoccur at the Follow-up Visit after clinical 
success at TOC 
Clinical recurrence 
Clinical failure 
1) The Baseline score is missing, or 
2) The Follow-up assessment is missing, 
or 
3) The participant received other 
systemic antimicrobials not for the 
current infection prior to the 
assessment (unless the clinical 
worsening or recurrence outcome 
criteria were met) 
Unable to determine 
Clinical failure 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (10.10), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
74 
Clinical Study Protocol template V16 dated 24-Jun-2021 
8.1.3.2. 
Investigator Assessment of Clinical Response 
The clinical signs and symptoms score will be determined for the primary endpoint, as 
described in Section 8.1.3.1 and 10.10. In addition, for secondary and exploratory 
purposes, a separate assessment of clinical response will be performed at the TOC and 
Follow-up Visits, or at the time of early withdrawal (Section 1.3). The investigator will 
assess the clinical response (clinical success, clinical failure, or indeterminate) for each 
participant based on the definitions in Section 10.11 and will document the response and 
reason(s) for clinical failure or indeterminate response, if applicable, in the eCRF. This 
assessment should be completed after the clinical signs and symptoms score is 
determined by the same study physician or otherwise appropriately medically trained 
staff who performed the clinical scoring assessment (Section 8.1.3.1 and 10.10). 
8.2. Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
• 
A physical examination will be performed at the timepoints indicated in the SoA 
(Section 1.3) as follows: 
• 
At Baseline, the examination will include assessments of the respiratory, CV, 
abdominal, gastrointestinal, neurological, and urogenital systems. Height and 
weight will also be measured and recorded at the Baseline Visit (before dosing). 
• 
At the TOC Visits, the physical examination may be symptom directed and is 
only required if indicated for a specific participant. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Clinically significant changes from baseline or clinically significant new clinical 
signs will be reported as AEs. 
8.2.2. 
Vital Signs 
• 
Vital signs will be measured at the time points indicated in the SoA (Section 1.3). 
• 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse rate. 
• 
Vital sign measurements should be obtained before any blood draws scheduled on 
the same assessment day. 
• Clinically significant changes from baseline will be reported as AEs. 
8.2.3. 
Electrocardiograms 
• 
Tripricate 12-lead ECGs (over an approximate 5- to 10-minute period) will be 
obtained as outlined in the SoA (see Section 1.3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
75 
Clinical Study Protocol template V16 dated 24-Jun-2021 
intervals. Refer to Section 7.1.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary. 
• 
Ideally, ECGs will be obtained before any vital sign measurements or blood draws 
scheduled on the same assessment day; however, sites may perform procedures in an 
order per their standard of care, as long as participants return to a resting state prior 
to the start of the ECG collections. 
• 
If any additional ECGs are performed during the study (if deemed necessary by the 
investigator), those may be collected as a single ECG; however, if that initial single 
reading shows QTc prolongation, then triplicate ECGs should also be performed (see 
Section 7.1.2). 
• 
If clinically significant changes occur during the study, they will be reported as AEs. 
• Electrocardiograms will be reviewed locally by the investigator for safety purposes.  
8.2.4. 
Clinical Safety Laboratory Tests 
• 
See 10.2 for the list of clinical laboratory tests to be performed and the SoA (Section 
1.3) for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
• 
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 should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator or 
medical monitor.  
• 
If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified and 
the sponsor notified. 
• 
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted 
in accordance with the laboratory manual and the SoA (Section 1.3). 
• 
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 or dose 
modification), then the results must be recorded. 
8.2.5. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• Women of childbearing potential (WOCBP) should only be included after a 
confirmed menstrual period and a negative urine pregnancy test. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
76 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• Pregnancy testing will be performed at Baseline (Day 1) before study treatment 
administration. The urine pregnancy test at Baseline will determine study 
contraception and abstinence requirements as follows: 
• Pregnancy testing at Baseline (Day 1) should be performed using the urine test kit 
provided to the study site (with a high sensitivity of ≤12.5 mIU/mL). Participants 
with a negative urine pregnancy test result from this test kit may be included in 
the study with no pretreatment contraception or abstinence requirements. Women 
of childbearing protentional are not required to be using contraception or to have 
practiced abstinence within 14 days prior to study entry if the high sensitivity 
urine pregnancy test results are negative at Baseline (Day 1). 
Note:  ONLY if the study-specific pregnancy kit provided to the study site is 
unavailable, a standard urine pregnancy test with a sensitivity of 25 mIU/mL may 
be used as an exception. A participant with a negative urine pregnancy test result 
from the standard test may be included in the study only if the participant has 
used a highly effective contraception method as described in Section 10.4.2 or has 
practiced abstinence from penile/vaginal intercourse for at least 14 days before 
receiving study treatment. 
• After Dose 4 and before Dose 8, an additional pregnancy test using the urine test kit 
provided to the study site (with a sensitivity of ≤12.5 mIU/mL) is required to be 
performed for WOCBP who have not used a highly effective contraception method 
(in Section 10.4.2) or have not practiced abstinence from penile/vaginal intercourse 
for at least 14 days prior to the first dose of study treatment. It is preferable for this 
pregnancy test to be performed at the study site; however, for participants for whom 
this is not possible, the urine pregnancy kit will be provided to the participant to 
perform as an outpatient during the defined window. For any participant with a 
positive pregnancy test result, study treatment must be immediately discontinued. 
• A pregnancy test will also be performed at the Test-of-Cure (Day 10 to 13) Visit, 5 to 
8 days after the last dose of study treatment.  
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study. 
8.3. Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting 
The definitions of adverse events (AEs) or serious adverse events (SAEs) can be found in 
Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and remain responsible for 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
77 
Clinical Study Protocol template V16 dated 24-Jun-2021 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention or study (see 
Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the start of study intervention until the follow-up 
visit at the timepoints specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a participant consents to participate in the study. 
• 
All AEs will be collected from the start of intervention until the follow-up visit at the 
timepoints specified in the SoA (Section 1.3). 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining 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 should this exceed 24 hours, as indicated in Section 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Section 
10.3. 
• 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-
ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 8.3.7), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Section 10.3. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
78 
Clinical Study Protocol template V16 dated 24-Jun-2021 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the follow-up visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant pregnancy. 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. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. 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 in the study will 
discontinue study intervention. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
79 
Clinical Study Protocol template V16 dated 24-Jun-2021 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.3.7. 
Adverse Events of Special Interest 
Predefined AEs of special interest for this study are CV events, gastrointestinal events, C. 
difficile infection or colitis events, and AEs related to acetylcholinesterase inhibition (see 
Section 2.3.1), which will be identified by a prespecified list of coded terms or 
determined by algorithm, as described in the Statistical Analysis Plan (SAP). 
8.4. Pharmacokinetics 
Whole blood, spot urine and pooled urine samples (approximately blood 3 mL and urine 
1mL, respectively) will be collected for measurement of plasma and urine concentrations 
of gepotidacin as specified in the SoA (Section 1.3). 
• 
Instructions for the collection and handling of biological samples will be 
provided by the sponsor. The actual date and time (24-hour clock time) of each 
sample collected will be recorded. 
Note: For the pooled urine sample, the volume of complete urination also will be 
recorded. 
• 
Complete urination is required when collecting a urine sample for 
bacteriological testing. The time of urination performed is set as the start of the 
urine pooling and will be recorded.  
• 
At the On-therapy Visit, as the spot urine sample collection coincides with the 
urine bacteriology sample collection, a single urine sample of adequate volume 
may be collected and split into separate samples for urine PK and 
microbiological purposes.  
• 
The date and time of the last dose taken before the PK sample (plasma and 
urine) collection will be recorded. 
Note: The date and time of the last dose taken at home before hospital visit is 
also needed for the baseline PK sample collection. 
• 
Samples will be used to evaluate the PK of gepotidacin. Each whole blood 
sample will be processed into plasma.  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
80 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• PK Samples will be analysed using an appropriately validated assay method by or 
under the supervision of the sponsor. 
• Intervention concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been 
unblinded. 
8.5. Pharmacodynamics 
Minimum inhibitory concentration values will be included for population PK/PD 
analyses examining the potential relationship between gepotidacin exposure and clinical 
and microbiological response at the TOC Visit, if data permit. (The related description is 
in Section 9.3.5) 
8.6. Genetics 
In this study, genetics may be evaluated after review by the ethical review committee 
established by GSK in accordance with Japanese Ethical Guidelines for Bioscience, 
Medical and Health Research Involving Human Subjects. 
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
Details on processes for collection and shipment and destruction of these samples can be 
found in Section 10.5. 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. Immunogenicity Assessments 
This section is not applicable. 
8.9. Medical Resource Utilization and Health Economics 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
81 
Clinical Study Protocol template V16 dated 24-Jun-2021 
9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will be finalized prior to DBL and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1. Statistical Hypotheses 
The primary objective is to assess “consistency” with the global study results, this will be 
compared with the predictive distribution of Japanese participants expected to achieve 
therapeutic response on the gepotidacin arm at the TOC visit, where the predictive 
distribution is estimated from the global studies (Studies 204989 and 212390). 
“Consistency” is defined as:  
𝑝̂𝑎>
𝑟𝑎𝑗
(10%)
𝑛𝑎𝑗
 
, where:  
𝑝̂𝑎: Observed proportion of participants achieving therapeutic success on gepotidacin in 
this study 
𝑛𝑎𝑗: Number of participants in gepotidacin of this study 
𝑟𝑎𝑗
(10%): The lower 10th percentile of the cumulative distribution of the prior predictive 
distribution derived from the global study data for the expected number of participants 
achieving therapeutic success out of 𝑛𝑎𝑗 participants.  
Therefore, 
𝑟𝑎𝑗
(10%)
𝑛𝑎𝑗 is the threshold response rate that needs to be observed to meet 
therapeutic success, assuming the response rate is consistent with the global study 
response rate. The predictive distribution is defined as:  
𝑟𝑎𝑗∼∫𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑟𝑎𝑗|𝑛𝑎𝑗, 𝑝𝑎) × 𝐵𝑒𝑡𝑎(𝑝𝑎|𝛼= 𝑟𝑎𝑔, 𝛽= 𝑛𝑎𝑔−𝑟𝑎𝑔)𝑑𝑝𝑎 
, where:  
𝑟𝑎𝑗: The expected number of participants achieving therapeutic success in the gepotidacin 
arm of this study 
𝑟𝑎𝑔: The pooled number of participants achieving therapeutic success in the gepotidacin 
arm across both global studies.  
𝑛𝑎𝑔: The pooled number of participants in the gepotidacin arms across both global 
studies.  
The two global studies (204989 and 212390) have almost the same study design and the 
therapeutic response would be almost the same as well. Therefore, the data will be simply 
pooled to derive the predictive distribution.  
Example:  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
82 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Assuming 884 participants on the gepotidacin arm and a 76% observed therapeutic 
response rate in the global studies, there is an approximately 10% probability of 
observing <= 56 out of 81 responders in this study if the true gepotidacin response rate in 
this study is consistent with the response rate estimated from the global studies. 
Therefore, the success rule for gepotidacin is set to require a therapeutic response rate 
greater than 69.1% (56/81) in order to demonstrate consistency with global results in this 
example.  
The secondary objective is to assess the difference between the therapeutic response of 
gepotidacin with the nitrofurantoin therapeutic response at the TOC Visit in Japanese 
female participants with acute uncomplicated cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin. The difference in the 
therapeutic response rate between gepotidacin and nitrofurantoin will be assessed 
descriptively.  
9.1.1. 
Multiplicity Adjustment 
No multiplicity approaches will be used.  
9.2. Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Intent-to-Treat (ITT) 
Population 
All participants randomly assigned to study treatment. Participants 
will be analyzed according to their randomized study treatment. 
Microbiological ITT 
(micro-ITT) Population 
All participants randomly assigned to study treatment who receive 
at least 1 dose of study treatment and have a qualifying baseline 
uropathogen (defined in 10.8), from a quantitative bacteriological 
culture of a pretreatment clean-catch midstream urine specimen. 
Participants will be analyzed according to their randomized study 
treatment. 
Micro-ITT NTF-S 
Population 
All participants in the micro-ITT Population whose baseline 
qualifying bacterial uropathogens all are susceptible to 
nitrofurantoin (NTF-S). Participants with missing MIC susceptibility 
results for any qualifying uropathogens will not be included in the 
NTF-S subpopulation. Participants will be analyzed according to 
their randomized study treatment. 
Micro-ITT NTF-S (Global 
Study) Population 
All participants from the global studies (Studies 204989 and 
212390) in the micro-ITT NTF-S Population defined in individual 
studies, who are not enrolled into this study but into each of the 
global studies.  


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
83 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Population 
Description 
Micro-ITT NTF-S (Entire) 
Population 
All participants from micro-ITT NTF-S Population and micro-ITT 
NTF-S Population (Global Study) Population.  
This is the primary analysis population.   
Micro-ITT MDR Population 
All participants in the micro-ITT Population who have any 
qualifying baseline bacterial uropathogens that are resistant to 
two or more classes of antimicrobials. Participants will be 
analyzed according to their randomized study treatment.  
Pharmacokinetic (PK) 
Population 
All randomized participants who receive at least 1 dose of study 
treatment and have at least 1 nonmissing plasma or urine PK 
concentration (Non-quantifiable [NQ] values will be considered as 
non-missing values). This population will be used in the 
assessment and characterization of plasma and urine 
concentrations (summary table).  
Safety Population 
All randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed according to their actual 
treatment received. 
 
9.3. Statistical Analyses 
9.3.1. 
Primary Estimand Analysis 
The primary analysis of the primary estimand will be performed using the micro-ITT 
NTF-S (Entire) population.  
The primary endpoint is therapeutic response (combined per-participant microbiological 
and clinical response) at the TOC Visit. Therapeutic success refers to participants who 
have been deemed both a microbiological success and a clinical success (i.e. responders).  
The primary treatment effect will be estimated regardless of treatment discontinuation, as 
per the treatment policy strategy. The ICE of use of other systemic antimicrobial therapy 
is captured through the definitions of microbiological and clinical response and will be 
counted as failures (composite strategy). If a participant experiences both ICEs of study 
treatment discontinuation and use of systemic antimicrobials, then a composite strategy 
(assigning therapeutic response as a failure) will be used from the point that the relevant 
systemic antimicrobial was taken. Further details on the primary estimand are provided in 
Section 3.  
The number and proportion of participants achieving a therapeutic success will be 
presented along with its 95% Exact Clopper Pearson CI at the TOC visit and compared 
with the threshold for consistency with the global studies (Studies 204989 and 212390). 
The threshold will be derived with covariate adjustment as follows. For this analysis, 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
84 
Clinical Study Protocol template V16 dated 24-Jun-2021 
participants who do not return for the TOC Visit or have missing data at the TOC Visit 
will be treated as failures.  
1. Derive the prior for therapeutic success rate in each stratum in EAGLE2/3 studies 
based on the definition of stratification factor in this study 
𝑝𝑘~𝐵𝑒𝑡𝑎(𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) 
, where 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙 𝑎𝑛𝑑 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙 are the pooled number of participants and 
therapeutic responders who are assigned to the gepotidacin group of 𝑘𝑡ℎ stratum 
in the micro-ITT NTF-S population across both global studies (Studies 204989 
and 212390), respectively.  
2. Derive the predictive distribution for the number of participants achieving 
therapeutic success in each stratum 
𝑟𝑘,𝐽𝑎𝑝𝑎𝑛~𝐵𝑒𝑡𝑎 𝑏𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) 
, where 𝑛𝑘,𝐽𝑎𝑝𝑎𝑛 𝑎𝑛𝑑 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛 are the number of participants and therapeutic 
responders who are assigned to the gepotidacin group of 𝑘𝑡ℎ stratum in the micro-
ITT NTF-S population, respectively.  
3. Derive lower 10%tile as a threshold using simulation 
a. Set 𝑗= 1 
b. Sample 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 from 𝐵𝑒𝑡𝑎 𝑏𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−
𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) for each stratum (𝑘= 1, … , 𝐾) 
c. Calculate 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
= 𝑟1,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ 𝑟2,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ ⋯+ 𝑟𝐾,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 and set 𝑗←𝑗+ 1 
d. Repeat the step b and c. 
e. Obtain the lower 10%tile (𝑟𝐽𝑎𝑝𝑎𝑛
(10%)) of 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
 
f. Calculate the threshold as 𝑟𝐽𝑎𝑝𝑎𝑛
(10%) 𝑛𝐽𝑎𝑝𝑎𝑛
⁄
 where 𝑛𝐽𝑎𝑝𝑎𝑛 is the number of 
participants in the gepotidacin group.  
Sensitivity analysis on the primary estimand will be done to assess the impact of missing 
data using a tipping point analysis. Tipping point analysis will vary assumption on the 
proportion of participants with missing data who achieve therapeutic success on the 
gepotidacin arm in the Japan study and global studies. For each combination of assumed 
therapeutic success rate on the gepotidacin arm in Japan study and global studies, the 
number of additional participants achieving therapeutic success among participants with 
missing therapeutic response will be imputed by drawing from a binomial distribution. 
The details will be provided in the SAP.  
9.3.2. 
Secondary Estimand(s) Analysis 
9.3.2.1. 
Therapeutic Response 
Therapeutic response (combined per-participant microbiological and clinical response) 
will be summarized using the micro-ITT NTF-S Population with the exception of the 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
85 
Clinical Study Protocol template V16 dated 24-Jun-2021 
assessment of therapeutic response of gepotidacin in female participants with acute 
uncomplicated cystitis who have qualifying uropathogen(s) resistant to “two or more” 
specific classes of antimicrobials at baseline where the micro-ITT MDR Population will 
be used. The number and proportion of participants with therapeutic success will be 
summarized, along with the 95% Exact Clopper Pearson CI, at the TOC Visit by 
treatment group. The ICE of use of other systemic antimicrobials is captured through the 
defining criteria of microbiological and clinical response (Section 8.1.2.1 and 8.1.3.1). 
Participants who do not return for the TOC Visit or have missing data at the TOC Visit 
will be treated as failures. 
The difference in proportions of participants achieving therapeutic success for 
gepotidacin compared to nitrofurantoin and the 95% CI of the difference will be 
summarized at TOC Visit. Miettinen-Nurminen (score) confidence limits for the 
treatment difference will be computed. The MN estimate of the common risk difference 
and variance is computed by combining the point estimates and variances from the 
individual strata using MN weights. The estimate uses inverse variance stratum weights 
to produce MN confidence limits for the stratum risk differences. In addition, 
supplementary analysis using Bayesian dynamic borrowing will be carried out to estimate 
the treatment difference in the Japanese population using data from each treatment group 
of the global studies (Studies 204989 and 212390). Further details will be provided in the 
SAP.  
For the micro-ITT MDR population, the number and proportion of participants with 
therapeutic success will be presented by treatment group at the TOC Visit along with the 
95% Exact Clopper Pearson CI. The ICE of use of other systemic antimicrobials is 
captured through the defining criteria of microbiological and clinical response (Section 
8.1.2.1 and 8.1.3.1).  
In addition, Bayesian dynamic borrowing will be used to estimate the treatment 
difference for therapeutic response in MDR subgroup of the Japanese population using 
data from each treatment group of the global studies. The details will be provided in the 
SAP.  
9.3.2.2. 
Clinical Outcome and Response 
Clinical outcome and response will be summarized using the micro-ITT NTF-S 
Population with the exception of the assessment of clinical response and outcome of 
gepotidacin in female participants with acute uncomplicated cystitis who have qualifying 
uropathogen(s) resistant to “two or more” specific classes of antimicrobials at baseline 
where micro-ITT MDR Population will be used. The number and proportion of 
participants with resolution of signs and symptoms will be presented by treatment group 
at the TOC Visit. The ICE of use of other systemic antimicrobials is captured through the 
defining criteria of clinical outcome and response (Section 8.1.3.1). Participants who do 
not return for the TOC Visit or have missing data at the TOC Visit will be treated as 
failures. 
For the micro-ITT MDR population, the number and proportion of participants with 
resolution of signs and symptoms will be presented by treatment group at the TOC Visit. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
86 
Clinical Study Protocol template V16 dated 24-Jun-2021 
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of clinical outcome and response (Section 8.1.3.1). 
In addition, Bayesian dynamic borrowing will be used to evaluate the efficacy in MDR 
subgroup in the Japanese population using the global study data. The details will be 
provided in the SAP.  
9.3.2.3. 
Microbiological Outcome and Response 
Microbiological outcome and response will be summarized using the micro-ITT NTF-S 
Population with the exception of the assessment of microbiological response and 
outcome of gepotidacin in female participants with acute uncomplicated cystitis who 
have qualifying uropathogen(s) resistant to “two or more” specific classes of 
antimicrobials at baseline where micro-ITT MDR Population will be used. The number 
and proportion of participants with microbiological success will be presented by 
treatment group at the TOC Visit. The ICE of use of other systemic antimicrobials is 
captured through the defining criteria of microbiological outcome and response (Section 
8.1.2.1). Participants who do not return for the TOC Visit or have missing data at the 
TOC Visit will be treated as failures. 
For the micro-ITT MDR population, the number and proportion of participants with 
microbiological success will be presented by treatment group at the TOC Visit. The ICE 
of use of other systemic antimicrobials is captured through the defining criteria of 
microbiological outcome and response (Section 8.1.2.1). 
In addition, Bayesian dynamic borrowing will be used to evaluate the efficacy in MDR 
subgroup in the Japanese population using the global study data. The details will be 
provided in the SAP.  
9.3.2.4. 
Investigator Assessment of Clinical Response 
The number and proportion of participants with investigator assessed clinical response of 
success, failure and indeterminate/missing at the TOC Visit by treatment group based on 
micro-ITT Population. Reasons for an assessment of failure and indeterminate responses 
will also be summarized.  
The 95% Exact Clopper Pearson CI for the proportion of participants with success will be 
presented as a binomial proportion for each treatment group.  
9.3.3. 
Exploratory Endpoint(s) Analysis 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
87 
Clinical Study Protocol template V16 dated 24-Jun-2021 
9.3.4. 
Safety Analysis 
All safety analyses will be performed on the Safety Population. All reported AEs will be 
coded using MedDRA and summarized by system organ class and preferred terms.  
The safety estimand will use a treatment policy strategy for the ICE of study treatment 
discontinuation, as safety will be assessed at all post-baseline assessments irrespective of 
whether the participant completed the treatment.  
Treatment-emergent AE (TEAE) is defined if AE onset date/time is on or after treatment 
start date/time. The number and proportion of treatment-emergent AEs, study treatment-
related AEs, deaths, SAEs, and AEs leading to study treatment or study withdrawal will 
be provided. Treatment-emergent AEs will be summarized by maximum intensity.  
Adverse events of special interest will include CV, gastrointestinal, and Clostridioides 
difficile infection or colitis events. In addition, AEs associated with acetylcholinesterase 
inhibition are also considered special interest. As described in the SAP, manual and 
programmatic reviews of AEs/preferred terms will be used to assess these events.  
The severity of specified AEs and laboratory abnormalities will be graded according to 
the modified DMID toxicity grading system (Section 10.12). Data will be tabulated and 
reported by absolute grade for Grades 3 and higher, and shift tables, as appropriate.  
Change from baseline over time in laboratory parameters, ECGs and vital signs will be 
summarized with descriptive statistics. The frequency of laboratory abnormality events 
along with the shift from baseline to the worst-case post-baseline value will be provided. 
Abnormal liver chemistry results will be determined using increases above the upper 
limit of normal.  
9.3.5. 
PK and PK/PD analyses 
Plasma and urine concentrations for the PK Population will be summarized using 
descriptive statistics. In addition, gepotidacin plasma concentrations will be analyzed 
using a population approach to allow for the estimation of gepotidacin exposure in each 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
88 
Clinical Study Protocol template V16 dated 24-Jun-2021 
participant. A nonlinear mixed-effects model will be used to determine population PK 
parameters and to identify relevant covariates (e.g., renal function, age, weight, or race).  
9.4. Interim Analysis 
No formal interim analysis is planned. On the other hand, blinded review for therapeutic, 
clinical and microbiological response at the TOC visit may be conducted during the study 
to evaluate if the blinded results have been far from the expected.  
9.5. Sample Size Determination 
This study is not designed to demonstrate non-inferiority of the gepotidacin to 
nitrofurantoin but designed to demonstrate consistency of this study with the global 
studies for therapeutic response of the gepotidacin.  
9.5.1. 
Gepotidacin Sample Size 
Approximately 81 participants in the gepotidacin treatment group is considered an 
appropriate sample size to evaluate consistency between this study and both global 
studies (Studies 204989 and 212390).  
Assuming 81 participants in the micro-ITT NTF-S population on gepotidacin and an 
observed 76% therapeutic success rate out of 884 participants in the global studies, the 
therapeutic response in the gepotidacin arm in this study would need to be greater than 
69.1% to declare “consistency” with the global studies.  
9.5.1.1. 
Sample Size Sensitivity 
Table 14 demonstrates a range of observed therapeutic response rates and the number of 
participants on the gepotidacin arm in this study against the corresponding consistency 
thresholds required in this study assuming 884 participants on the gepotidacin arm in 
both global studies.  
 
Table 14 
Gepotidacin Consistency Thresholds for Different Observed 
Gepotidacin Therapeutic Response Rate in the Global Studies and 
the Number of Participants on the Gepotidacin arm in this study 
Observed 
Therapeutic 
Response Rate 
in the Global 
Studies 
Number of Participants on the Gepotidacin arm in this study 
75 
77 
79 
81 
83 
85 
87 
45% 
37.3% 
37.7% 
38.0% 
37.0% 
37.3% 
37.6% 
37.9% 
50% 
42.7% 
42.9% 
43.0% 
42.0% 
42.2% 
42.4% 
42.5% 
55% 
46.7% 
46.8% 
48.1% 
48.1% 
48.2% 
48.2% 
48.3% 
60% 
52.0% 
51.9% 
53.2% 
53.1% 
53.0% 
52.9% 
52.9% 
65% 
57.3% 
57.1% 
58.2% 
58.0% 
57.8% 
57.6% 
58.6% 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
89 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Observed 
Therapeutic 
Response Rate 
in the Global 
Studies 
Number of Participants on the Gepotidacin arm in this study 
75 
77 
79 
81 
83 
85 
87 
70% 
62.7% 
63.6% 
63.3% 
63.0% 
62.7% 
63.5% 
63.2% 
75% 
68.0% 
68.8% 
68.4% 
67.9% 
68.7% 
68.2% 
69.0% 
80% 
73.3% 
74.0% 
73.4% 
74.1% 
73.5% 
74.1% 
74.7% 
 
9.5.2. 
Nitrofurantoin Sample Size 
The sample size on the nitrofurantoin arm is based on the precision estimate of 95%CI 
for the treatment difference.  
The treatment difference between gepotidacin and nitrofurantoin will be assessed 
descriptively. Table 15 demonstrates a range of observed differences and corresponding 
95% CIs assuming a 3:1 randomization (i.e. 81 participants on gepotidacin and 27 on 
nitrofurantoin in micro-ITT NTF-S population).  
 
Table 15 
95% Confidence Intervals for Different Observed Therapeutic 
Response Rates on the Gepotidacin arm across a Range of 
Differences in Therapeutic Response Rate in Gepotidacin – 
Nitrofurantoin assuming a 3:1 randomization.  
Observed 
Gepo TRR 
Observed difference of TRR in Gepotidacin from that in Nitrofurantoin and 
corresponding 95% CI (%) 
10% 
5% 
0% 
-5% 
-10% 
45% 
(-11.0,31.0) 
(-16.4,26.4) 
(-21.7,21.7) 
(-26.8,16.8) 
(-31.7,11.7) 
50% 
(-11.4,31.4) 
(-16.7,26.7) 
(-21.8,21.8) 
(-26.7,16.7) 
(-31.4,11.4) 
55% 
(-11.7,31.7) 
(-16.8,26.8) 
(-21.7,21.7) 
(-26.4,16.4) 
(-31.0,11.0) 
60% 
(-11.7,31.7) 
(-16.6,26.6) 
(-21.3,21.3) 
(-25.9,15.9) 
(-30.3,10.3) 
65% 
(-11.4,31.4) 
(-16.2,26.2) 
(-20.8,20.8) 
(-25.2,15.2) 
(-29.4,9.4) 
70% 
(-11.0,31.0) 
(-15.6,25.6) 
(-20.0,20.0) 
(-24.1,14.1) 
(-28.1,8.1) 
75% 
(-10.3,30.3) 
(-14.7,24.7) 
(-18.9,18.9) 
(-22.8,12.8) 
(-26.4,6.4) 
80% 
(-9.4,29.4) 
(-13.5,23.5) 
(-17.4,17.4) 
(-21.0,11.0) 
(-24.3,4.3) 
 
9.5.3. 
Proposed Sample Size 
Assuming a 36% evaluability rate, approximately 300 participants will be enrolled and 
randomized to either or nitrofurantoin in a 3:1 ratio to achieve 108 participants in the 
micro-ITT NTF-S population (i.e. approximately 81 participants on gepotidacin and 27 
on nitrofurantoin). Enrolment will continue until the approximate target number of 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
90 
Clinical Study Protocol template V16 dated 24-Jun-2021 
participants in the micro-ITT NTF-S Population has been reached. This study will be 
conducted at multiple sites in Japan. 
Note: Enrolled means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any study activity after 
screening. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
91 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) international ethical guidelines 
Applicable ICH Good Clinical Practice (GCP) guidelines 
The study will be conducted in accordance with “the Ministerial Ordinance on 
the Standards for the Conduct of Clinical Trials of Medicinal Products 
(MHW Notification No.28 dated 27th March, 1997)” and Pharmaceuticals 
and Medical Devices Act. 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF/assent form/eConsent (if applicable), IB, 
and other relevant documents (e.g., advertisements) must be submitted to an 
IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before the 
study is initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• 
Protocols and any substantial 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: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
• 
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
GSK will submit the Clinical Trial Notification (CTN) to the regulatory authorities in 
accordance with Pharmaceuticals and Medical Devices Act before conclusion of any 
contract for the conduct of the study with study sites. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
92 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.1.2. 
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. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study, 
including the risk and benefits, to the participant or their legally authorized 
representative and answer all questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent and/or eConsent (if applicable) that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, privacy and data protect requirements, 
where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent and/or 
eConsent (if applicable) was obtained before the participant was enrolled in the study 
and the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s)/eConsent 
during their participation in the study.  
• 
A copy of the ICF(s)/eConsent must be provided to the participant or their legally 
authorized representative. 
• 
Adolescent participants should be asked for their written assent or eConsent (if 
applicable) to participate in the study. 
• 
As applicable, the IRB/IEC will be consulted before assent form development for 
guidance around age-appropriate groupings and any specific IRB/IEC requirements 
or local laws for conducting and documenting assent. 
• 
Participants who are rescreened are required to sign a new ICF or provide eConsent 
(if applicable). 
• 
If follow-up information from a treating physician or other licensed medical 
practitioner is required for a medical device incident with an AE/SAE involving an 
associated person(s), the Associated Person Safety Reporting Information and 
Authorization Letter must be signed by the associated person to obtain consent. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about gepotidacin or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have gepotidacin approved for 
medical use or approved for payment coverage.  
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
93 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.1.4. 
 Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.  
• 
The participant must be informed that her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent.  
• 
The participant must be informed that her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
To protect the safety interests of participants, a GlaxoSmithKline (GSK) Safety Review 
Team will review blinded safety data instream on a regular basis throughout study 
conduct. Data reviewers will include but are not limited to the following participants: 
medical monitor, safety team lead, statistician, clinical team lead, and data manager. 
A Microbiology Review Team will monitor blinded uropathogen identification and 
susceptibility data instream, including the enrollment rate of participants with a 
qualifying bacterial uropathogen at Baseline and the resistance profile of uropathogens. 
Written documentation regarding key decisions made by the review teams/committee will 
be promptly distributed to participating investigators and IRB/IECs. 
10.1.6. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report. The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location. 
• 
GSK will also provide all investigators who participated in the study with a summary 
of the study results and will tell the investigators what treatment their patients’ 
received.  The investigator(s) is/are encouraged to share the summary results with the 
study subjects, as appropriate. 
• 
Under the framework of the SHARE initiative, 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. Requests 
for access may be made through www.clinicalstudydatarequest.com. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
94 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
GSK will provide the investigator with the information of the treatment assignments 
for their site only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-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. 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• 
Guidance on completion of CRFs will be provided in the electronic data capture 
system. 
• 
Quality tolerance limits (QTLs) will be pre-defined in the QTL report (field within 
the TMF) to identify systematic issues that can impact participant safety and/or 
reliability of study results. These pre-defined parameters will be monitored during 
and at the end of the study and all deviations from the QTLs and remedial actions 
taken will be summarized in the clinical study report. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
Monitoring details describing strategy 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), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the Monitoring Plan. In addition, refer to Section 10.9 for details 
regarding allowed revisions to study conduct and/or monitoring due to COVID-19. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the study 
Data Management Plan. 
• 
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 Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
95 
Clinical Study Protocol template V16 dated 24-Jun-2021 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• 
Definition of what constitutes source data and its origin can be found in the Study 
Reference Manual. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF 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.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The first participant enrolled is considered the first act of recruitment and will be the 
study start date. 
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. 
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: 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
96 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate or no recruitment of participants (evaluated after a reasonable amount of 
time) by the investigator 
• 
If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The investigator 
shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up 
10.1.10. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
97 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 16 except where indicated 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 either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response evaluation, 
the results must be recorded.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 
Table 16 
Protocol-required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC Indices: 
MCV 
MCH 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
 
Creatinine and 
creatinine clearance 
Sodium 
ALT/SGPT 
Total protein 
 
Glucose (non-
fasting) 
Calcium 
Alkaline 
phosphatase 
Albumin 
 
Chloride 
Magnesium 
Phosphorus 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, nitrite, and leukocyte esterase by 
dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• Urine human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential)2 
Note: See Section 8.2.5 for pregnancy test sensitivity requirements and 
additional pregnancy testing details. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
98 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Other Screening 
Tests 
• Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• Serology [HIV antibody, hepatitis B surface antigen (HBsAg), and 
hepatitis C virus antibody]. If serology testing was performed within 3 
months prior to the first dose of study intervention and results were 
positive, testing at Baseline is not required. If testing was performed 
within 3 months and any result was negative, testing at Baseline is 
required.  
• All study-required laboratory tests will be performed by a central 
laboratory, with the exception of dipstick urinalysis and urine pregnancy 
tests which will be performed locally. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN= blood urea nitrogen; HBsAg=hepatitis B 
surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=while blood cell. 
NOTES : 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Section 10.6 All events of ALT  3 × upper limit of normal 
(ULN) and total bilirubin 2  × ULN (>35% direct bilirubin) or ALT   3 × ULN and international normalized 
ratio (INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s law), must be reported 
to GSK in an expedited manner (excluding studies of hepatic impairment or cirrhosis). 
2. 
Local urine testing will be standard for the protocol unless serum testing is required by IRB/IEC. 
 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study will not be reported to study sites or other 
blinded personnel until the study has been unblinded. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
99 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
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 should be reported regardless of sequelae. 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
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. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
100 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. 
Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
• 
In general, hospitalization signifies that the participant has been 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 AE. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) that may 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
101 
Clinical Study Protocol template V16 dated 24-Jun-2021 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should 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 should usually be considered serious. 
o 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. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following 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 
 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
102 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study.  
• 
The severity of AEs and SAEs will be determined by the investigator according to 
the US National Institute of Allergy and Infectious Diseases Division of 
Microbiology and Infectious Diseases criteria for adult toxicity assessment, with 
the exception of serum creatinine adolescent laboratory data, which be assessed 
using paediatric toxicity criteria (Section 10.12). 
 
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. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
103 
Clinical Study Protocol template V16 dated 24-Jun-2021 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any postmortem 
findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE 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 off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor or SAE coordinator by 
telephone. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
104 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
Contacts for SAE reporting can be found in relevant study user manual located in 
the Investigator Site File (ISF). 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Secure email transmission of the scanned SAE paper data collection tool is the 
preferred method to transmit this information to the medical monitor or the SAE 
coordinator. 
• In rare circumstances and in the absence of secure email facilities, 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 time 
frames. 
• 
Contacts for SAE reporting can be found in relevant study user manual located in 
the ISF. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
105 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. 
Following menarche 
2. 
From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
106 
Clinical Study Protocol template V16 dated 24-Jun-2021 
1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
 
• 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance: 
Refer to Section 8.2.5 regarding pregnancy testing for female participants at Baseline 
(Day 1) and associated pretreatment contraception and abstinence requirements. Female 
participants who enter the study using contraception must continue to do so throughout 
the study. 
As described in Section 5.3, participants will be requested to abstain from sexual activity 
from the Baseline Visit through the TOC Visit to prevent possible re-infection. 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc (not approved in Japan as contraceptive method) 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
107 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Azoospermic partner (vasectomized or due to a to medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle 
is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview. 
• 
Highly Effective Methods b 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 (not approved in Japan as contraceptive method) 
• 
transdermal (not approved in Japan as contraceptive method) 
• 
injectable (not approved in Japan as contraceptive method) 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral (not approved in Japan as contraceptive method) 
• 
injectable (not approved in Japan as contraceptive method) 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 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 should 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 (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
108 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.5. 
Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis. 
• DNA samples will be used for research related to gepotidacin or uncomplicated 
urinary tract infections and related diseases. They may also be used to develop 
tests/assays (including diagnostic tests) related to gepotidacin and uncomplicated 
urinary tract infection. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome or analysis 
of the entire genome (as appropriate). 
• Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to gepotidacin or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• The samples will be retained while research on gepotidacin (or study interventions of 
this class) or uncomplicated urinary tract infections continues but no longer than 15 
years after the last subject last visit or other period as per local requirements. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
109 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 3-4 Liver Chemistry Stopping and Increased Monitoring Criteria are designed 
to assure participant safety and evaluate liver event etiology 
Phase 3/4 Liver Chemistry Stopping criteria and Required Follow up Assessments  
Liver Chemistry Stopping Criteria  
ALT-absolute ALT  8xULN 
ALT Increase 
ALT  5xULN but <8xULN persists for 2 weeks 
ALT  3xULN but <5xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and total bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention  
• Report the event to GSK within 24 hours 
• Complete the liver event form and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform follow up assessments as 
described in the Follow up Assessment 
column. 
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
MONITORING: 
If ALT 3xULN AND total bilirubin 2xULN or 
INR >1.5:  
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, within 24 hours after last 
dose5 
• Obtain a serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma glutamyl transferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin. 
• Fractionate bilirubin, if total bilirubin 
2xULN 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
110 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow up 
assessments within 24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For all other stopping criteria (total bilirubin 
<2xULN and INR 1.5):  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow up 
assessments within 24-72 hours  
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
RESTART/RECHALLENGE 
• Do not restart/rechallenge participant with 
study intervention since not allowed per 
protocol; continue participant in the study 
for any protocol specified follow up 
assessments. 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on liver event form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, recreational drugs and other 
over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake form 
If ALT 3xULN AND total bilirubin 2xULN 
or INR >1.5 obtain the following in addition to 
the assessments listed above: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct assay 
should be conducted (where available) to 
assess potential acetaminophen 
contribution to liver injury unless 
acetaminophen use is very unlikely in the 
preceding week (e.g., where the 
participant has been resident in the 
clinical unit throughout)  
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) to 
evaluate liver disease; complete Liver 
Imaging form 
• Liver biopsy may be considered and 
discussed with local specialist if 
available, for instance: 
o In participants when serology 
raises the possibility of 
autoimmune hepatitis (AIH) 
o In participants when suspected 
DILI progresses or fails to 
resolve on withdrawal of study 
intervention 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
111 
Clinical Study Protocol template V16 dated 24-Jun-2021 
o In participants with acute or 
chronic atypical presentation:  
• If liver biopsy conducted complete liver 
biopsy form 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT ≥3xULN and total bilirubin ≥ 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN 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 
3. 
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)    
4. 
Includes: hepatitis A Immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); 
and hepatitis E IgM antibody. In those with underlying chronic hepatitis B at study entry (identified by positive hepatitis 
B surface antigen) quantitative hepatitis B DNA and hepatitis delta antibody.  If hepatitis delta antibody assay cannot 
be performed, it can be replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le 
Gal, 2005]. 
5. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
the PK blood sample draw on the CRF. 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 SRM. 
 
Phase 3/4 Liver Chemistry Increased Monitoring Criteria with Continued Study 
Intervention 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study 
Intervention 
Criteria 
Actions 
 
ALT 5xULN and <8xULN and total 
bilirubin <2xULN or INR≤1.5 without 
symptoms believed to be related to 
liver injury or hypersensitivity, and who 
can be monitored weekly for 2 weeks. 
OR 
ALT 3xULN and <5xULN and total 
bilirubin <2xULN or INR≤1.5 without 
symptoms believed to be related to 
liver injury or hypersensitivity, and who 
can be monitored weekly for 4 weeks. 
• Notify the GSK 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, 
total bilirubin and INR) until they resolve, stabilise 
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 5xULN and <8xULN 
to ≥3xULN but <5xULN, (total bilirubin <2xULN 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
112 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
and INR ≤1.5) continue to monitor liver 
chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3xULN and 
total bilirubin <2xULN and INR ≤1.5, monitor 
participants twice monthly until liver chemistries 
resolve or return to within baseline. 
References 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. J 
Clin Microbiol. 2005;43(5):2363–2369.  
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
113 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.7. 
Appendix 7: Clostridioides Difficile Testing Procedure and 
Algorithm 
 
 
CRA = clinical research associate; EIA = enzyme immunoassay; GDH = glutamate 
dehydrogenase; NAAT = nucleic acid amplification test; SRM = Study Reference 
Manual 
Note: This algorithm is subject to investigator discretion when the clinical presentation 
and time course of diarrhea (e.g., during or within 12 hours immediately after dosing) 
do not fit the Clostridioides difficile-associated diarrhea definition; consideration 
should be given to diarrhea occurring in this early time frame to be suggestive of a 
cholinergic effect. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
114 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.8. 
Appendix 8: Algorithm for Determining Qualifying 
Uropathogens 
In addition to other criteria indicated in Section 9.3, to be included in the micro-ITT 
Population, participants must have a qualifying bacterial uropathogen (defined in 
Figure 2) at Baseline from a quantitative bacteriology culture of a pretreatment 
clean-catch midstream urine specimen. For inclusion into the micro-ITT NTF-S 
Population, all baseline qualifying uropathogen(s) must also be susceptible to 
nitrofurantoin. Qualifying uropathogen susceptibilities will be monitored in stream to 
ensure sufficient and balanced enrollment of participants with uropathogens resistant to 
specific microbiological classes. 
The algorithm for determining qualifying uropathogens based on microbiology laboratory 
quantitative culture results is provided in Figure 2, with additional algorithm details 
provided in the SAP. 
Figure 2 
Baseline Algorithm for Determining Qualifying Uropathogens 
 
CFU=colony-forming units. 
Note:  Only the following uropathogen species/groups will be considered for inclusion in the micro-ITT and other 
microbiological populations: Gram-negative bacilli (e.g., E. coli, K. pneumoniae, P. mirabilis), S. saprophyticus, 
and Enterococcus spp. Analysis details for the other uropathogens and uropathogen groups will be described in 
the SAP, as applicable. 
 
References 
McCarter YS, Burd EM, Hall GS, Zervos M. Cumitech 2C, Laboratory diagnosis of 
urinary tract infections. Coordinating ed., Sharp SE. Washington, DC; ASM Press; 
2009.1-26. 
Chan WW. Chapter 3.12: Urine cultures. In: Leber AL, editor. Clinical microbiology 
procedures handbook, 4th ed. Vol 1-3. Washington, DC; ASM Press; 2016. 
 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
115 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.9. 
Appendix 9: COVID-19 Protocol Information 
10.9.1. 
Overall Rationale for this Appendix 
The COVID-19 pandemic may impact the conduct of clinical studies. Challenges may 
arise from quarantines, site closures, travel limitations, interruptions to the supply chain 
for the investigational product or other considerations if site personnel or study 
participants become infected with COVID-19. These challenges may lead to difficulties 
in meeting protocol-specified procedures. 
This appendix outlines measures that may be applicable for any study site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. These measures are expected to be temporary and study sites will be notified of 
any change to these allowances as the COVID-19 pandemic evolves. 
10.9.2. 
Study Procedures During the COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, sites 
should consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit/risk when making enrollment and treatment decisions for study participants. 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study treatment, including follow-up assessments; however, when not possible, for the 
duration of these special circumstances, the following measures may be implemented: 
• 
Only where applicable country and local regulations and infrastructure allow, home 
healthcare (home visits and telemedicine visits) may be performed at the discretion 
of the investigator and following the participant signing of an informed 
consent/assent form specific for home healthcare. Specific details will be described 
in the Study Reference Manual. The participant should be informed of the home 
healthcare plan and any potential risks associated with home visits and telemedicine. 
The participant must sign an informed consent form specific to home healthcare. 
• 
For all study visits, to minimize the amount of time that participants spend at the 
clinic, eConsent may be utilized and remote collection of study-related data may be 
obtained as described in the Study Reference Manual. Thus, some visit data may be 
collected through a combination of telemedicine and on-site visits. Collection of 
information via telemedicine will be performed only where local regulations permit. 
• 
Clinical investigators should document in site/participant/source files how 
restrictions related to COVID-19 led to changes in study conduct, the duration of 
those changes, and indicate which trial participants were impacted and how those 
trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance). 
• 
Missing protocol-required data/visits due to COVID-19 should be noted in 
site/participant/source files and recorded as a COVID-19 protocol deviation. 
Specifically for data management and monitoring the following will apply: 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
116 
Clinical Study Protocol template V16 dated 24-Jun-2021 
• 
If on-site monitoring is no longer permitted, GSK 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 will work with the site to ensure 
participant privacy. 
• 
eCRF/CRF Final or Interim Sign-Off Process: The principal investigator is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and consistent 
with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The principal 
investigator may sign/re-sign the eCRF from any computer/location by accessing the 
validated system using his/her unique eCRF log-in credentials. The principal 
investigator may delegate this activity to another medically qualified and trained 
subinvestigator and this must be documented on the Delegation of Responsibilities 
Log. It is recommended that the principal investigator identifies a subinvestigator as 
a back-up for eCRF signatures and that appropriate training on the protocol and 
eCRF requirements is provided and documented. 
Essential Document Sign-Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol/Amendment signature page then e-mail approval 
can be accepted by replying to the relevant e-mail that is sent by GSK. 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
117 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.10. 
Appendix 10: Clinical Signs and Symptoms Score for Acute 
Cystitis 
Clinical signs and symptoms of acute cystitis will be recorded as follows: 
Clinical Signs 
and Symptoms 
None 
 
Mild 
Symptom is 
easily tolerated, 
causing minimal 
discomfort and 
not interfering 
with everyday 
activities 
Moderate 
Symptom is 
sufficiently 
discomforting to 
interfere with 
normal everyday 
activities 
Severe 
Symptom 
prevents normal 
everyday 
activities 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Dysuria 
 
 
 
 
Frequency 
 
 
 
 
Urgency 
 
 
 
 
Lower abdominal 
or suprapubic pain 
 
 
 
 
 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
118 
Clinical Study Protocol template V16 dated 24-Jun-2021 
CCI


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
119 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.11. 
Appendix 11: Investigator Assessment of Clinical Response 
Definitions 
For secondary and exploratory purposes, a separate assessment of clinical response will 
be performed at the TOC and Follow-up Visits, or at the time of early withdrawal 
(Section 1.3). This assessment should be completed after the clinical signs and symptoms 
score is determined by the same study physician or otherwise appropriately medically 
trained staff who performed the clinical scoring assessment (Section 8.1.3.1and 10.10). 
Clinical response will be assessed and documented in the eCRF according to the clinical 
response definitions as follows: 
Clinical Success 
• 
Sufficient resolution of acute cystitis signs and symptoms such that no additional 
systemic antimicrobial therapy is required for the current infection 
Clinical Failure 
Participant meets any one of the criteria below: 
• 
No apparent response to treatment (persistence or progression of any 
pretreatment clinical signs and symptoms) 
• 
Use of additional systemic antibiotic(s) for the current infection 
• 
Death related to acute cystitis prior to the visit 
Indeterminate 
Determination of clinical response cannot be made at the visit for any of the 
following reasons: 
• 
Participant was lost to follow-up and/or the clinical assessment was not 
undertaken 
• 
Use of confounding systemic antibiotic(s) for another infection 
• 
Death prior to the visit where acute cystitis was clearly noncontributory 
 


TMF-15095845 
CONFIDENTIAL 
 
214144 
 
 
 
 
120 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.12. 
Appendix 12: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment 
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity: 
GRADE 1 
Mild 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate 
Mild to moderate limitation in activity – some 
assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-
threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy 
required, hospitalization or hospice care probable 
 
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a Grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to: 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DMID) 
and modified to better meet the needs of participants in Division of Microbiology 
and Infectious Diseases (DMID) trials. 
• 
For parameters not included in the following Toxicity Tables, study sites should refer 
to the “Guide for Estimating Severity Grade” located above. 
• 
Criteria are generally grouped by body system. 
Note: Adult DMID toxicity criteria will be applied for all laboratory parameters, with the 
exception of serum creatinine adolescent laboratory data, which will be assessed using 
paediatric DMID toxicity criteria. 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
121 
Clinical Study Protocol template V16 dated 24-Jun-2021 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 to 10.5 g/dL 
8.0 to 9.4 g/dL 
6.5 to 7.9 g/dL 
<6.5 g/dL 
Absolute Neutrophil Count 
1000 to 1500 /mm3 
750 to 999 /mm3` 
500 to 749 /mm3 
<500 /mm3 
Platelets 
75,000 to 99,999 /mm3 
50,000 to 
74,999 /mm3 
20,000 to 49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
11,000 to 13,000 /mm3 
13,000 to 
15,000 /mm3 
15,000 to 30,000 /mm3 
>30,000 or <1000 /mm3 
% Polymorphonuclear 
Leukocytes + Band Cells 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
Low: 100 to 
200 mg/dL 
High: 400 to 
600 mg/dL 
Low: <100 mg/dL 
High: >600 mg/dL 
Low: <50 mg/dL 
High: N/A 
Fibrinogen associated with gross 
bleeding or with disseminated 
coagulation 
Fibrin Split Product 
20 to 40 µg/mL 
41 to 50 µg/mL 
51 to 60 µg/dL 
>60 µg/dL 
Prothrombin Time (PT) 
1.01 to 1.25 x ULN 
1.26 to 1.5 x ULN 
1.51 to 3.0 x ULN 
>3 x ULN 
Activated Partial Thromboplastin 
(APTT) 
1.01 to 1.66 x ULN 
1.67 to 2.33 x ULN 
2.34 to 3 x ULN 
>3 x ULN 
Methemoglobin 
5.0 to 9.9% 
10.0 to 14.9% 
15.0 to 19.9% 
>20% 
N/A = not applicable; ULN = upper limit of normal.  
 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
122 
Clinical Study Protocol template V16 dated 24-Jun-2021 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 to 135 mEq/L 
123 to 129 mEq/L 
116 to 122 mEq/L 
<116 mEq/L or abnormal sodium with 
mental status changes or seizures 
Hypernatremia 
146 to 150 mEq/L 
151 to 157 mEq/L 
158 to 165 mEq/L 
>165 mEq/L or abnormal sodium with 
mental status changes or seizures 
Hypokalemia 
3.0 to 3.4 mEq/L 
2.5 to 2.9 mEq/L 
2.0 to 2.4 mEq/L or intensive 
replacement therapy of hospitalization 
required 
<2.0 mEq/L or abnormal potassium with 
paresis, ileus, or life-threatening 
arrhythmia 
Hyperkalemia 
5.6 to 6.0 mEq/L 
6.1 to 6.5 mEq/L 
6.6 to 7.0 mEq/L 
>7.0 mEq/L or abnormal potassium with 
life-threatening arrhythmia 
Hypoglycemia 
55 to 64 mg/dL 
40 to 54 mg/dL 
30 to 39 mg/dL 
<30 mg/dL or abnormal glucose with 
mental status changes or coma 
Hyperglycemia 
(nonfasting and no prior diabetes) 
116 to 160 mg/dL 
161 to 250 mg/dL 
251 to 500 mg/dL 
>500 mg/dL or abnormal glucose with 
ketoacidosis or seizures 
Hypocalcemia 
(corrected for albumin) 
8.4 to 7.8 mg/dL 
7.7 to 7.0 mg/dL 
6.9 to 6.1 mg/dL 
<6.1 mg/dL or abnormal calcium with 
life-threatening arrhythmia or tetany 
Hypercalcemia 
(corrected for albumin) 
10.6 to 11.5 mg/dL 
11.6 to 12.5 mg/dL 
12.6 to 13.5 mg/dL 
>13.5 mg/dL or abnormal calcium with 
life-threatening arrhythmia 
Hypomagnesemia 
1.4 to 1.2 mEq/L 
1.1 to 0.9 mEq/L 
0.8 to 0.6 mEq/L 
<0.6 mEq/L or abnormal magnesium with 
life-threatening arrhythmia 
Hypophosphatemia 
2.0 to 2.4 mg/dL 
1.5 to 1.9 mg/dL or 
replacement Rx required 
1.0 to 1.4 mg/dL 
intensive therapy or hospitalization 
required 
<1.0 mg/dL or abnormal phosphate with 
life-threatening arrhythmia 
Hyperbilirubinemia (when accompanied 
by any increase in other liver function 
test) 
1.1 to <1.25 x ULN 
1.25 to <1.5 x ULN 
1.5 to 1.75 x ULN 
>1.75 x ULN 
Hyperbilirubinemia (when other liver 
function tests are in the normal range) 
1.1 to <1.5 x ULN 
1.5 to <2.0 x ULN 
2.0 to 3.0 x ULN 
>3.0 x ULN 
Blood urea nitrogen  
1.25 to 2.5 x ULN 
2.6 to 5 x ULN 
5.1 to 10 x ULN 
>10 x ULN 
Hyperuricemia (uric acid) 
7.5 to 10.0 mg/dL 
10.1 to 12.0 mg/dL 
12.1 to 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 to 1.5 x ULN 
1.6 to 3.0 x ULN 
3.1 to 6.0 x ULN 
>6 x ULN or dialysis required 
mEq/L = milliequivalent per litre; Rx = therapy; ULN = upper limit of normal. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
123 
Clinical Study Protocol template V16 dated 24-Jun-2021 
ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Aspartate aminotransferase (AST) 
1.1 to <2.0 x ULN 
2.0 to <3.0 x ULN 
3.0 to 8.0 x ULN 
>8.0 x ULN 
Alanine aminotransferase (ALT) 
1.1 to <2.0 x ULN 
2.0 to <3.0 x ULN 
3.0 to 8.0 x ULN 
>8.0 x ULN 
Gamma glutamyl transferase (GGT) 
1.1 to <2.0 x ULN 
2.0 to <3.0 x ULN 
3.0 to 8.0 x ULN 
>8.0 x ULN 
Alkaline Phosphatase 
1.1 to <2.0 x ULN 
2.0 to <3.0 x ULN 
3.0 to 8.0 x ULN 
>8.0 x ULN 
Amylase 
1.1 to 1.5 x ULN 
1.6 to 2.0 x ULN 
2.1 to 5.0 x ULN 
>5.1 x ULN 
Lipase 
1.1 to 1.5 x ULN 
1.6 to 2.0 x ULN 
2.1 to 5.0 x ULN 
>5.1 x ULN 
ULN = upper limit of normal. 
 
URINALYSIS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
1+ or 200 mg to 1 g loss/day 
2 to 3+ or 1 to 2 g loss/day 
4+ or 2 to 3.5 g loss/day 
Nephrotic syndrome or 
>3.5 g loss/day 
Hematuria 
Microscopic only <10 RBC/HPF 
Gross, no clots >10 RBC/HPF 
Gross, with or without clots, or red blood 
cells casts 
Obstructive or required transfusion 
HPF = high-power field; RBC = red blood cells. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
124 
Clinical Study Protocol template V16 dated 24-Jun-2021 
CARDIOVASCULAR 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac rhythm 
N/A 
Asymptomatic, transient signs, no 
Rx required 
Recurrent/persistent; symptomatic 
Rx required 
Unstable dysrhythmia; 
hospitalization and treatment 
required 
Hypertension 
Transient increase >20 mm/Hg; 
no treatment  
Recurrent, chronic increase 
>20 mm/Hg; 
treatment required  
Acute treatment required; 
outpatient treatment or 
hospitalization possible  
End organ damage or 
hospitalization required  
Hypotension 
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP. 
No treatment required 
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable 
with oral fluid treatment 
Requires IV fluids; 
no hospitalization required 
Mean arterial pressure <60 mmHg 
or end organ damage or shock; 
requires hospitalization and 
vasopressor treatment 
Pericarditis 
Minimal effusion 
Mild/moderate asymptomatic 
effusion, no treatment 
Symptomatic effusion; pain; ECG 
changes 
Tamponade; pericardiocentesis or 
surgery required 
Hemorrhage, Blood Loss 
Microscopic/occult 
Mild, no transfusion 
Gross blood loss;  
1 to 2 units transfused 
Massive blood loss; >3 units 
transfused 
BP = blood pressure; mmHg = millimetre of mercury; IV = intravenous; ECG = electrocardiogram; N/A = not applicable; Rx = therapy. 
 
RESPIRATORY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cough 
Transient; no treatment 
Persistent cough; treatment responsive 
Paroxysmal cough; uncontrolled with 
treatment 
N/A 
Bronchospasm, 
Acute 
Transient; no treatment; 
FEV1 70 to 80% of peak 
flow 
Requires treatment; normalizes with 
bronchodilator; FEV1 50 to 70% of peak 
flow 
No normalization with bronchodilator; FEV1 25 
to 50% of peak flow; or retractions present 
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary 
Dyspnea 
Dyspnea on exertion 
Dyspnea with normal activity 
Dyspnea at rest 
Dyspnea requiring oxygen 
therapy 
FEV1 = forced expiratory volume in 1 second; N/A = not applicable. 
 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
125 
Clinical Study Protocol template V16 dated 24-Jun-2021 
GASTROINTESTINAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
Mild or transient; maintains 
reasonable intake 
Moderate discomfort; intake 
decreased significantly; some 
activity limited 
No significant intake; requires IV fluids Hospitalization required 
Vomiting 
1 episode in 24 hours 
2 to 5 episodes in 24 hours 
>6 episodes in 24 hours or needing IV 
fluids 
Physiologic consequences requiring 
hospitalization or requiring parenteral 
nutrition 
Constipation 
Requiring stool softener or 
dietary modification 
Requiring laxatives 
Obstipation requiring manual 
evacuation or enema 
Obstruction or toxic megacolon 
Diarrhea 
Mild or transient; 3 to 4 loose 
stools/day or mild diarrhea lasting 
<1 week 
Moderate or persistent; 5 to 7 loose 
stools/day or diarrhea lasting 
>1 week 
>7 loose stools/day or bloody diarrhea; 
or orthostatic hypotension or 
electrolyte imbalance or >2 L IV fluids 
required 
Hypotensive shock or physiologic 
consequences requiring hospitalization 
Oral discomfort/ 
Dysphagia 
Mild discomfort; no difficulty 
swallowing 
Some limits on eating/drinking 
Eating/talking very limited; unable to 
swallow solid foods 
Unable to drink fluids; requires IV fluids 
IV = intravenous. 
 
NEUROLOGICAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro-Cerebellar 
Slight incoordination 
dysdiadochokinesis 
Intention tremor, dysmetria, slurred 
speech; nystagmus 
Locomotor ataxia 
Incapacitated 
Psychiatric 
Mild anxiety or depression 
Moderate anxiety or depression; 
therapy required; change in normal 
routine 
Severe mood changes requiring 
therapy; or suicidal ideation; or 
aggressive ideation 
Acute psychosis requiring 
hospitalization; or suicidal 
gesture/attempt or hallucinations 
Muscle strength 
Subjective weakness; no objective 
symptoms/signs 
Mild objective signs/symptoms; no 
decrease in function 
Objective weakness; function limited 
Paralysis 
Paresthesia (burning, 
tingling, etc.) 
Mild discomfort; no treatment 
required 
Moderate discomfort; non-narcotic 
analgesia required 
Severe discomfort; or narcotic analgesia 
required with symptomatic improvement 
Incapacitating; or not responsive 
to narcotic analgesia 
Neurosensory 
Mild impairment in sensation 
(decreased sensation, e.g., 
vibratory, pinprick, hot/cold in great 
toes) in focal area or symmetrical 
distribution; or change in taste, 
smell, vision, and/or hearing 
Moderate impairment (moderately 
decreased sensation, e.g., 
vibratory, pinprick, hot/cold to 
ankles) and/or joint position or mild 
impairment that is not symmetrical 
Severe impairment (decreased or loss 
of sensation to knees or wrists) or loss 
of sensation of at least moderate degree 
in multiple different body areas (i.e., 
upper and lower extremities) 
Sensory loss involves limbs and 
trunk; paralysis; or seizures 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
126 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
(joint pain) 
Mild pain not interfering with function 
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL 
Severe paid; pain and/or analgesics 
interfering with ADL 
Disabling pain 
Arthritis 
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function 
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL 
Severe pain with inflammation, 
erythema or joint swelling, and 
interfering with ADL 
Permanent and/or 
disabling joint 
destruction 
Myalgia 
Myalgia with no limitation of activity 
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity 
Severe muscle tenderness with marked 
impairment of activity 
Frank myonecrosis 
ADL = activities of daily living. 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
Erythema; pruritus 
Diffuse, maculopapular rash, dry 
desquamation 
Vesiculation or moist 
desquamation or ulceration 
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery 
Induration 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Erythema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Edema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Rash at injection site 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Pruritus 
Slight itching at injection site 
Moderate itching at injection extremity 
Itching over entire body 
N/A 
N/A = not applicable. 
 
SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic reaction 
Pruritus without rash 
Localized urticaria 
Generalized urticaria; angioedema 
Anaphylaxis 
Headache 
Mild, no treatment required 
Transient, moderate; treatment 
required 
Severe; responds to initial narcotic 
therapy 
Intractable; requires repeated 
narcotic therapy 
Fever: oral 
37.7 to 38.5°C or 100.0 to 
101.5°F 
38.6 to 39.5°C or 101.6 to 102.9°F 
39.6 to 40.5°C or 103 to 105°F 
>40°C or >105°F 


TMF-15095845 
CONFIDENTIAL 
 
 
214144 
 
 
 
127 
Clinical Study Protocol template V16 dated 24-Jun-2021 
 
Fatigue 
Normal activity reduced <48 hours 
Normal activity decreased 25 to 50%; 
>48 hours 
Normal activity decreased >50%; 
cannot work 
Unable to care for self 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
128 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.13. 
Appendix 13: Abbreviations and Trademarks 
ABSSSI 
acute bacterial skin and skin structure infection 
AE 
adverse event 
AESI 
adverse event of special interest 
AIH 
autoimmune hepatitis 
ALT 
alanine aminotransferase 
APTT 
Activated Partial Thromboplastin 
AST 
aspartate aminotransferase 
AUC 
area under the drug concentration-curve 
AUC12h 
area under the drug concentration-time curve over 12 hours 
AUC24h 
area under the drug concentration-time curve over 24 hours 
BID 
twice daily 
BLI 
β-Lactamase inhibitor 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CDC 
Centers for Disease Control and Prevention  
C. difficile 
Clostridioides difficile 
CFR 
Code of Federal Regulations 
CFU 
colony-forming units 
CI 
confidence interval  
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum concentration 
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
coronavirus disease 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CrCl 
creatinine clearance 
CSR 
Clinical Study Report 
CTFG 
Clinical Trial Facilitation Group 
CTN 
Clinical Trial Notification 
CV 
cardiovascular  
CYP3A4 
cytochrome P450 enzyme 3A4 
DAIDS 
Division of AIDS 
ΔΔQTcF 
placebo-corrected change from-baseline in corrected QT interval 
using the Fridericia formula 
DHHS 
Department of Health and Human Services 
DILI 
drug-induced liver injury 
DMID 
Division of Microbiology and Infectious Diseases 
EAGLE-J 
Efficacy of Antibacterial Gepotidacin Evaluated in Japan 
EAU 
European Association of Urology 
E. coli 
Escherichia coli 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form  
E. faecalis 
Enterococcus faecalis 
EIA 
enzyme immunoassay 
EMA 
European Medicines Agency  
ESBL 
extended-spectrum -lactamase 
CCI


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
129 
Clinical Study Protocol template V16 dated 24-Jun-2021 
ESRD 
end-stage renal disease 
fAUC 
free-drug concentration-time curve 
fAUC/MIC 
ratio of the area under the free-drug concentration-time curve to 
minimum inhibitory concentration over 24 hours 
FDA 
Food and Drug Administration  
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GDH/ GLDH 
glutamate dehydrogenase 
GGT 
gamma glutamyl transferase 
GSK 
GlaxoSmithKline  
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HPF 
high-power field 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
Informed Consent Form  
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalised ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat  
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous  
K. pneumoniae 
Klebsiella pneumoniae 
LAM 
lactational amenorrhoea method 
LDH 
lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDR 
multidrug resistant 
MedDRA 
Medical Dictionary for Regulatory Activities  
mEq/L 
milliequivalent per litre 
MIC 
minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat  
Micro-ITT NTF-S 
Microbiological Intent-to-Treat Nitrofurantoin-Susceptible 
mmHg 
millimetre of mercury 
MN 
Miettinen-Nurminen 
MSDS 
Material Safety Data Sheet 
NA 
not applicable 
NAAT 
nucleic acid amplification test 
NIMP 
noninvestigational medicinal product 
NTF 
nitrofurantoin 
PD 
pharmacodynamic 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
130 
Clinical Study Protocol template V16 dated 24-Jun-2021 
PK 
pharmacokinetic  
PMDA 
Pharmaceuticals and Medical Devices Agency 
QID 
four times a day 
QRS 
the series of deflections in an electrocardiogram that represent 
electrical activity generated by ventricular depolarization prior to 
contraction of the ventricles 
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 limits 
RBC 
red blood cell 
Rx 
therapy 
S. saprophyticus 
Staphylococcus saprophyticus 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV/SDR 
Source Data Verification/Source Document Review 
SGOT 
serum glutamic-oxaloacetic transaminase  
SGPT 
serum glutamic-pyruvic transaminase 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual  
SRT 
Safety Review Team 
SUSAR 
suspected unexpected serious adverse reactions 
Tbili 
Total bilirubin 
TdP 
torsades de pointes  
TEAE 
treatment-emergent adverse event 
TOC 
Test-of-Cure 
TMP-SXT 
trimethoprim-sulfamethoxazole 
ULN 
upper limit of normal 
UTI 
urinary tract infection 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential  
WONCBP 
women of non-childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
MedDRA 
 
 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
131 
Clinical Study Protocol template V16 dated 24-Jun-2021 
10.14. 
Appendix 14: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
 
Amendment 01: 12-OCT-2022 
Overall Rationale for the Amendment 
This amendment included the detailed description about the purpose of unblinding for 
population PK and PKPD evaluation. The description for the unblinding process of 
microbiology sample data for closure of trial enrolment was removed. The criteria on the 
management of enrolled participants in the view of baseline creatinine clearance was 
added. The adverse event related to acetylcholinesterase inhibition were added, and the 
description in mitigation strategy for reproductive system effects were edited. The 
amendment also included the correction of description and/or minor editorial revision in 
Section 10.2 Clinical Laboratory Test, Section 4.3 Justification for Dose and Section 6.7 
Treatment of Overdose. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
2.3.1. Risk 
Assessment 
Added the adverse 
event related to 
acetylcholinesterase 
inhibition and edited 
the description in 
mitigation strategy for 
reproductive system 
effects 
To provide additional 
information of adverse events 
and clarify the mitigation 
strategy 
4.3. Justification 
for Dose 
Corrected the value of 
gepotidacin Cmax 
To correct the description 
6.3. Measures to 
Minimize Bias: 
Randomization 
and Blinding 
Included the following 
expression 
"Independent 
representative may be 
unblinded for draft 
model development" 
To provide more detailed 
information 
6.3. Measures to 
Minimize Bias: 
Randomization 
and Blinding 
Removed the 
description about a 
limited degree of 
unblinding of a 
minority of participant 
The unblinding process is not 
appropriate for this study 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
132 
Clinical Study Protocol template V16 dated 24-Jun-2021 
microbiology sample 
data for closure of trial 
enrolment 
6.7. Treatment of 
Overdose 
Included the description 
to refer the study 
reference manual 
To make reference to the 
manual 
7.1.3. Renal 
Stopping and 
Monitoring 
Criteria 
Included criteria on the 
management of enrolled 
participants who are 
found to have a baseline 
creatinine clearance <60 
mL/min while on study 
treatment 
To provide the criteria for 
management of participants 
10.2. Appendix 2: 
Clinical 
Laboratory Tests 
Corrected the testing 
parameters and minor 
editorial revisions 
To correct the description 
 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
133 
Clinical Study Protocol template V16 dated 24-Jun-2021 
11. 
REFERENCES 
Abreu AG, Marques SG, Monteiro-Neto V, Gonçalves AG. Extended-spectrum β-
lactamase-producing enterobacteriaceae in community-acquired urinary tract infections 
in Sãn Luís, Brazil. Braz J Microbiol. 2013;44(2):469-71.  
Arcilla MS, van Hattem JM, Haverkate MR, et al. Import and spread of extended-
spectrum β-lactamase-producing Enterobacteriaceae by international travellers 
(COMBAT study): a prospective, multicentre cohort study. Lancet Infect Dis. 2017 
Jan;17(1):78-85.  
Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the 
United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-
threats-report-508.pdf 
Doi Y, Park YS, Rivera JI. Community-associated extended-spectrum β-lactamase 
producing Escherichia coli infection in the United States. Clin Infect Dis. 
2013;56(5):641-8.  
European Association of Urology (EAU). EAU guidelines. Edn. presented at the EAU 
Annual Congress Barcelona 2019. ISBN 978-94-92671-04-2. 
https://uroweb.org/guideline/urological-infections/. 
European Medicines Agency (EMA). Addendum to the guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. CPMP/EWP/558/95 
rev 2. 24-Oct-2013. 
Fihn SD, Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl 
J Med. 2003;349(3):259-66.  
Flamm RK, Sader HS, Farell DJ, Jones RN. Ceftazidime-avibactam and comparator 
agents tested against urinary tract isolates from a global surveillance program (2011). 
Diagn Microbiol Infect Dis. 2014;80(3):233-8.  
Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-
reported incidence and associated costs. Ann Epidemiol. 2000;10(8):509-15.  
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic 
costs. Am J Med. 2002;113(Suppl 1A):5S-13S.  
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 2010;7(12):653-
60.  
Gupta K, Hooton TM, Miller L. Uncomplicated UTI IDSA Guideline Committee. 
Managing uncomplicated urinary tract infection−making sense out of resistance data. 
Clin Infect Dis. 2011a;53(10):1041-2.  
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International 
clinical practice guidelines for the treatment of acute uncomplicated cystitis and 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
134 
Clinical Study Protocol template V16 dated 24-Jun-2021 
pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America 
and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 
2011b;52(5):e103-20.  
Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the 
treatment of acute uncomplicated cystitis in women. Arch Intern Med. 
2007;167(20):2207-12.  
Hassing RJ, Alsma J, Arcilla MS, van Genderen PJ, Stricker BH, Verbon A. International 
travel and acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. 
Euro Surveill 2015;20(47). doi: 10.2807/1560-7917.ES.2015.20.47.30074. 
Hayami H, Takahashi S, Ishikawa K, Yasuda M, Yamamoto S, Uehara S, et al. 
Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated 
cystitis conducted by the Japanese surveillance committee during 2009 and 2010: 
antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus. J 
Infect Chemother. 2013;19(3):393-403. 
Hayami H, Takahashi S, Ishikawa K, Yasuda M, Yamamoto S, Wada K, et al. Second 
nationwide surveillance of bacterial pathogens in patients with acute uncomplicated 
cystitis conducted by Japanese Surveillance Committee from 2015 to 2016: antimicrobial 
susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus 
saprophyticus. J Infect Chemother. 2019;25(6):413-22. 
Ho PL, Poon WW, Loke SL, Leung MS, Chow KH, Wong RC, et al. COMBAT study 
group. Community emergence of CTX-M type extended-spectrum β-lactamases among 
urinary Escherichia coli from women. J Antimicrob Chemother. 2007;60(1):140-4.  
Hooton TM, Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 
2012;366(11):1028-37.  
Kusama, Y, Ishikane, M, Kihara, T, Ohmagari, N. Epidemiology of antibiotic treatment 
for uncomplicated cystitis in adults in Japan. J. Infect. Chemother. 2021;27:113-6.  
Lob SH, Nicolle LE. Hoban DJ, Kazmierczak KM, Badal RE, Sahm DF. Susceptibility 
patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and 
the United States, SMART 2010-2014. Diagn Microbiol Infect Dis. 2016;85(4):459-65.  
Macrobid. United States Prescribing Information. Almatica Pharma LLC; 2020. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020064Orig1s029lbl.pdf 
Nakagawa S, Kurimoto Y, Ezumi M, Nakatani K, Mizunaga S, Yamagishi Y, et al. In 
vitro and in vivo antibacterial activity of nitrofurantoin against clinical isolates of E. coli 
in Japan and evaluation of biological cost of nitrofurantoin resistant strains using a mouse 
urinary tract infection model. J Infect Chemother. 2021;27(2):250-255. 
Oteo J, Bautista V, Lara N, Cuevas O, Arroyo M, Fernández S, et al. Spanish ESBL-
EARS-Net Study Group. Parallel increase in community use of fosfomycin and resistance 


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
135 
Clinical Study Protocol template V16 dated 24-Jun-2021 
to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. 
J Antimicrob Chemother. 2010;65(11):2459-63.  
Ookita K, Matsumoto T. Clinical effect of furadantin C on urological infection. Acta Urol 
Jpn. 1970;16(7):357-61.  
Pelletier LL, Michalak DP, Carter JZ, Daughtry JD, Madden RA, Barnard L, et al. A 
comparison of Macrobid (nitrofurantoin monohydrate/macrocrystals) and Macrodantin 
(nitrofurantoin macrocrystals) in the treatment of acute episodes of uncomplicated lower 
urinary-tract infections. Advances in Therapy. 1992;9(1):32-45.  
Sako, A, Yasunaga H, Matsui H, Fushimi K, Yanai H, Gu Y, et al. Hospitalization for 
urinary tract infections in Japan, 2010 – 2015 : a retrospective study using a national 
inpatient database. BMC Infect Dis. 2021;21:1048. doi: 10.1186/s12879-021-06735-y.  
Sanchez GV, Babiker A, Master RN, Luu T, Mathur A, Bordon J. Antibiotic resistance 
among urinary isolates from female outpatients in the United States in 2003 and 2012. 
Antimicrob Agents Chemother. 2016;60(5):2680-3.  
Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of 
urinary Escherichia coli isolates among US outpatients from 2000 to 2010. Antimicrob 
Agents Chemother. 2012;56(4):2181-3.  
Schito GC, Naber KG, Botto H, Palou J, Mazzei T, Gualco L, et al. The ARESC study: 
an international survey on the antimicrobial resistance of pathogens involved in 
uncomplicated urinary tract infections. Int J Antimicrob Agents. 2009;34(5):407-13.  
Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med. 
1993;329(18):1328-34.  
Takahashi M, Hagiya H, Higashionna T, Nakano Y, Sato K, Haruki Y, et al. 
Antimicrobial prescription practices for outpatients with uncomplicated cystitis in Japan. 
Sci Rep. 2022 Apr 8;12(1):5921. doi: 10.1038/s41598-022-09946-8.  
Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, et al. Comparison of 
ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute 
uncomplicated pyelonephritis in women: a randomized trial. JAMA. 2000;283(12):1583-
90.  
Ten Doesschate T, Groenwold RHH, Bonten MJM, van Werkhoven CH. Effectiveness of 
extended- versus normal-release nitrofurantoin for cystitis: an instrumental variable 
analysis. J Antimicrob Chemother. 2019;74(11):3337-43.  
The Government of Japan. National action plan on antimicrobial resistance (AMR); 
2016–2020. Available from: https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-
Kenkoukyoku/0000138942.pdf. 
Tsunoda K, Ohi Y. Clinical use of furadantin macrocrystal on urinary tract infection with 
a consideration on its side effect. Nishinihon J Urol. 1970;32(6):605-8.  


TMF-15095845 
CONFIDENTIAL  
 
214144 
 
 
 
136 
Clinical Study Protocol template V16 dated 24-Jun-2021 
Tofukuji H. Furadantin macrocrystal. Japanese J Clin Urol. 1970;24(3):273-5.  
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Draft guidance for 
industry. Uncomplicated urinary tract infections: developing drugs for treatment. 
https://www.fda.gov/media/129531/download. Last updated August 2019. 
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Guidance for industry. 
Complicated urinary tract infections: developing drugs for treatment. 
https://www.fda.gov/media/71313/download. Last updated June 2018. 
Wada K, Yokoyama T, Uno S, et al. Nationwide surveillance of bacterial pathogens 
isolated from patients with acute uncomplicated cystitis in 2018: Conducted by the 
Japanese Research Group for Urinary Tract Infections (JRGU). J Infect Chemother. 
2021:DOI:https://doi.org/10.1016/j.jiac.2021.03.012.  
Wijma RA, Koch BC, van Gelder T, Van Haren E, Karim H, Muller AE, et al. The 
urinary pharmacokinetics of nitrofurantoin in patients with uncomplicated urinary tract 
infections: interim analysis. Abstract presented at the 30th European Congress of Clinical 
Microbiology and Infectious Diseases (ECCMID), April 18-21, 2020, Paris, France 
Abstract No. 4693. 
https://www.escmid.org/fileadmin/src/media/PDFs/Abstractbook2020_05.05.2020_Part3.
pdf. 
World Health Organization (WHO). Antimicrobial resistance global report on 
surveillance, 2014. 
http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf. 
World Health Organization (WHO). Prioritization of pathogens to guide discovery, 
research and development of new antibiotics for drug-resistant bacterial infections, 
including tuberculosis. 2017. 
Yamamoto S, Ishikawa K, Hayami H, Nakamura T, Miyairi I, Hoshino T, et al. 
JAID/JSC guidelines for clinical management of infectious disease 2015 – urinary tract 
infection/male genital infection. J Infect Chemother. 2017;23:733e51.  
 
CCI


Signature Page for  214144 TMF-15095845 v1.0
Signature Page for TMF-15095845 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 07-Nov-2022 15:33:10 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  214144
Official Title of Study: A Phase III, Multicenter, Randomized, Active 
Reference, Double Blind, Double-dummy Study in Japanese Female 
Participants to Evaluate the Efficacy and Safety of Gepotidacin in the 
Treatment of Uncomplicated Urinary Tract Infection (Acute Cystitis)
NCT ID: NCT05630833
Date of Document: 02-Apr-24


 
CONFIDENTIAL 
 
214144 
 
Page 1 of 93 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A Phase III, Multicenter, Randomized, Active Reference, 
Double-blind, Double-dummy Study in Japanese Female 
Participants to Evaluate the Efficacy and Safety of 
Gepotidacin in the Treatment of Uncomplicated Urinary Tract 
Infection (Acute Cystitis) 
Study Number: 
214144 
Compound Number: GSK2140944 
Abbreviated Title: 
A study to investigate the efficacy and safety with gepotidacin 
in Japanese female participants with uncomplicated urinary 
tract infection (acute cystitis) 
Acronym: 
EAGLE-J 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clintrials.gov 
NCT05630833 
 
XBU Statistical Analysis Plan (SAP) Template v2.0 17 January 2022 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 


 
CONFIDENTIAL 
 
214144 
 
Page 2 of 93 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 7 
1. 
INTRODUCTION .................................................................................................... 11 
1.1. 
Objectives, Estimands and Endpoints ......................................................... 11 
1.2. 
Study Design .............................................................................................. 14 
2. 
STATISTICAL HYPOTHESES ............................................................................... 14 
2.1. 
Multiplicity Adjustment ................................................................................ 16 
3. 
ANALYSIS SETS ................................................................................................... 16 
4. 
STATISTICAL ANALYSES ..................................................................................... 20 
4.1. 
General Considerations .............................................................................. 20 
4.1.1. 
General Methodology .................................................................. 20 
4.1.2. 
Baseline Definition ....................................................................... 21 
4.1.3. 
Strata ........................................................................................... 21 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 21 
4.2.1. 
Definition of Estimands ................................................................ 21 
4.2.2. 
Main analytical approach ............................................................. 22 
4.2.3. 
Sensitivity analyses ..................................................................... 23 
4.2.3.1. 
Unadjusted threshold .................................................. 23 
4.2.3.2. 
Adjustment with randomization strata ......................... 23 
4.2.3.3. 
Missing data in the global studies ............................... 23 
4.2.3.4. 
Tipping point analysis for missing data ....................... 25 
4.2.3.5. 
Impact by GCP violation ............................................. 26 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 26 
4.3.1. 
Therapeutic Response at TOC Visit ............................................. 26 
4.3.1.1. 
Definition of Estimands ............................................... 26 
4.3.1.2. 
Main analytical approach ............................................ 27 
4.3.1.3. 
Supplementary analyses ............................................ 27 
4.3.2. 
Clinical Outcome and Response at the TOC Visit ........................ 28 
4.3.2.1. 
Definition of Estimand ................................................. 28 
4.3.2.2. 
Main analytical approach ............................................ 28 
4.3.3. 
Microbiological Outcome and Response at the TOC .................... 29 
4.3.3.1. 
Definition of Estimand ................................................. 29 
4.3.3.2. 
Main analytical approach ............................................ 29 
4.3.4. 
Therapeutic Response at the TOC Visit in MDR .......................... 29 
4.3.4.1. 
Definition of Estimand ................................................. 29 
4.3.4.2. 
Main analytical approach ............................................ 30 
4.3.4.3. 
Supplementary analyses ............................................ 30 
4.3.5. 
Clinical Outcome and Response at the TOC Visit in MDR ........... 32 
4.3.5.1. 
Definition of Estimand ................................................. 32 
4.3.5.2. 
Main analytical approach ............................................ 32 
4.3.5.3. 
Supplementary analyses ............................................ 32 
4.3.6. 
Microbiological Outcome and Response at the TOC Visit 
in MDR ........................................................................................ 33 
4.3.6.1. 
Definition of Estimand ................................................. 33 


 
CONFIDENTIAL 
 
214144 
 
Page 3 of 93 
4.3.6.2. 
Main analytical approach ............................................ 33 
4.3.6.3. 
Supplementary analyses ............................................ 34 
4.3.7. 
Investigator Assessment of Clinical Response at the TOC 
Visit .............................................................................................. 34 
4.3.7.1. 
Definition of Estimand ................................................. 34 
4.3.7.2. 
Main analytical approach ............................................ 35 
4.3.8. 
Gepotidacin plasma and urine PK concentrations ........................ 35 
4.3.8.1. 
Definition of Estimand ................................................. 35 
4.3.8.2. 
Main analytical approach ............................................ 36 
4.4. 
Exploratory Endpoint(s) Analyses ............................................................... 36 
4.5. 
4.6. 
Safety Analyses .......................................................................................... 44 
4.6.1. 
Extent of Exposure ...................................................................... 44 
CCI
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 4 of 93 
4.6.2. 
Adverse Events............................................................................ 45 
4.6.2.1. 
Adverse Events of Special Interest ............................. 46 
4.6.2.2. 
COVID-19 Assessment and COVID-19 AEs ............... 49 
4.6.2.3. 
Impact of COVID-19 Pandemic on Safety 
Results ....................................................................... 49 
4.6.2.4. 
Quantitative Screening for Identification of 
Potential Adverse Reaction ........................................ 49 
4.6.2.5. 
Impact of GCP violation .............................................. 50 
4.6.3. 
Additional Safety Assessments .................................................... 50 
4.6.3.1. 
Laboratory Data .......................................................... 50 
4.6.3.2. 
Vital Signs .................................................................. 52 
4.6.3.3. 
ECG ........................................................................... 52 
4.7. 
Other Analyses ........................................................................................... 52 
4.7.1. 
Subgroup analyses ...................................................................... 52 
4.8. 
Interim Analyses ......................................................................................... 53 
4.8.1. 
Blinded review ............................................................................. 53 
4.9. 
Changes to Protocol Defined Analyses ....................................................... 54 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 54 
5.1. 
Gepotidacin Sample Size ............................................................................ 54 
5.1.1. 
Sample Size Sensitivity ................................................................ 55 
5.1.2. 
Nitrofurantoin Sample Size .......................................................... 55 
5.1.3. 
Proposed Sample Size ................................................................ 56 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 57 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 57 
6.1.1. 
Study Population .......................................................................... 57 
6.1.2. 
Participant Disposition ................................................................. 57 
6.1.3. 
Demographic and Baseline Characteristics .................................. 57 
6.1.4. 
Protocol Deviations ...................................................................... 58 
6.1.5. 
Prior and Concomitant Medications ............................................. 59 
6.1.6. 
Study Intervention Compliance .................................................... 59 
6.1.7. 
Additional Analyses Due to the COVID-19 Pandemic .................. 59 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 60 
6.2.1. 
Efficacy ........................................................................................ 60 
6.2.1.1. 
Microbiological Outcome and Response ..................... 60 
6.2.1.2. 
Clinical Outcome and Response................................. 63 
....... 67 
....... 67 
....... 68 
....... 69 
6.2.2. 
Safety .......................................................................................... 69 
6.2.2.1. 
Adverse Events of Special Interest ............................. 69 
6.2.2.2. 
Renal impairment ....................................................... 77 
6.2.3. 
Criteria for Potential Clinical Importance ...................................... 78 
6.2.3.1. 
ECG ........................................................................... 78 
6.2.3.2. 
Vital Signs .................................................................. 78 
6.2.4. 
Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment............................ 79 
6.2.4.1. 
Laboratory Values ...................................................... 79 
6.2.5. 
Study Period ................................................................................ 84 
6.2.5.1. 
Study Phases for Concomitant medication ................. 84 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 5 of 93 
6.2.5.2. 
Treatment Emergent Flag for Adverse Events ............ 84 
6.2.5.3. 
Participant and Study Completion ............................... 84 
6.2.6. 
Study Day and Reference Dates .................................................. 85 
6.2.7. 
Assessment Window ................................................................... 85 
6.2.8. 
Multiple measurements at One Analysis Time Point .................... 86 
6.2.9. 
Handling of Partial Dates ............................................................. 86 
6.2.10. 
Qualifying Uropathogen Algorithm ............................................... 87 
6.2.11. 
Uropathogen Phenotype Algorithm .............................................. 89 
6.2.12. 
Trademarks ................................................................................. 92 
7. 
REFERENCES ....................................................................................................... 93 
 


 
CONFIDENTIAL 
 
214144 
 
Page 6 of 93 
LIST OF TABLES 
PAGE 
Table 1 
PK Summary by sampling windows........................................................ 36 
Table 2 
AchE-I Cumulative Grade Score Scale ................................................... 47 
Table 3 
Criteria for Quantitative Screening for Potential ARs. ............................. 49 
Table 4 
Maximum number of participants achieving therapeutic success ........... 54 
Table 5 
Gepotidacin Consistency Thresholds for Different Observed 
Gepotidacin Therapeutic Response Rate in the Global Studies 
and the Number of Participants on the Gepotidacin arm in this 
study ...................................................................................................... 55 
Table 6 
95% Confidence Intervals for Different Observed Therapeutic 
Response Rates on the Gepotidacin arm across a Range of 
Differences in Therapeutic Response Rate in Gepotidacin – 
Nitrofurantoin assuming a 3:1 randomization. ........................................ 56 
Table 7 
Microbiological Outcome by Baseline Qualifying Uropathogen at 
the On-Therapy Visit .............................................................................. 60 
Table 8 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Test of Cure Visit .................................................... 60 
Table 9 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Follow Up Visit ........................................................ 61 
Table 10 
Participant-Level Microbiological Outcome and Response 
Definitions per Study Visit ...................................................................... 62 
Table 11 
Microbiological Outcome by New Qualifying Uropathogen at the 
On Therapy Visit .................................................................................... 62 
Table 12 
Microbiological Outcome by New Qualifying Uropathogen at the 
Test-of-Cure Visit ................................................................................... 62 
Table 13 
Microbiological Outcome by New Qualifying Uropathogen at the 
Follow up Visit ........................................................................................ 63 
Table 14 
Clinical Signs and Symptoms Scoring System ....................................... 64 
Table 15 
Clinical Outcome at the On-Therapy Visit ............................................... 64 
Table 16 
Clinical Outcome and Response at the Test-of-Cure Visit ...................... 65 
Table 17 
Clinical Outcome and Response at the Follow-up Visit........................... 66 


 
CONFIDENTIAL 
 
214144 
 
Page 7 of 93 
VERSION HISTORY 
SAP Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
SAP 
28 Nov 2022 
Amendment 02 
(07 Nov 2022) 
Not Applicable 
Original version 
SAP Amendment 
1 
02 Apr 2024 
Amendment 02 
(07 Nov 2022) 
• 
Modified the 
analysis 
populations to 
exclude the 
participants 
affected by GCP 
violation.  
• 
Modified the 
analysis population 
(micro-ITT NTF-S 
(Global)) to align 
with the primary 
analysis population 
in the global 
studies (204989 
and 212390).  
• 
Added the analysis 
population 
including the 
participants 
affected by GCP 
violation for the 
supplementary 
analysis.  
• 
(Section 4.1.1.) 
Added the way of 
handling zero cell 
when computing 
the risk difference, 
and out-of-stability 
data for 
microbiological 
urine samples.  
• 
(Section 4.2.3.3.) 
Changed handling 
of missing data to 
that missing data 
will not be imputed 
in this study and 
missing data in the 
global studies will 
be imputed.  
• 
(Section 4.2.3.3.) 
Modified 
imputation model 
to align with the 
analyses in the 
global studies 
(204989 and 
212390).  
SAP was amended 
based on  
dry-run review 
comments 
impact on the analysis 
populations based on 
the GCP violation 
issues that occurred in 
one of the sites (Site 
ID: 
), caused 
by 
 
other minor edits or 
updates based on 
comparison with phase 
3 studies.  
PPD
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 8 of 93 
SAP Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
• 
(Section 4.2.3.3. 
and4.2.3.4.) 
Removed the 
computation of 
posterior 
probability.  
• 
(Section 4.2.3.5. 
and 4.6.2.5.) 
Added the 
supplementary 
analysis including 
the participants 
affected by GCP 
violation for 
transparency.  
• 
(Section 4.3.1.3, 
and 4.3.4.3.) 
Clarified vague 
component of 
mixture prior has 
“weak” information.  
• 
(Section 4.3.1.3., 
and 4.3.4.3.) 
Added displaying 
median and 
95%CrI of the prior 
for each initial 
weight.  
• 
(Section 4.3.7.2. 
and 4.4.9.2.) 
Changed the 
analysis population 
from micro-ITT to 
ITT) 
• 
(Section 4.3.8.2.) 
Added way of 
handling not 
quantifiable 
concentration data.  
• 
(Section 4.3.8.2.) 
Changed sampling 
window for PK 
summary 
• 
 
 
 
 
 
 
  
 
 
 
 
  
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 9 of 93 
SAP Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
• 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
• 
 
 
 
  
• 
(Section 4.6.1.) 
Clarified the 
definition of 
duration.  
• 
(Section 4.6.2.) 
Added the 
specification that 
missing grade of 
AE will be imputed 
as “severe”.  
• 
(Section 4.6.2.1.) 
Clarified the 
definition of the 
time of onset, 
duration, and time 
since end of 
treatment.  
• 
(Section 4.6.2.4.) 
Added summary of 
AE to screen 
potential adverse 
reactions.  
• 
(Section 4.6.3.1.) 
Corrected the 
definition of 
increasing fold in 
liver chemistry.  
• 
(Section 6.1.2.) 
Removed the 
summary of the 
participants who is 
CCI
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 10 of 93 
SAP Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
ongoing in this 
study.  
• 
(Section 6.1.3.) 
Added and clarified 
some parameters 
in summary of 
baseline 
characteristics.  
• 
(Section 6.1.7.) 
Removed the 
summary of visit 
impact due to 
COVID-19.  
• 
(Table 15, 16 and 
17) Clarified the 
derivation of 
clinical worsening.  
• 
(Section 6.2.1.4.) 
Clarified MIC50 
and MIC90 
• 
(Section 6.2.2.1.) 
Updated the list of 
AE term to identify 
AESI 
• 
(Section 6.2.4.1.) 
Clarified the 
derivation of DMID 
grading.  
• 
(Section 6.2.7) 
Amended the 
assessment 
window.  
• 
(Section 6.2.9) 
Amended 
missing/partial 
date of AE 
• 
(Section 6.2.11) 
Clarified the 
derivation of MDR 
 


 
CONFIDENTIAL 
 
214144 
 
Page 11 of 93 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the CSR for 
Study 214144. Details of the final analyses are provided. 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the consistency of therapeutic response 
of gepotidacin at the Test of cure (TOC) Visit (Day 
10 to 13) in female participants with acute 
uncomplicated cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are susceptible 
to nitrofurantoin in Japan, with that from global 
studies (Studies 204989 and 212390). 
• 
Therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC 
Visit 
Secondary 
 
• 
To assess the therapeutic response of gepotidacin 
compared to nitrofurantoin as an active reference 
descriptively, at the TOC Visit, in female 
participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at Baseline that 
all are susceptible to nitrofurantoin 
• 
Therapeutic response at the TOC Visit 
• 
To assess the clinical efficacy and microbiological 
efficacy of gepotidacin at the TOC Visit in female 
participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at Baseline that 
all are susceptible to nitrofurantoin 
• 
Clinical outcome and response at the TOC Visit 
• 
Microbiological outcome and response at the 
TOC Visit 
• 
To assess the therapeutic response, clinical 
efficacy and microbiological efficacy of gepotidacin 
at the TOC Visit in female participants with acute 
uncomplicated cystitis who have qualifying 
uropathogen(s) resistant to two or more specific 
classes of antimicrobials at Baseline 
• 
Therapeutic response at the TOC Visit 
• 
Clinical outcome and response at the TOC Visit 
• 
Microbiological outcome and response at the 
TOC Visit 
• 
To assess the clinical efficacy of gepotidacin at the 
TOC Visit in female participants with acute 
uncomplicated cystitis 
• 
Investigator assessment of clinical response at 
the TOC Visit 
• 
To assess the safety and tolerability of gepotidacin 
in female participants with acute uncomplicated 
cystitis 
• 
Occurrence of treatment-emergent adverse 
events (AEs), serious AEs (SAEs) and adverse 
events of special interest (AESIs) 
• 
Change from baseline in clinical laboratory tests 
• 
Change from baseline in electrocardiograms 
(ECGs) 
• 
Change from baseline in vital sign measurements 
• 
To determine the plasma and urine PK 
concentrations of gepotidacin in female participants 
with acute uncomplicated cystitis 
• 
Gepotidacin plasma and urine concentrations  


 
CONFIDENTIAL 
 
214144 
 
Page 12 of 93 
Objectives 
Endpoints 
Exploratory 
 
Primary estimand 
The primary clinical question of interest is: Whether the therapeutic response at the TOC 
visit in female participants with acute uncomplicated cystitis who have qualified 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin in this study is 
consistent with that from the global studies, regardless of intervention discontinuation for 
any reason. Receipt of systemic antimicrobials will impact the endpoint definition (see 
Section 6.2.1.1 and Section 6.2.1.2).  
The estimand is described by the following attributes: 
• 
Population: Japanese and non-Japanese (from Studies 204989 and 212390) female 
participants with acute uncomplicated cystitis who have qualifying uropathogen(s) at 
Baseline that all are susceptible to nitrofurantoin. 
• 
Treatment condition: Gepotidacin 1500 mg BID for 5 days in this study versus 
gepotidacin 1500 mg BID for 5 days in the global studies (Studies 204989 and 
212390) regardless of adherence. 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 13 of 93 
• 
Variable: Therapeutic response (combined per-participant microbiological and 
clinical response) at the TOC Visit (the detailed definitions are provided in  
Section 6.2.1). Microbiological success is defined as eradication (i.e., reduction) of 
all qualifying bacterial uropathogens recovered at baseline to <103 colony-forming 
units/mL (CFU/mL) as observed on quantitative urine culture without the participant 
receiving other systemic antimicrobials. Clinical success is defined as resolution of 
signs and symptoms of acute cystitis present at Baseline (and no new signs and 
symptoms) without the participant receiving other systemic antimicrobials.  
• 
Summary measure: Comparison of the proportion of Japanese participants achieving 
therapeutic success in this study with 10th percentile of the predicted distribution for 
the proportion of participants achieving therapeutic success in this study derived 
from the global studies (Studies 204989 and 212390)  
• 
Intercurrent events (ICEs):  
• 
Study treatment discontinuation (due to any reason) – treatment policy strategy 
(interest is in the treatment effect regardless of study treatment discontinuation) 
• 
Use of systemic antimicrobials – composite strategy. This ICE is captured 
through the definitions of microbiological and clinical response 
(see Section 6.2.1.1 and Section 6.2.1.2) 
Rationale for estimand:  
Interest in this study lies in whether the efficacy of gepotidacin treatment in this study is 
consistent with the global studies.  
The clinical question of interest in this study and the global studies (Studies 204989 and 
212390) lies in the treatment effect of gepotidacin regardless of whether the full course of 
5 days of treatment was taken or not, which reflects how patients may be treated in 
clinical practice. Hence, a treatment policy strategy is appropriate for treatment 
withdrawal before completing 5 days of treatment. Use of other systemic antimicrobials 
may confound the bacterial culture results; thus, the microbiological response will be 
considered failure. For clinical data, the use of a systemic antimicrobial for acute 
uncomplicated cystitis is a sign of treatment failure and use of a systemic antimicrobial 
for another infection cannot be considered a success as it confounds the assessment of 
efficacy. Therefore, the definition of a successful therapeutic response precludes the use 
of other systemic antimicrobials.  
Secondary estimands are provided in Section 4.3.  


 
CONFIDENTIAL 
 
214144 
 
Page 14 of 93 
1.2. 
Study Design 
Overview of Study Design and Key Features 
Design Features 
• 
This is a Phase III randomized, multicentre, active reference, double-blind, double-
dummy study in adolescent and adult Japanese female participants to evaluate the 
efficacy and safety of gepotidacin. The primary objective is to assess consistency of this 
study with global studies (Studies 204989 and 212390) for therapeutic response of 
gepotidacin. 
• 
The study duration will be approximately 28 days with 4 visits. 
• 
Participants will be stratified by age category (≤50 years, or >50 years) and acute 
uncomplicated cystitis recurrence (recurrent or nonrecurrent) and will be randomly 
assigned in a 3:1 ratio to receive either oral gepotidacin or oral nitrofurantoin (active 
reference). 
Study 
intervention 
• 
Gepotidacin: 1500 mg administered orally BID for 5 days 
• 
Nitrofurantoin: 100 mg administered orally BID for 5 days 
Study 
intervention 
Assignment 
Participants will be stratified by age category and acute uncomplicated cystitis recurrence 
(recurrent or nonrecurrent). Recurrence is defined as a confirmed infection [not including the 
current infection in the calculation] with at least 1 prior episode within the past 3 months, at 
least 2 prior episodes within the past 6 months, or at least 3 prior episodes within the past 12 
months before study entry). Participants will be randomly assigned in a 3:1 ratio to receive 
either oral gepotidacin or oral nitrofurantoin.  
Interim Analysis 
No formal interim analysis will be planned. Blinded review for therapeutic, clinical, and 
microbiological response at the TOC visit may be conducted during the study.  
2. 
STATISTICAL HYPOTHESES  
The primary objective is to assess the “consistency” of therapeutic success rate between 
the gepotidacin arm in this Eagle-J study with the pooled gepotidacin arm in the two 
global studies (Studies 204989 and 212390). The observed proportion of participants in 
the gepotidacin arm at the TOC visit achieving therapeutic success in this study will be 
compared with the predictive distribution of the therapeutic success rate estimated from 
the two global studies (Studies 204989 and 212390). “Consistency” is defined as:  
𝑝̂𝑎>
𝑟𝑎𝑗
(10%)
𝑛𝑎𝑗
 


 
CONFIDENTIAL 
 
214144 
 
Page 15 of 93 
, where:  
𝑝̂𝑎: Observed proportion of participants achieving therapeutic success on gepotidacin in 
this study 
𝑛𝑎𝑗: Number of participants in gepotidacin of this study 
𝑟𝑎𝑗
(10%): The lower 10th percentile of the cumulative distribution of the prior predictive 
distribution derived from the global study data for the expected number of participants 
achieving therapeutic success out of 𝑛𝑎𝑗 participants.  
Therefore, 
𝑟𝑎𝑗
(10%)
𝑛𝑎𝑗 is the threshold response rate that needs to be observed to meet 
therapeutic success, assuming the response rate is consistent with the global study 
response rate. The predictive distribution is defined as:  
𝑟𝑎𝑗∼∫𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑟𝑎𝑗|𝑛𝑎𝑗, 𝑝𝑎) × 𝐵𝑒𝑡𝑎(𝑝𝑎|𝛼= 𝑟𝑎𝑔, 𝛽= 𝑛𝑎𝑔−𝑟𝑎𝑔)𝑑𝑝𝑎 
, where:  
𝑟𝑎𝑗: The expected number of participants achieving therapeutic success in the gepotidacin 
arm of this study 
𝑟𝑎𝑔: The pooled number of participants achieving therapeutic success in the gepotidacin 
arm across both global studies.  
𝑛𝑎𝑔: The pooled number of participants in the gepotidacin arms across both global 
studies.  
The two global studies (204989 and 212390) have almost the same study design and the 
therapeutic response would be similar as well. Therefore, the data will be simply pooled 
to derive the predictive distribution.  
Example:  
Assuming 884 participants on the gepotidacin arm and a 76% observed therapeutic 
response rate in the global studies, there is an approximately 10% probability of 
observing <= 56 out of 81 responders in this study if the true gepotidacin response rate in 
this study is consistent with the response rate estimated from the global studies. 
Therefore, the success rule for gepotidacin is set to require a therapeutic response rate 
greater than 69.1% (56/81) in order to demonstrate consistency with global results in this 
example.  
The secondary objective is to assess the difference between the therapeutic response of 
gepotidacin with the nitrofurantoin therapeutic response at the TOC Visit in Japanese 
female participants with acute uncomplicated cystitis with qualifying bacterial 
uropathogen(s) at Baseline that all are susceptible to nitrofurantoin. The difference in the 
therapeutic response rate between gepotidacin and nitrofurantoin will be assessed 
descriptively.  


 
CONFIDENTIAL 
 
214144 
 
Page 16 of 93 
2.1. 
Multiplicity Adjustment 
No multiplicity adjustment approaches will be used.  
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were 
screened for eligibility 
• 
Study Population 
Intent-to-Treat (all participants)  
 (ITT-ALL) 
• 
All participants who were 
randomly assigned to study 
treatment in the study. 
• 
Participants will be analyzed 
according to their randomized 
study treatment.  
• 
Listing 
Intent-to-Treat (ITT) 
• 
All participants in ITT-ALL 
population, except for 
participants from the site (Site 
ID: 
) due to GCP 
violation 
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
Study Population 
• 
Efficacy 
Microbiological ITT (all participants) 
(micro-ITT-ALL) 
• 
All participants randomly 
assigned to study treatment 
who receive at least 1 dose of 
study treatment and have a 
qualifying baseline 
uropathogen (defined in 
Section 6.2.10), from a 
quantitative bacteriological 
culture of a pretreatment 
clean-catch midstream urine 
specimen.  
• 
Participants will be analyzed 
according to their randomized 
study treatment.  
• 
Note that qualifying 
uropathogens include only the 
uropathogen species/groups 
[Gram-negative bacilli (e.g. E. 
coli, K. pneumoniae, P. 
mirabilis), S. saprophyticus, 
and Enterococcus spp.], 
defined in Section 6.2.10.  
• 
Listing  
Microbiological ITT (micro-ITT) 
• 
All participants in micro-ITT-
ALL, except for participants 
from the site (Site ID: 
) 
due to GCP violation. 
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
Study Population 
• 
Efficacy 
Micro-ITT NTF-S (all participants) 
(micro-ITT-ALL NTF-S) 
• 
All participants in the micro-
ITT-ALL Population whose 
baseline qualifying bacterial 
• 
Listing 
PPD
PPD


 
CONFIDENTIAL 
 
214144 
 
Page 17 of 93 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
uropathogens that all are 
susceptible to nitrofurantoin 
(NTF-S). Broth microdilution 
nitrofurantoin MIC result from 
JMI Laboratories (if available) 
will take precedence over 
global central laboratory 
(GCL) nitrofurantoin MIC 
result for determining 
susceptibility to nitrofurantoin.  
• 
Nitrofurantoin susceptibility 
interpretations will be based 
on the Clinical and Laboratory 
Standards Institute (CLSI) 
guidelines 
• 
Participants with missing MIC 
susceptibility results for any 
qualifying uropathogens will 
not be included in the NTF-S 
subpopulation.  
• 
Participants will be analyzed 
according to their randomized 
study treatment.  
Micro-ITT NTF-S 
• 
All participants in the micro-
ITT Population whose 
baseline qualifying bacterial 
uropathogens that all are 
susceptible to nitrofurantoin 
(NTF-S). Broth microdilution 
nitrofurantoin MIC result from 
JMI Laboratories (if available) 
will take precedence over 
global central laboratory 
(GCL) nitrofurantoin MIC 
result for determining 
susceptibility to nitrofurantoin.  
• 
Nitrofurantoin susceptibility 
interpretations will be based 
on the Clinical and Laboratory 
Standards Institute (CLSI) 
guidelines 
• 
Participants with missing MIC 
susceptibility results for any 
qualifying uropathogens will 
not be included in the NTF-S 
subpopulation.  
• 
Participants will be analyzed 
according to their randomized 
study treatment.  
• 
Note that this population does 
not include the participants in 
the affected site by GCP 
violation (Site ID: 
).  
• 
Study Population 
• 
Efficacy 
PPD


 
CONFIDENTIAL 
 
214144 
 
Page 18 of 93 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Micro-ITT NTF-S (Global Study) 
• 
All participants from the global 
studies (Studies 204989 and 
212390) in the micro-ITT NTF-
S (IA set) Population defined 
in individual studies, who are 
not enrolled into this study but 
into each of the global studies. 
See the individual RAP for the 
detailed definition of this 
analysis population.  
• 
Note: this population will be 
referred as non-Japanese 
population.  
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
NA 
Micro-ITT NTF-S (Entire) 
• 
All participants from micro-ITT 
NTF-S Population and micro-
ITT NTF-S (Global Study) 
Population.  
• 
This is the primary analysis 
population.  
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
Efficacy 
Micro-ITT-ALL NTF-S (Entire) 
• 
All participants from micro-
ITT-ALL NTF-S Population 
and micro-ITT NTF-S (Global 
Study) Population.  
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
Efficacy 
Micro-ITT MDR 
• 
All participants in the micro-
ITT Population who have any 
qualifying baseline bacterial 
uropathogens that are 
resistant to two or more 
classes of antimicrobials. See 
the detail for MDR definition in 
Section 6.2.11.  
• 
Participants will be analyzed 
according to their randomized 
study treatment.  
• 
Efficacy 
Micro-ITT MDR (Global Study) 
• 
All participants from the global 
studies (Studies 204989 and 
212390) in the micro-ITT 
Population who have any 
qualifying baseline bacterial 
uropathogens that are 
resistant to two or more 
classes of antimicrobials. See 
the detail for MDR definition in 
Section 6.2.11. 
• 
Efficacy 


 
CONFIDENTIAL 
 
214144 
 
Page 19 of 93 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
Micro-ITT MDR (Entire) 
• 
All participants from micro-ITT 
MDR Population and micro-
ITT MDR (Global Study) 
Population.  
• 
Participants will be analyzed 
according to their randomized 
study treatment. 
• 
Efficacy 
Safety (all participants) (Safety-ALL) 
• 
All randomized participants 
who receive at least 1 dose of 
study treatment.  
• 
Participants will be analyzed 
according to their actual 
treatment received.  
• 
Note: if a participant receives 
both gepotidacin and 
nitrofurantoin, they will be 
summarized within 
gepotidacin 1500 mg BID. 
• 
Safety 
Safety 
• 
All randomized participants in 
Safety-ALL population, except 
for the participants from the 
site (Site ID: 
) due to 
GCP violation. 
• 
Note: if a participant receives 
both gepotidacin and 
nitrofurantoin, they will be 
summarized within 
gepotidacin 1500 mg BID.  
• 
Participants will be analyzed 
according to their actual study 
treatment received. 
• 
Safety 
Pharmacokinetics (all participants) 
(PK-ALL) 
• 
All randomized participants 
who receive at least 1 dose of 
study treatment and have at 
least 1 non-missing plasma or 
urine PK concentration (Non-
quantifiable [NQ] values will 
be considered as non-missing 
values). 
• 
This population will be used in 
the assessment and 
characterization of plasma 
and urine concentrations 
(summary table). Note: if a 
participant receives both 
gepotidacin and nitrofurantoin, 
they will be listed only (i.e. not 
summarized within 
gepotidacin 1500 mg BID). 
Plasma and/or urine samples 
for participant randomized 
• 
Listing 
PPD


 
CONFIDENTIAL 
 
214144 
 
Page 20 of 93 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
nitrofurantoin will not be 
measured.  
Pharmacokinetic (PK) 
• 
All randomized participants in 
PK-ALL population, except for 
the participants from the site 
(Site ID: 
) due to GCP 
violation.  
• 
This population will be used in 
the assessment and 
characterization of plasma 
and urine concentrations 
(summary table). Note: if a 
participant receives both 
gepotidacin and nitrofurantoin, 
they will be listed only (i.e., not 
summarized within 
gepotidacin 1500 mg BID). 
Plasma and/or urine samples 
for participant randomized 
nitrofurantoin will not be 
measured.  
• 
PK 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Participants who prematurely withdrew from study will not be replaced.  
In the case of wrong stratification assigned at the time of randomization, the analyses will 
be performed based on the actual stratum per data collected in the CRF. 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center would unlikely be informative and will not, therefore, be provided.  
For any efficacy analyses of binary outcomes for which a risk difference will be 
estimated, if 100% (or 0%) success rates are observed in both treatment arms then a 
constant of 1E-10 will be added to each zero cell in the resultant contingency table to 
overcome software limitations and enable determination of the risk difference and two-
sided 95% CI.  
PPD


 
CONFIDENTIAL 
 
214144 
 
Page 21 of 93 
Out of stability (OOS) data may be delivered for microbiological urine samples. This data 
will not be included in any analysis, participants with OOS data will have their 
microbiological response missing and will be counted under the Unable to determine 
category.  
Susceptibility interpretations will be based on CLSI M100 with the exception of 
nitroxoline and cefadroxil which are based on EUCAST guidelines and faropenem which 
is based on [Fuchs, 1995]. 
4.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value (or randomization date in participants who are randomized but did not 
receive study treatment), including those from unscheduled visits. If time is not collected, 
Day 1 Pre-dose assessments are assumed to be taken prior to first dose and used as 
baseline. 
For clinical signs and symptoms assessments and microbiological assessments, all Day 1 
symptom assessments and urine samples (collected for identification of uropathogens) are 
used as baseline regardless of if they were taken pre or post dose. Urine samples collected 
on Day -1 or Day 1 can be considered as baseline.  
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. If baseline data is missing, then change from baseline 
calculations will not be performed and will be set to missing. 
4.1.3. 
Strata 
Participants will be randomized to a study treatment using stratification by age category 
(≤ 50 years, or >50 years) and acute cystitis recurrence (nonrecurrent infection or 
recurrent infection). In the case of a difference between the stratification assigned at the 
time of randomization and the data collected in the eCRF, the data collected in the eCRF 
will be considered actual and used unless specified. 
Stratification Value (k) 
Stratification Description 
1 
≤50 years, Nonrecurrent infection 
2 
≤50 years, Recurrent infection 
3 
>50 years, Nonrecurrent infection 
4 
>50 years, Recurrent infection 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of Estimands 
Refer to Section 1.1.  


 
CONFIDENTIAL 
 
214144 
 
Page 22 of 93 
4.2.2. 
Main analytical approach 
The primary analysis of the primary estimand will be performed using the micro-ITT 
NTF-S (Entire) population.  
The primary endpoint is therapeutic response (combined per-participant microbiological 
and clinical response) at the TOC Visit. Therapeutic success refers to participants who 
have been deemed both a microbiological success and a clinical success (i.e., responders).  
The primary treatment effect will be estimated regardless of treatment discontinuation, as 
per the treatment policy strategy. The ICE of use of other systemic antimicrobial therapy 
is captured through the definitions of microbiological and clinical response and will be 
counted as failures (composite strategy). If a participant experiences both ICEs of study 
treatment discontinuation and use of systemic antimicrobials, then a composite strategy 
(assigning therapeutic response as a failure) will be used from the point that the relevant 
systemic antimicrobial was taken.  
The number and proportion of participants achieving a therapeutic success will be 
presented along with its 95% Exact Clopper Pearson CI at the TOC visit and compared 
with the threshold for consistency with the global studies (Studies 204989 and 212390). 
The threshold will be derived with covariate adjustment, the covariates are the 
combinations of age-groups and uUTI recurrence of the participants (refer to Section 
4.1.3, k=1, 2, 3, 4). For this analysis, participants who do not return for the TOC Visit or 
have missing data due to any reason at the TOC Visit will be treated as failures.  
1. Derive the prior for therapeutic success rate in each stratum in EAGLE2/3 studies 
based on the definition of stratification factor (combination of age-groups and uUTI 
recurrence per CRF in this study 
𝑝𝑘~𝐵𝑒𝑡𝑎(𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) 
, where 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙 𝑎𝑛𝑑 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙 are the pooled number of participants and therapeutic 
responders who are assigned to the gepotidacin group of 𝑘𝑡ℎ stratum (k=1, 2, 3, 4) in 
the micro-ITT NTF-S (Global) population , respectively.  
2. Derive the predictive distribution for the number of participants achieving 
therapeutic success in each stratum k, (k=1, 2, 3, 4) 
𝑟𝑘,𝐽𝑎𝑝𝑎𝑛~𝐵𝑒𝑡𝑎 𝑏𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) 
, where 𝑛𝑘,𝐽𝑎𝑝𝑎𝑛 𝑎𝑛𝑑 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛 are the number of participants and therapeutic 
responders who are assigned to the gepotidacin group of 𝑘𝑡ℎ stratum in the micro-
ITT NTF-S population, respectively.  
3. Derive lower 10 percentile as a threshold using simulation 
a. Set 𝑗= 1 
b. Sample 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 from 𝐵𝑒𝑡𝑎 𝑏𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−
𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) for each stratum (𝑘= 1, … ,4) 


 
CONFIDENTIAL 
 
214144 
 
Page 23 of 93 
c. Calculate 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
= 𝑟1,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ 𝑟2,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ ⋯+ 𝑟4,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 and set 𝑗←𝑗+ 1 
d. Repeat the step b and c until 𝑗= 1,000,000.  
e. Obtain the lower 10th percentile value (𝑟𝐽𝑎𝑝𝑎𝑛
(10%)) of 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
 
f. 
Calculate the threshold as 𝑟𝐽𝑎𝑝𝑎𝑛
(10%) 𝑛𝐽𝑎𝑝𝑎𝑛
⁄
 where 𝑛𝐽𝑎𝑝𝑎𝑛 is the number of 
participants in the gepotidacin group.  
4.2.3. 
Sensitivity analyses 
4.2.3.1. 
Unadjusted threshold 
The predictive distribution unadjusted of stratification factor (combination of age-groups 
and uUTI recurrence) is:  
𝑟𝑎𝑗∼∫𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑟𝑎𝑗|𝑛𝑎𝑗, 𝑝𝑎) × 𝐵𝑒𝑡𝑎(𝑝𝑎|𝛼= 𝑟𝑎𝑔, 𝛽= 𝑛𝑎𝑔−𝑟𝑎𝑔)𝑑𝑝𝑎 
, where:  
𝑟𝑎𝑗: The expected number of participants achieving therapeutic success in the gepotidacin 
arm of this study 
𝑟𝑎𝑔: The pooled number of participants achieving therapeutic success in the gepotidacin 
arm across both global studies.  
𝑛𝑎𝑔: The pooled number of participants in the gepotidacin arms across both global 
studies.  
The unadjusted threshold value is defined as 𝑟𝑎𝑗
(10%) 𝑛𝑎𝑗
⁄
, where 𝑟𝑎𝑗
(10%) is the lower 10% 
tile of the above predictive distribution.  
4.2.3.2. 
Adjustment with randomization strata 
The adjusted threshold will be calculated based on the randomization stratum the 
participant was randomized to (instead of the actual stratum the participant should be 
assigned to) using the same approach as the primary analysis (Section 4.2.2) 
4.2.3.3. 
Missing data in the global studies 
Sensitivity analysis on the primary estimand will be done to assess the impact of missing 
data using the multiple imputation method in the global studies. If the entire TOC Visit, 
bacteriology samples or clinical signs and symptoms assessment were missing due to 
COVID-19 pandemic, then the missed values will be imputed under the missing at 
random (MAR) assumption. If the TOC bacteriology sample was taken but a result is not 
available for the sample for any reason then the missed values will also be imputed under 
the MAR assumption. All other missing data will be considered as a failure (i.e. non-
responder). A conservative approach will be taken in this study where all missing data 
(regardless of the reason for missingness) will be imputed as therapeutic failure.  


 
CONFIDENTIAL 
 
214144 
 
Page 24 of 93 
Missing microbiological response values and clinical response values (if any) in the 
global studies will be imputed using separate logistic regression models under the MAR 
assumption in the micro-ITT NTF-S (Global) Population. The imputation models for the 
global studies will be estimated using the data from the global studies, respectively. The 
missing data in each of the global studies will be imputed using the above imputation 
model of each individual study. Note that the imputation models will be estimated using 
data on the gepotidacin arm only. The variables to be included in the imputation models 
are:  
Models for microbiological response in the global studies:  
• 
Age (<=50 years, or >50 years)  
• 
Acute cystitis recurrence (nonrecurrent infection or recurrent infection) at Baseline 
• 
Interaction term between treatment, Baseline qualifying uropathogen species/group 
and MIC (gepotidacin or nitrofurantoin) for randomized treatment. This is the same 
variable used for multiple imputation analysis in the global studies. See the details in 
the study material of the global studies (204989 and 212390).  
• 
Prior visit (On-therapy Visit) microbiological outcome  
Models for clinical response in the global studies:  
• 
Age (<=50 years, or >50 years)  
• 
Acute cystitis recurrence (nonrecurrent infection or recurrent infection) at Baseline 
• 
Baseline clinical signs and symptoms total score 
• 
Prior visit (On-therapy Visit) clinical outcome 
• 
Site (Sites with <10 participants in the micro-ITT NTF-S Population was combined 
prior to unblinding of the global studies) 
Any subjects that had a missing value for one or more variables listed above were 
excluded from the relevant imputation model(s).  
Proportion of Participants achieving therapeutic success in this study 
The same approach as the primary analysis will be used.  
Threshold using the data from both global studies.  
The threshold = for the lower 10th percentile of the predicted therapeutic success in this 
study will be calculated based on the pooled data from both global studies as follows. 
Note that the number of replication is set to 1,000,000. 
1. Set 𝑗= 1 
2. Impute missing values using separate logistic models that will be estimated using the 
data from both global studies.  
3. Derive therapeutic response from the imputed values.  


 
CONFIDENTIAL 
 
214144 
 
Page 25 of 93 
4. Sample 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 from 𝐵𝑒𝑡𝑎 𝑏𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−
𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙) for each stratum (𝑘= 1, … ,4) 
, where 𝑛𝑘,𝐽𝑎𝑝𝑎𝑛 𝑎𝑛𝑑 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛 are the number of participants and therapeutic 
responders who are assigned to the gepotidacin group of 𝑘𝑡ℎ stratum in the micro-
ITT NTF-S population, respectively after imputation. 
5. Calculate 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
= 𝑟1,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ 𝑟2,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ ⋯+ 𝑟4,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 
6. 𝑗←𝑗+ 1 
7. Repeat step 2-8 until 𝑗= 1,000,000 
8. Obtain the 10th percentile value 𝑟̃𝐽𝑎𝑝𝑎𝑛
(10%) from {𝑟𝐽𝑎𝑝𝑎𝑛
(1)
, 𝑟𝐽𝑎𝑝𝑎𝑛
(2)
, … , 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
} and calculate 
the threshold as 𝑟̃𝐽𝑎𝑝𝑎𝑛
(10%) 𝑛𝐽𝑎𝑝𝑎𝑛
⁄
, where 𝑛𝐽𝑎𝑝𝑎𝑛 is the number of participants in the 
gepotidacin group.  
4.2.3.4. 
Tipping point analysis for missing data 
The observed proportion of participants achieving therapeutic success on the gepotidacin 
arm in this study will be calculated using the same approach as the primary analysis.  
The threshold will be derived given the assumed success rate as follows. Note that the 
number of replications is set to 1,000,000. 
1. Set 𝑝𝑔𝑙𝑜𝑏𝑎𝑙
(𝑖)
 as the assumed success rate on the gepotidacin arm in the participants 
with missing therapeutic response of the global studies. 
2. Set 𝑗= 1 
i. 
Set 𝑘= 1 
ii. Draw 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
 𝑗,𝑚𝑖𝑠𝑠 from a binomial distribution (𝑠𝑖𝑧𝑒= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
𝑚𝑖𝑠𝑠
, 𝑝𝑟𝑜𝑏𝑎𝑏𝑖𝑙𝑖𝑡𝑦=
𝑝𝑔𝑙𝑜𝑏𝑎𝑙
(𝑖)
) 
, where 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
𝑚𝑖𝑠𝑠
 and 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
 𝑗,𝑚𝑖𝑠𝑠 are the number of subjects with missing 
therapeutic response and the number of responders out of those with missing 
therapeutic response, respectively.  
iii. Draw 𝑟𝑘,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 from Beta-binomial distribution (𝑠𝑖𝑧𝑒= 𝑛𝑘,𝐽𝑎𝑝𝑎𝑛, 𝛼=
𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
∗
, 𝛽= 𝑛𝑘,𝑔𝑙𝑜𝑏𝑎𝑙−𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
∗
) 
𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
∗
= 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
𝑜𝑏𝑠
+ 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
 𝑗,𝑚𝑖𝑠𝑠, where 𝑟𝑘,𝑔𝑙𝑜𝑏𝑎𝑙
𝑜𝑏𝑠
 is the observed number of 
participants achieving therapeutic success on the gepotidacin arm in 𝑘𝑡ℎ stratum 
of the global studies.  
iv. 𝑘←𝑘+ 1 
v. Repeat step I-V until 𝑘 =  𝐾 
3. Calculate 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
= 𝑟1,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ 𝑟2,𝐽𝑎𝑝𝑎𝑛
(𝑗)
+ ⋯+ 𝑟4,𝐽𝑎𝑝𝑎𝑛
(𝑗)
 


 
CONFIDENTIAL 
 
214144 
 
Page 26 of 93 
4. 𝑗←𝑗+ 1 
5. Repeat step 2-8 until 𝑗= 1,000,000 
6. Obtain 10th percentile 𝑟̃𝐽𝑎𝑝𝑎𝑛
(10%) from {𝑟𝐽𝑎𝑝𝑎𝑛
(1)
, 𝑟𝐽𝑎𝑝𝑎𝑛
(2)
, … , 𝑟𝐽𝑎𝑝𝑎𝑛
(𝑗)
} and calculate the 
threshold as 𝑟̃𝐽𝑎𝑝𝑎𝑛
(10%) 𝑛𝐽𝑎𝑝𝑎𝑛
⁄
, where 𝑛𝐽𝑎𝑝𝑎𝑛 is the number of participants in the 
gepotidacin group.  
Tipping point analysis will be done as follows.  
1. A grid of values will be established, ranging from 0.0 to 1.00 in steps of 2.5%, 
establishing the assumed therapeutic success rates on the gepotidacin arm in 
participants with missing therapeutic response of the global studies.  
2. For each assumed response rate, 𝑝𝑔𝑙𝑜𝑏𝑎𝑙
(𝑖)
, calculate the threshold through simulation 
steps which is shown above.  
4.2.3.5. 
Impact by GCP violation 
There was GCP violation in Site 
 and the participants from the site were excluded 
from the primary analysis. For transparency, the sensitivity analysis including those 
participants will be done. This analysis is based on micro-ITT-ALL NTF-S (Entire) 
population. The same approach as the primary analysis except for the analysis population 
will be done.  
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Therapeutic Response at TOC Visit 
4.3.1.1. 
Definition of Estimands 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at Baseline that all are susceptible to 
nitrofurantoin 
• 
Treatment Condition: Gepotidacin 1500mg BID for 5 days versus nitrofurantoin 
100 mg BID for 5 days, regardless of adherence.  
• 
Variable: Therapeutic response at the TOC Visit (see Section 6.2.1.1 and Section 
6.2.1.2) 
• 
Summary Measure: Difference in proportions of participants achieving therapeutic 
success in the gepotidacin and nitrofurantoin treatment groups.  
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of microbiological and 
clinical response (see Section 6.2.1.1 and Section 6.2.1.2) 
PPD


 
CONFIDENTIAL 
 
214144 
 
Page 27 of 93 
4.3.1.2. 
Main analytical approach 
This analysis is based on micro-ITT NTF-S Population.  
The number and proportion of participants achieving therapeutic success will be 
summarized, along with the 95% Exact Clopper Pearson CI at the TOC Visit by 
treatment group. ICE of use of other systemic antimicrobials is captured through the 
defining criteria of microbiological and clinical response (Section 6.2.1.1 and Section 
6.2.1.2). Participants who do not return for the TOC Visit or have missing data at the 
TOC Visit will be treated as failures.  
The difference in proportions of participants achieving therapeutic success for 
gepotidacin compared to nitrofurantoin and the 95%CI of the difference will be 
summarized at TOC Visit. Miettinen-Nurminen (score) confidence limits of the treatment 
difference will be computed. The MN estimate of the common risk difference and 
variance is computed by combining the point estimates and variances from individual 
strata using MN weights. The estimate uses inverse variance stratum weights to produce 
MN confidence limits for the stratum risk differences. The mathematics and algorithm of 
MN method can be found in the SAS procedure guide under “Summary Score Estimate 
of the Common Risk Difference” [SAS, 2018]. 
4.3.1.3. 
Supplementary analyses 
Bayesian dynamic borrowing will be carried out to estimate the treatment difference in 
the Japanese population using data from each treatment group of the global studies 
(Studies 204989 and 212390).  
The prior distribution is a mixture distribution with 2 components, one reflecting the 
results from the global studies, and a vague component reflecting ‘weak information’ 
about the treatment difference [Schmidli, 2014]  
Denoting the difference (gepotidacin – nitrofurantoin) as Δ, the prior has the form:  
𝑓(Δ) = 𝑤× 𝑓𝑖𝑛𝑓(Δ) + (1 −𝑤) × 𝑓𝑣𝑎𝑔(Δ) 
• 
𝑓𝑖𝑛𝑓(Δ) = 𝑁𝑜𝑟𝑚𝑎𝑙(Δ|𝜇̂𝑔, 𝑠̂𝑔
2): 𝑖𝑛𝑓𝑜𝑟𝑚𝑎𝑡𝑖𝑣𝑒 𝑐𝑜𝑚𝑝𝑜𝑛𝑒𝑛𝑡 
• 
𝑓𝑣𝑎𝑔(Δ) = 𝑁𝑜𝑟𝑚𝑎𝑙(Δ|−0.10, 𝑠̂𝑔
2 (
1
𝑛𝑎𝑔+
1
𝑛𝑐𝑔)
⁄
) : 𝑣𝑎𝑔𝑢𝑒 𝑐𝑜𝑚𝑝𝑜𝑛𝑒𝑛𝑡 
• 
𝑤∈[0, 1]: 𝑓𝑖𝑥𝑒𝑑 𝑖𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 
, where 𝜇̂𝑔, 𝑠̂𝑔
2 are the MN estimate of the common risk difference and variance on the 
proportion of participants achieving therapeutic success between gepotidacin and 
nitrofurantoin using the pooled data of both global studies. Similarly, 𝑛𝑎𝑔 𝑎𝑛𝑑 𝑛𝑐𝑔 are 
the pooled number of participants on the gepotidacin and nitrofurantoin arms in the 
global studies, respectively. Note that this prior will be based on micro-ITT NTF-S 
(Global) Population.  


 
CONFIDENTIAL 
 
214144 
 
Page 28 of 93 
The prior mixture will be updated with the MN estimate of the common risk difference 
and variance on the proportion of participants achieving therapeutic success between 
gepotidacin and nitrofurantoin using the data from this study (micro-ITT NTF-S 
Population) to obtain the posterior mixture. The prior and posterior median of treatment 
difference and 95% credible interval will be presented by each initial weight (w = 0 to 1.0 
by 0.05). The other set of initial weights may be explored.  
4.3.2. 
Clinical Outcome and Response at the TOC Visit 
4.3.2.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at Baseline that all are susceptible to 
nitrofurantoin 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Clinical outcome and response at the TOC Visit (see Section 6.2.1.2) 
• 
Summary Measure:  
• 
Proportion of participants in each outcome category in the gepotidacin arm 
(Clinical outcome) 
• 
Proportion of participants achieving clinical success in the gepotidacin arm 
(Clinical response) 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of clinical response (see 
Section 6.2.1.2) 
4.3.2.2. 
Main analytical approach 
This analysis is based on micro-ITT NTF-S Population.  
The number and proportion of participants achieving clinical success will be summarized, 
along with the 95% Exact Clopper Pearson CI at the TOC Visit by treatment group. In 
addition, the number and proportion of participants in each outcome category will be 
summarized at the TOC Visit by treatment group.  
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of clinical outcome and response (Section 6.2.1.2). Participants who do not return for the 
TOC Visit or have missing data at the TOC Visit will be treated as failures.  


 
CONFIDENTIAL 
 
214144 
 
Page 29 of 93 
4.3.3. 
Microbiological Outcome and Response at the TOC  
4.3.3.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) at Baseline that all are susceptible to 
nitrofurantoin 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Microbiological outcome and response at the TOC Visit (see Section 
6.2.1.1) 
• 
Summary Measure:  
• 
Proportion of participants in each outcome category in the gepotidacin arm 
(Microbiological outcome) 
• 
Proportion of participants achieving microbiological success in the gepotidacin 
arm (Microbiological response) 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials prior to the visit of interest – composite strategy. 
This ICE is captured through the definitions of microbiological response (see 
Section 6.2.1.1) 
4.3.3.2. 
Main analytical approach 
This analysis is based on micro-ITT NTF-S Population.  
The number and proportion of participants achieving microbiological success will be 
summarized, along with the 95% Exact Clopper Pearson CI at the TOC Visit by 
treatment group. In addition, the number and proportion of participants in each outcome 
category will be summarized at the TOC Visit by treatment group.  
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of microbiological outcome and response (Section 6.2.1.1). Participants who do not 
return for the TOC Visit or have missing data at the TOC Visit will be treated as failures.  
4.3.4. 
Therapeutic Response at the TOC Visit in MDR 
4.3.4.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline(see the details in Section 6.2.11) 


 
CONFIDENTIAL 
 
214144 
 
Page 30 of 93 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Therapeutic response at the TOC Visit (see Section 6.2.1.1 and Section 
6.2.1.2) 
• 
Summary Measure: Proportion of participants achieving therapeutic success in the 
gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of microbiological and 
clinical response (see Section 6.2.1.1 and Section 6.2.1.2) 
4.3.4.2. 
Main analytical approach 
This analysis is based on micro-ITT MDR Population.  
The number and proportion of participants with therapeutic success will be presented by 
treatment group at the TOC Visit along with the 95% Exact Clopper Pearson CI. 
Participants who do not return for the TOC Visit or have missing data a t the TOC Visit 
will be treated as failures.  
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of microbiological and clinical response (Section 6.2.1.1 and Section 6.2.1.2).  
4.3.4.3. 
Supplementary analyses 
Additional estimand is described by the following attributes: 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days vs Nitrofurantoin 100 
mg BID for 5 days, regardless of adherence 
• 
Variable: Therapeutic response at the TOC Visit 
• 
Summary Measure: Proportion of participants achieving therapeutic success in the 
gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of microbiological and 
clinical response (see Section 6.2.1.1 and Section 6.2.1.2) 


 
CONFIDENTIAL 
 
214144 
 
Page 31 of 93 
Bayesian dynamic borrowing will be carried out to estimate the treatment difference in 
MDR subgroup in the Japanese population using pooled data from each treatment group 
of the global studies (Studies 204989 and 212390).  
The prior distribution is a mixture distribution with 2 components, one reflecting the 
results from the global studies, and a vague component reflecting ‘weak information’ 
about the treatment difference [Schmidli, 2014].  
Denoting the difference (gepotidacin – nitrofurantoin) as ΔMDR, the prior has the form:  
ℎ(ΔMDR) = 𝑤× ℎ𝑖𝑛𝑓(ΔMDR) + (1 −𝑤) × ℎ𝑣𝑎𝑔(ΔMDR) 
• 
ℎ𝑖𝑛𝑓(Δ) = 𝑁𝑜𝑟𝑚𝑎𝑙(Δ|𝜇̂𝑔,𝑀𝐷𝑅, 𝑠̂𝑔,𝑀𝐷𝑅
2
): 𝑖𝑛𝑓𝑜𝑟𝑚𝑎𝑡𝑖𝑣𝑒 𝑐𝑜𝑚𝑝𝑜𝑛𝑒𝑛𝑡 
• 
ℎ𝑣𝑎𝑔(ΔMDR) = 𝑁𝑜𝑟𝑚𝑎𝑙(Δ|−0.1, 𝑠̂𝑔,𝑀𝐷𝑅
2
(
1
𝑛𝑎𝑔,𝑀𝐷𝑅+
1
𝑛𝑐𝑔,𝑀𝐷𝑅)
⁄
) : 𝑣𝑎𝑔𝑢𝑒 𝑐𝑜𝑚𝑝𝑜𝑛𝑒𝑛𝑡 
• 
𝑤∈[0, 1]: 𝑓𝑖𝑥𝑒𝑑 𝑖𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 
, where 𝜇̂𝑔,𝑀𝐷𝑅, 𝑠̂𝑔,𝑀𝐷𝑅
2
 are crude estimate of the risk difference and variance on the 
proportion of participants achieving therapeutic success between gepotidacin and 
nitrofurantoin using the pooled data from MDR subgroup of both global studies. 
Similarly, 𝑛𝑎𝑔,𝑀𝐷𝑅 𝑎𝑛𝑑 𝑛𝑐𝑔,𝑀𝐷𝑅 are the pooled number of participants on the gepotidacin 
and nitrofurantoin arms in MDR subgroup of the global studies, respectively. Note that 
this prior will be based on micro-ITT MDR (Global) Population.  
The prior mixture will be updated with the risk difference and its standard deviation 
derived from MDR subgroup data in this study (micro-ITT MDR population). The risk 
difference and its standard deviation will be obtained as follows to avoid 0 cell problem.  
1. Beta (0.5, 0.5) will be updated with (𝑛𝑎𝑗,𝑀𝐷𝑅, 𝑟𝑎𝑗,𝑀𝐷𝑅) 𝑎𝑛𝑑 (𝑛𝑐𝑗,𝑀𝐷𝑅, 𝑟𝑐𝑗,𝑀𝐷𝑅), 
respectively.  
2. Mean and variance on each treatment arm, 
(𝜇𝑎𝑗,𝑀𝐷𝑅, 𝑠𝑎𝑗,𝑀𝐷𝑅
2
) 𝑎𝑛𝑑 (𝜇𝑐𝑗,𝑀𝐷𝑅, 𝑠𝑐𝑗,𝑀𝐷𝑅
2
), will be obtained from each posterior.  
3. Risk difference = 𝜇𝑎𝑗,𝑀𝐷𝑅−𝜇𝑐𝑗,𝑀𝐷𝑅 
4. Standard deviation = √𝑠𝑎𝑗,𝑀𝐷𝑅
2
+ 𝑠𝑐𝑗,𝑀𝐷𝑅
2
 
, where 𝑛𝑎𝑗,𝑀𝐷𝑅 𝑎𝑛𝑑 𝑛𝑐𝑗,𝑀𝐷𝑅 are the number of participants on gepotidacin and 
nitrofurantoin arms, respectively, and 𝑟𝑎𝑗,𝑀𝐷𝑅 𝑎𝑛𝑑 𝑟𝑐𝑗,𝑀𝐷𝑅 are the number of participants 
achieving therapeutic success on gepotidacin and nitrofurantoin arms, respectively. The 
prior and posterior median and 95% credible interval will be presented by each initial 
weight (w = 0 to 1.0 by 0.05). The other set of initial weights may be explored.  


 
CONFIDENTIAL 
 
214144 
 
Page 32 of 93 
4.3.5. 
Clinical Outcome and Response at the TOC Visit in MDR 
4.3.5.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis who 
have qualifying uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Clinical outcome and response at the TOC Visit (see Section 6.2.1.2) 
• 
Summary Measure:  
• 
Proportion of participants in each outcome category in the gepotidacin arm 
(Clinical outcome) 
• 
Proportion of participants achieving clinical success in the gepotidacin arm 
(Clinical response) 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of clinical response (see 
Section 6.2.1.2) 
4.3.5.2. 
Main analytical approach 
This analysis is based on micro-ITT MDR Population.  
The number and proportion of participants with clinical success will be presented by 
treatment group at the TOC Visit along with the 95% Exact Clopper Pearson CI. In 
addition, the number and proportion of participants in each outcome category will be 
summarized by treatment group at the TOC Visit.  
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of clinical outcome and response (Section 6.2.1.2). Participants who do not return for the 
TOC Visit or have missing data at the TOC Visit will be treated as failures.  
4.3.5.3. 
Supplementary analyses 
Additional estimand is described by the following attributes: 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days vs Nitrofurantoin 100 
mg BID for 5 days, regardless of adherence 


 
CONFIDENTIAL 
 
214144 
 
Page 33 of 93 
• 
Variable: Clinical response at the TOC Visit 
• 
Summary Measure: Proportion of participants achieving clinical success in the 
gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy. This ICE is captured through the definitions of clinical response (see 
Section 6.2.1.2) 
The same BDB approach will be used as therapeutic response in MDR (Refer to Section 
4.3.4.3).  
4.3.6. 
Microbiological Outcome and Response at the TOC Visit in MDR 
4.3.6.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis who 
have qualifying uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Microbiological outcome and response at the TOC Visit (see Section 
6.2.1.1) 
• 
Summary Measure:  
• 
Proportion of participants in each outcome category in the gepotidacin arm 
(Microbiological outcome) 
• 
Proportion of participants achieving clinical success in the gepotidacin arm 
(Microbiological response) 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials prior to the visit of interest – composite strategy. 
This ICE is captured through the definitions of microbiological response (see 
Section 6.2.1.1) 
4.3.6.2. 
Main analytical approach 
This analysis is based on micro-ITT MDR Population.  
The number and proportion of participants with microbiological success will be presented 
by treatment group at the TOC Visit along with the 95% Exact Clopper Pearson CI. In 
addition, the number and proportion of participants in each outcome category will be 
summarized by treatment group at the TOC Visit.  


 
CONFIDENTIAL 
 
214144 
 
Page 34 of 93 
The ICE of use of other systemic antimicrobials is captured through the defining criteria 
of microbiological outcome and response (Section 6.2.1.1). Participants who do not 
return for the TOC Visit or have missing data at the TOC Visit will be treated as failures.  
4.3.6.3. 
Supplementary analyses 
Additional estimand is described by the following attributes: 
• 
Population: Japanese female participants with acute uncomplicated cystitis with 
qualifying bacterial uropathogen(s) resistance to “two or more” specific classes of 
antimicrobials at Baseline 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days vs Nitrofurantoin 100 
mg BID for 5 days, regardless of adherence 
• 
Variable: -Microbiological response at the TOC Visit 
• 
Summary Measure: Proportion of participants achieving microbiological success in 
the gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials prior to the visit of interest – composite strategy. 
This ICE is captured through the definitions of microbiological response (see 
Section 6.2.1.1) 
The same BDB approach will be used as therapeutic response in MDR (Refer to Section 
4.3.4.3).  
4.3.7. 
Investigator Assessment of Clinical Response at the TOC Visit 
4.3.7.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Investigator assessment of clinical response at the TOC Visit 
• 
Summary Measure: Proportion of participants with investigator assessed clinical 
response of success, failure and indeterminate/missing on the gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – treatment policy 
• 
Use of systemic antimicrobials on or prior to the visit of interest – composite 
strategy 


 
CONFIDENTIAL 
 
214144 
 
Page 35 of 93 
4.3.7.2. 
Main analytical approach 
This analysis is based on ITT Population. Below are the categories of response and 
response.  
Definition 
Clinical Response 
Sufficient resolution of acute cystitis signs and symptoms such that no additional 
systemic antimicrobial therapy is required for the current infection 
Clinical Success 
Participant met any one of the criteria below: 
• 
No apparent response to treatment (persistence or progression of any 
pretreatment clinical signs and symptoms) 
• 
Use of additional systemic antibiotic(s) for the current infection 
• 
Death related to acute cystitis prior to the visit 
Clinical Failure 
Determination of clinical response could not be made at the visit for any of the following 
reasons: 
• 
Participant was lost to follow-up and/or the clinical assessment was not 
undertaken 
• 
Use of confounding systemic antibiotic(s) for another infection 
• 
Death prior to the visit where acute cystitis was clearly noncontributory 
Indeterminate 
The missing data at TOC visit including outside the analysis window will be handled as 
shown in Section 6.2.1.5.  
The number and proportion of participants with investigator assessed clinical response of 
success, failure and indeterminate/missing at the TOC Visit by treatment group based on 
ITT Population. Reasons for an assessment of failure and indeterminate responses will 
also be summarized.  
The 95% Exact Clopper Pearson CI for the proportion of participants with success will be 
presented as a binomial proportion for each treatment group.  
4.3.8. 
Gepotidacin plasma and urine PK concentrations 
4.3.8.1. 
Definition of Estimand 
• 
Population: Japanese female participants with acute uncomplicated cystitis 
• 
Treatment Condition: Gepotidacin 1500 mg BID for 5 days, regardless of 
adherence 
• 
Variable: Gepotidacin plasma and urine PK concentrations 
• 
Summary Measure: Summary statistics (appropriate for each type of endpoint) in 
the gepotidacin arm 
• 
Handling of Intercurrent Event:  
• 
Study treatment discontinuation (due to any reason) – while on treatment 
strategy (treatment phase defined as from first dose to On-therapy Visit) 


 
CONFIDENTIAL 
 
214144 
 
Page 36 of 93 
4.3.8.2. 
Main analytical approach 
The analysis is based on the PK population.  
All calculations of PK concentrations will be based on actual sampling times that fall 
within the set PK windows described below.  
Summary statistics (n, arithmetic mean, geometric mean, median, standard deviation, 
minimum, maximum, 95% CI of the arithmetic and geometric means and between 
participant coefficient of variation [%CV and %CVb]) for plasma and urine gepotidacin 
concentrations will be provided by the sampling windows in Table 1. If PK 
concentrations are not quantifiable, these values will be imputed as 0.  
PK samples collected outside of the treatment phase will only be listed.  
If more than one concentration data is available within the same PK window at a 
scheduled time point, the data closer to 12 hours post-latest dose will only be used for the 
summary statistics of Pre-Dose. For Post-Dose, data closer to 2 hours post-latest dose 
will only be used for the summary statistics. 
PK concentrations will be listed based on PK (Full) population (i.e. including the 
participants impacted by GCP violation).  
Table 1 
PK Summary by sampling windows 
Visit 
Parameter 
PK Window 
Baseline Study Day 1 
Cday1, 0-2h 
Average concentration post-dose 0 to ≤ 2 hours 
Cday1, >2h 
Average concentration post-dose >2 hours 
 
Cday2-5, pre-dose 
Average concentration pre-dose 
On-Therapy Study Day 2 to 
5 
Cday2-5, 0-2h 
Average concentration post-dose 0 to ≤ 2 hours 
Cday2-5, >2h 
Average concentration post-dose >2 hours 
4.4. 
Exploratory Endpoint(s) Analyses 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 37 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 38 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 39 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 40 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 41 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 42 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 43 of 93 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 44 of 93 
4.6. 
Safety Analyses 
The safety analyses will be based on the Safety Analysis population, unless otherwise 
specified. 
4.6.1. 
Extent of Exposure 
Exposure will be summarized by treatment group for the Safety population using the 
following parameters.  
• 
Duration of treatment (days): Rounding of the last dose date/time – the first dose 
date/time + (0.5 in days) to the nearest integer.  
• 
Average daily dose (mg) 
• 
Cumulative actual dose (mg) 
• 
Compliance rate (%) 
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 45 of 93 
In addition, the number of participants with <80%, >=80%-<100% and 100% compliance 
rate will be summarized. In addition, listing will be produced for the exposure data.  
Compliance rate (%) will be calculated as:  
Study intervention 
Formula 
Gepotidacin/gepotidacin placebo 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑡𝑎𝑘𝑒𝑛
20
∗100 (%) 
Nitrofurantoin/nitrofurantoin placebo 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
10
∗100 (%) 
4.6.2. 
Adverse Events 
An adverse event (AE) is considered treatment emergent if the AE onset date/time is on 
or after study intervention start date/time. If time is missing, only date will be compared. 
All AE and SAE summaries (including AESI) will be based on Treatment emergent 
adverse events unless otherwise specified.  
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary).  
An overview summary of AEs, including counts and percentages of participants will be 
produced with:  
• 
Any AE 
• 
AE by maximum grade 
• 
Study intervention related AEs 
• 
AEs leading to withdrawal from study 
• 
AEs leading to permanent discontinuation of study intervention 
• 
AEs leading to permanent discontinuation of study intervention or withdrawal from 
study 
• 
Study intervention related AEs leading to permanent discontinuation of study 
intervention 
• 
SAEs 
• 
Non-serious AEs 
• 
Study intervention related SAE 
• 
Fatal SAEs 
• 
SAEs leading to permanent discontinuation of study intervention 
• 
AEs of special interest (3 types of AESI will be provided separately) 
In addition to overall summary, separate summaries of AE will be produced according to 
the below table. Note that missing grade of AE will be imputed as “Severe”.  


 
CONFIDENTIAL 
 
214144 
 
Page 46 of 93 
 
Summary by PT 
Summary by PT and SOC 
Summary by PT, SOC 
and Maximum Grade 
Any AEs 
 
Y 
Y 
Study intervention related 
AEs 
 
Y 
Y 
AEs leading to permanent 
discontinuation of study 
intervention 
 
Y 
Y 
Common (>= 1%) AEs 
Y 
 
 
Serious AEs 
 
Y 
Y 
Non-serious study 
intervention related AEs 
Y 
 
 
Serious Fatal and Non-Fatal 
study intervention related 
AEs 
Y 
 
 
Furthermore, the following summaries will be produced for disclosure purpose.  
• 
Summary of Common (>=5%) non-serious Adverse Events by SOC and PT 
(Number of Subjects and Occurrences) 
• 
Summary of SAEs by SOC and PT (Number of Subjects and Occurrences) 
A study intervention-related AE is defined as an AE for which the investigator classifies 
the possible relationship to study intervention as “Yes”. A worst-case scenario approach 
will be taken to handle missing relatedness data, i.e., the summary table will include 
events with the relationship to study intervention as ‘Yes’ or missing.  
A study intervention-related SAE is defined as an SAE for which the investigator 
classifies the relationship to study intervention as “Yes”. A worst-case scenario approach 
will be taken to handle missing data, i.e., the summary table will include events with the 
relationship to study intervention as ‘Yes’ or missing. 
Common (>=X%) AEs are defined as AEs with >=X% incidence (before rounding) in 
any treatment group.  
The following listings will be produced.  
• 
All Adverse Events 
• 
Serious Adverse Events and Reasons for Considering as a Serious Adverse Event.  
• 
Subject Profile for Death 
4.6.2.1. 
Adverse Events of Special Interest 
The following will be considered adverse events of special interest (AESI) for the 
purpose of analyses: Clostridium difficile, Cardiovascular, Gastrointestinal, and Potential 
Acetylcholinesterase-Inhibition AESIs. The definitions and derivations are provided for 
each AESI in Section 6.2.2.1.  


 
CONFIDENTIAL 
 
214144 
 
Page 47 of 93 
Clostridium difficile AESIs 
This will be included in the overall summary of AEs.  
Cardiovascular and Gastrointestinal AESIs 
The number and percentage of participants with an event will be summarized by PT, 
SOC and maximum grade. In addition, the incidence of AEs of GI effects and time to the 
first occurrence will be summarized.  
Potential Acetylcholinesterase-Inhibition AESIs 
Any reported AE listed in the Section 6.2.2.1 with a start time no later than 12 hours after 
the latest dose administered, as evaluated by the investigator as per the DMID grading 
criteria provided in the protocol Section 10.12 Appendix 12: Division of Microbiology 
and Infectious Disease Adult Toxicity Tables for Adverse Event Assessment, will be 
included in the programmatic identification of a potential Acetylcholinesterase-Inhibition 
(AchE-I) AESI.  
Cumulative grade score of potential AchE-I events will be calculated as the sum of the 
grade of each reported AE. This enables the number of AEs and the severity of each AE 
to be taken into account. The grading scale is defined in Table 2.  
Table 2 
AchE-I Cumulative Grade Score Scale 
Cumulative Grade: 
0 
1 
2 
3 
4 
Cumulative Grade Score: 
0 
1 to 3 
4 to 6 
7 to 10 
≥11 
For instance, if a participant reports two AEs, one of Grade 1 and the other of Grade 3, 
their cumulative grade score of 4 would result in cumulative grade 2. If a participant 
reports no AEs, their cumulative grade score of 0 would result in cumulative grade 0. 
This will be calculated for All AchE-I events, non-GI AchE-I events and GI aChE-T 
events, however only All AchE-I events and non-GI AchE-I events will be summarized.  
AchE-I AESIs and non-GI AchE-I events will be summarized by SOC, PT and maximum 
grade. Separate tables will summarize AchE-I AESI by number of events and unique PT. 
In addition, the following parameters of AchE-I events will also be summarized, and 
repeated for non-GI AchE-I and GI AchE-I events. 
Time of onset (hours):  
1. Definition  
Time of onset (hours) is defined as time from first dose to the start date of the first 
event in hours. The first event is defined as the treatment emergent AE of which start 
date is the earliest within each participant. If the start time of the first event is 
missing, 00:00 will be imputed to calculate the time of onset. Time of onset will be 
rounded to the nearest hour, which will be zero hour if time of onset is <30 minutes.  


 
CONFIDENTIAL 
 
214144 
 
Page 48 of 93 
2. Analytical approach 
Time of onset will be summarised for each type of AChE-I by treatment group.  
Time since end of treatment (hours):  
1. Definition  
Time since end of treatment is defined as the time from the end date of the treatment 
to the non-missing end date of the last event, which will be derived as follows.  
1) For missing end date of the treatment emergent AEs, the earliest date of death and 
the last contact date will be imputed.  
2) The last event will be identified as the treatment emergent AEs of the latest end 
date including the imputed end date per each participant. If there are more than 
one AEs that have the same end date but some AEs have missing end time and the 
other has non-missing end time, the AE with non-missing end time will be chosen 
as the last event.  
3) For missing end time of the last event, 23:59 will be imputed.  
4) Time since end of treatment will be computed as (End date/time of the last event 
– treatment end date/time) 
2. Analytical approach 
For participants with the positive value of time since end of treatment which was 
calculated from non-missing end date, the time since end of treatment will be 
summarised for each category of AChE-I event (if any) by treatment group.  
In addition, the following numbers will be presented for each AChE-I categories by 
treatment group.  
1) The number of participants with the last AChE-I event end date imputed  
2) The number of participants who have no event of any type of AChE-I with an end 
date after the end of treatment  
Duration (days): 
1. Definition 
Duration in days will be computed as the difference from the start date of the first 
event to the end date of the last event (imputed end date of last event – start date of 
first event + 1). The first and last events defined are the same also for the time of 
onset and time since end of treatment, respectively.  
2. Analytical approach 
Duration will be summarised for each AChE-I categories by treatment group.  
AchE-I events with a start time less than or equal to 6 hours after the latest dose 
administered will also be flagged in the dataset.  


 
CONFIDENTIAL 
 
214144 
 
Page 49 of 93 
4.6.2.2. 
COVID-19 Assessment and COVID-19 AEs 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
COVID-19 assessments for participants with COVID-19 AEs will be summarized. 
4.6.2.3. 
Impact of COVID-19 Pandemic on Safety Results 
The summary of the incident rates of AE before and after the start of the COVID-19 will 
not be producedsince this study starts after the beginning of the COVID-19 pandemic.  
4.6.2.4. 
Quantitative Screening for Identification of Potential Adverse Reaction 
Frequentist approach to screen for potential ARs will be used. Specifically, the Crowe 
method [Crowe, 2013] will be applied for initial screening of the large number of adverse 
events to generate a “short list” of potential ARs. Due to the smaller sample size than the 
global studies, this method is based on the HLT relative risk (incidence rate on 
gepotidacin arm divided by that on nitrofurantoin arm).  
Screening criteria endorsed are displayed in Table 3.  
Table 3 
Criteria for Quantitative Screening for Potential ARs. 
Absolute Incidence in Nitrofurantoin 
Subjects 
HLT relative risk (Gepotidacin vs 
Nitrofurantoin) 
95% CI for HLT RR* 
No condition 
1.25 
No condition 
Note that any event which has not occurred on nitrofurantoin arm but occurred on 
gepotidacin arm will be included in the “short list”. In addition, the following AEs will 
automatically be included in the “short list” of potential ARs for further qualitative 
evaluation: 
• 
QT Prolongation: It is a very rare serious event that has been observed in early phase 
gepotidacin studies and therefore needs further evaluation. It is identified using HLT 
“ECG investigations”. 
• 
Serious and severe adverse events: The incidence of serious and severe AEs is 
expected to be very low and the qualitative assessment will be applied directly to 
these events without going through the quantitative screening process. 
• 
Fungal infections: It is a known AR for nitrofurantoin. It is identified using HLT 
“Fungal infections NEC”. 
• 
Hepatobiliary disorders: It is a known AR for nitrofurantoin. It is identified using 
HLT “Hepatic and hepatobiliary disorders”. 
• 
AESI specified in Section 6.2.2.1.  
• 
AEs with PT as “Hyperhidrosis” or “Dysarthria” 


 
CONFIDENTIAL 
 
214144 
 
Page 50 of 93 
A summary table of treatment emergent adverse events meeting the pre-specified 
quantitative screening criteria by SOC, HLTs and PTs with incidence (%) for each 
treatment group, RR, and the associated 95% CI will be generated.  
In addition, the following outputs will be generated.  
• 
Summary of treatment emergent adverse events by SOC, HLT and PTs by subgroups 
(Consistency check between subgroups: Actual Age Category, and Renal 
Impairment Evaluated by Baseline CrCL)  
• 
Actual Age Category: <18, 18-64 and >=65 
• 
Renal Impairment (Baseline Creatinine Clearance): Normal (>=90mL/min), 
Mid-Impairment (>=60 to 89 mL/min), Moderate Impairment (>= 30 to 59 
mL/min), Severe Impairment (< 30mL/min), Missing 
• 
Incidence rate of treatment emergent AEs according to different attributes by HLT 
and treatment group (Consistency check in AE attribute: AEs related to study 
treatment, AEs leading to permanent discontinuation of study treatment, AE leading 
to dose reduction, AE leading to dose interruption /delay, SAEs related to study 
treatment, Fatal SAEs, and Fatal SAEs related to study treatment)  
• 
Summary of treatment emergent AEs by HLT and Maximum Grade (Consistency 
check in AE attribute)  
• 
Summary of Cumulative Incidence of Treatment Emergent Adverse Events (HLTs) 
by Time to First Occurrence (Temporal association). The categories of time to first 
occurrence are below.  
• 
<= 2 days, <= 3 days, <= 4 days, <= 5 days, <= 6 days, <= 7 days, <= 8 days, <= 
9 days, >= 10 days 
4.6.2.5. 
Impact of GCP violation 
This analysis is based on Safety-ALL population. For transparency, the number and 
percentage of participants experiencing any adverse events will be presented by treatment 
arm, SOC and PT.  
4.6.3. 
Additional Safety Assessments 
4.6.3.1. 
Laboratory Data 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by DMID criteria (Section 6.2.4). These summaries will display 
the number and percentage of subjects with a maximum post-baseline grade increasing 
from their baseline grade. Any increase in grade from baseline will be summarized along 
with any increase to a maximum grade of 3 and any increase to a maximum grade of 4. 
Missing baseline grade will be assumed as grade 0. For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labelled by 
direction, e.g., sodium will be summarized as hyponatremia and hypernatremia 
separately. The determination of worst case post-baseline takes into account both planned 
and unscheduled assessments. 


 
CONFIDENTIAL 
 
214144 
 
Page 51 of 93 
For lab tests that are not gradable by DMID criteria (Section 6.2.4), summaries of worst-
case changes from baseline with respect to normal range will be generated. Decreases to 
low, changes to normal or no changes from baseline, and increases to high will be 
summarized for the worst-case post-baseline. If a subject has a decrease to low and an 
increase to high during the same time interval, then the subject is counted in both the 
“Decrease to Low” categories and the “Increase to High” categories.  
Separate summary tables for change from baseline in haematology, and chemistry 
laboratory tests will be produced. Liver function laboratory tests will be included with 
chemistry lab tests. 
A summary of Liver Monitoring/Stopping Event Reporting will be summarized. For 
participants with more than one liver stopping or liver monitoring event, only data related 
to the earliest most severe criteria event is included in the summary. 
Abnormal liver chemistry results will be summarized by increasing folds above the upper 
limit of normal (ULN) including tests of interest and thresholds as follows (including 
data at all the visit including unscheduled visits): 
• 
ALT or AST > 3xULN and Total Bilirubin > 2xULN* 
• 
ALT or AST > 3xULN and ALP < 2xULN and Total Bilirubin ≥ 2xULN 
• 
ALT or AST > 3xULN and Total Bilirubin > 1.5xULN 
• 
Hepatocellular injury: (ALT/ALT ULN)/(ALP/ALP ULN)) >= 5 and ALT >= 
3xULN ** 
• 
ALT or AST ≥ 20xULN 
• 
ALT or AST ≥ 10xULN 
• 
ALT or AST ≥ 8xULN 
• 
ALT or AST ≥ 5xULN 
• 
ALT or AST ≥ 3xULN 
• 
ALT ≥ 20xULN 
• 
ALT ≥ 10xULN 
• 
ALT ≥ 8xULN 
• 
ALT ≥ 5xULN 
• 
ALT ≥ 3xULN 
• 
AST ≥ 20xULN 
• 
AST ≥ 10xULN 
• 
AST ≥ 8xULN 
• 
AST ≥ 5xULN 
• 
AST ≥ 3xULN 


 
CONFIDENTIAL 
 
214144 
 
Page 52 of 93 
• 
Total Bilirubin > 2xULN 
• 
Total Bilirubin > 1.5xULN 
• 
Total Bilirubin > 2xULN and a portion of Direct Bilirubin >= 35% on the same day 
• 
Total Bilirubin > 1.5xULN and a portion of Direct Bilirubin >= 35% on the same 
day 
*: The total Bilirubin elevation must occur on or up to 28 days after the ALT elevation 
**: sign of hepatocellular injury, ALT and ALP values must occur on the same day.  
Urinalysis results will be summarized using descriptive statistics. The severity of renal 
impairment will be evaluated and summarized according to the method in Section 6.2.2.2.  
4.6.3.2. 
Vital Signs 
The number of participants with worst case vital sign results relative to potential clinical 
importance (PCI) criteria which are post-baseline relative to baseline will be summarised 
by test and category. The summary will include baseline data and worst case post-
baseline, and planned visit. The baseline categories are: Low, within Range and High for 
PCI criteria. The change categories for PCI criteria are: To Low, To within Range or No 
Change, To High. The determination of worst case post-baseline takes into account both 
planned and unscheduled assessments. Changes in value from baseline for each vital sign 
will be summarized at every assessed time point. All vital sign data will be listed.  
4.6.3.3. 
ECG 
The number of participants with worst case QTc values relative to potential clinical 
importance criteria which are post-baseline relative to baseline will be summarised. The 
summary will include baseline data and worst case post-baseline, and visits (i.e. On-
Therapy and TOC visits). The baseline categories are: Low, within Range and High for 
PCI criteria. The change categories for PCI criteria are: To Low, To within Range or No 
Change, To High. The determination of worst case post-baseline takes into account both 
planned and unscheduled assessments. A summary of change from baseline in ECG 
values will be produced by visit.  
4.7. 
Other Analyses 
4.7.1. 
Subgroup analyses 
The estimands of these subgroup analyses are the same as that provided in the  
Section 4.3.1.1 (therapeutic response), Section 4.3.2.1 (clinical response) and 
Section 4.3.3.1 (microbiological response).  
These analyses are based on the micro-ITT NTF-S Population. The number and 
proportion of participants achieving therapeutic, clinical and microbiological success at 
the TOC Visit will be presented by treatment arm and the following subgroup:  


 
CONFIDENTIAL 
 
214144 
 
Page 53 of 93 
• 
Age group: < 65 vs ≥ 65 years 
• 
Age category (<=50, >50) 
• 
Acute cystitis recurrence 
• 
Actual stratification combinations as above for age category and acute cystitis 
recurrence  
• 
Qualifying uropathogen species/group isolated at Baseline (including phenotypic 
(e.g., ESBL, MDR) and genotypic subcategories), which is defined in Section 6.2.10.  
• 
Number of Qualified Uropathogens at Baseline (only 1 qualifying uropathogen, two 
qualified uropathogens, one qualified plus additional any number of non-qualified 
uropathogens, only for therapeutic response). If the number of participants in each 
subgroup is >=10, the data will be summarized. Otherwise, these will be provided in 
the dataset. 
4.8. 
Interim Analyses 
No formal interim analysis is planned. Blinded review for therapeutic, clinical and 
microbiological response will be conducted.  
4.8.1. 
Blinded review 
This blinded review aims to assess if the blinded results for the response rates are far 
from the expected. Once approximately 30 participants in micro-ITT NTF-S Population 
have completed the TOC visit, the blinded review will be done using the data from those 
participants. If the following criterion has been met, we will consider the response rate 
may be more variable than planned and the mitigation will be conducted (e.g. training for 
sites).  
Pr(𝑝< 0.6) > 0.5 
This is based on the Bayesian probability and p is pooled therapeutic success rate among 
gepotidacin and nitrofurantoin arms. The prior for p is Beta(0.5, 0.5) and this prior will 
be updated with the number of participants achieving therapeutic success and the number 
of participants in the blinded review (i.e. approximately 30 participants).  
The maximum number of participants achieving therapeutic success to trigger 
considering the mitigation is provided in the Table 4. For example, if we observe <= 18 
participants achieving therapeutic success in 30 participants, we will consider the 
mitigation.  


 
CONFIDENTIAL 
 
214144 
 
Page 54 of 93 
Table 4 
Maximum number of participants achieving therapeutic success 
Number of Participants in blinded review 
Maximum number of participants achieving 
therapeutic success 
25 
15 
26 
15 
27 
16 
28 
16 
29 
17 
30 
18 
31 
18 
32 
19 
33 
19 
34 
20 
35 
21 
4.9. 
Changes to Protocol Defined Analyses 
There were changes below to the originally planned statistical analysis specified in the 
protocol amendment 2 (Dated: [07-NOV-2022]). 
• 
Added the analysis populations due to GCP violation 
• 
Amended the micro-ITT NTF-S (Global) population to align with the primary 
analysis population (i.e., IA set) in the global studies (204989 and 212390).  
• 
Originally, missing data in this study was to be imputed for tipping point analysis 
and multiple imputation sensitivity analysis for missing data. However, a 
conservative approach will be taken in this study where all missing data (regardless 
of the reason for missingness) will be imputed as therapeutic failure. Note that the 
missing data in the global studies (204989 and 212390) will be imputed for tipping 
point analysis and multiple imputation sensitivity analysis.  
5. 
SAMPLE SIZE DETERMINATION 
This study is not designed to demonstrate non-inferiority of the gepotidacin to 
nitrofurantoin but designed to demonstrate consistency of this study with the global 
studies for therapeutic response of the gepotidacin.  
5.1. 
Gepotidacin Sample Size 
Approximately 81 participants in the gepotidacin treatment group is considered an 
appropriate sample size to evaluate consistency between this study and both global 
studies (Studies 204989 and 212390).  
Assuming 81 participants in the micro-ITT NTF-S population on gepotidacin and an 
observed 76% therapeutic success rate out of 884 participants in the global studies, the 


 
CONFIDENTIAL 
 
214144 
 
Page 55 of 93 
therapeutic response in the gepotidacin arm in this study would need to be greater than 
69.1% to declare “consistency” with the global studies.  
5.1.1. 
Sample Size Sensitivity 
Table 5 demonstrates a range of observed therapeutic response rates and the number of 
participants on the gepotidacin arm in this study against the corresponding consistency 
thresholds required in this study assuming 884 participants on the gepotidacin arm in 
both global studies.  
Table 5 
Gepotidacin Consistency Thresholds for Different Observed 
Gepotidacin Therapeutic Response Rate in the Global Studies and 
the Number of Participants on the Gepotidacin arm in this study 
Observed 
Therapeutic 
Response Rate in 
the Global Studies 
Number of Participants on the Gepotidacin arm in this study 
75 
77 
79 
81 
83 
85 
87 
45% 
37.3% 
37.7% 
38.0% 
37.0% 
37.3% 
37.6% 
37.9% 
50% 
42.7% 
42.9% 
43.0% 
42.0% 
42.2% 
42.4% 
42.5% 
55% 
46.7% 
46.8% 
48.1% 
48.1% 
48.2% 
48.2% 
48.3% 
60% 
52.0% 
51.9% 
53.2% 
53.1% 
53.0% 
52.9% 
52.9% 
65% 
57.3% 
57.1% 
58.2% 
58.0% 
57.8% 
57.6% 
58.6% 
70% 
62.7% 
63.6% 
63.3% 
63.0% 
62.7% 
63.5% 
63.2% 
75% 
68.0% 
68.8% 
68.4% 
67.9% 
68.7% 
68.2% 
69.0% 
80% 
73.3% 
74.0% 
73.4% 
74.1% 
73.5% 
74.1% 
74.7% 
5.1.2. 
Nitrofurantoin Sample Size 
The sample size on the nitrofurantoin arm is based on the precision estimate of 95%CI 
for the treatment difference.  
The treatment difference between gepotidacin and nitrofurantoin will be assessed 
descriptively. Table 6 demonstrates a range of observed differences and corresponding 
95% CIs assuming a 3:1 randomization (i.e. 81 participants on gepotidacin and 27 on 
nitrofurantoin in micro-ITT NTF-S population).  


 
CONFIDENTIAL 
 
214144 
 
Page 56 of 93 
Table 6 
95% Confidence Intervals for Different Observed Therapeutic 
Response Rates on the Gepotidacin arm across a Range of 
Differences in Therapeutic Response Rate in Gepotidacin – 
Nitrofurantoin assuming a 3:1 randomization. 
Observed Gepo 
TRR 
Observed difference of TRR in Gepotidacin from that in Nitrofurantoin and corresponding 
95% CI (%) 
10% 
5% 
0% 
-5% 
-10% 
45% 
(-11.0,31.0) 
(-16.4,26.4) 
(-21.7,21.7) 
(-26.8,16.8) 
(-31.7,11.7) 
50% 
(-11.4,31.4) 
(-16.7,26.7) 
(-21.8,21.8) 
(-26.7,16.7) 
(-31.4,11.4) 
55% 
(-11.7,31.7) 
(-16.8,26.8) 
(-21.7,21.7) 
(-26.4,16.4) 
(-31.0,11.0) 
60% 
(-11.7,31.7) 
(-16.6,26.6) 
(-21.3,21.3) 
(-25.9,15.9) 
(-30.3,10.3) 
65% 
(-11.4,31.4) 
(-16.2,26.2) 
(-20.8,20.8) 
(-25.2,15.2) 
(-29.4,9.4) 
70% 
(-11.0,31.0) 
(-15.6,25.6) 
(-20.0,20.0) 
(-24.1,14.1) 
(-28.1,8.1) 
75% 
(-10.3,30.3) 
(-14.7,24.7) 
(-18.9,18.9) 
(-22.8,12.8) 
(-26.4,6.4) 
80% 
(-9.4,29.4) 
(-13.5,23.5) 
(-17.4,17.4) 
(-21.0,11.0) 
(-24.3,4.3) 
5.1.3. 
Proposed Sample Size 
Assuming a 36% evaluability rate, approximately 300 participants will be enrolled and 
randomized to either gepotidacin or nitrofurantoin in a 3:1 ratio to achieve 108 
participants in the micro-ITT NTF-S population (i.e. approximately 81 participants on 
gepotidacin and 27 on nitrofurantoin). Enrolment will continue until the approximate 
target number of participants in the micro-ITT NTF-S Population has been reached. This 
study will be conducted at multiple sites in Japan. 
Note: Enrolled means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. A participant will be considered enrolled if the 
informed consent is not withdrawn prior to participating in any study activity after 
screening. 


 
CONFIDENTIAL 
 
214144 
 
Page 57 of 93 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the ITT and, 
micro-ITT NTF-S Population. A summary of the number of participants in each of the 
participant level analysis set will be provided. 
6.1.1. 
Study Population 
A summary of the number of participants included in each population will be displayed 
based on the Screened Population. In addition, a summary and listing of exclusions from 
study population will be produced based on the ITT population.  
6.1.2. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized. Reasons for study withdrawal will be listed.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the study intervention and the 
ToC visit or have discontinued the study intervention prematurely, as well as primary 
reasons for discontinuation of study intervention and the ToC visit.  
A summary of the number and percentage of participants who passed screening and 
entered the study, who failed screening and therefore were not entered into the study, and 
participants who met eligibility criteria but were not needed will be provided along with 
the reasons for screen failure. The number of participants will be summarized by 
Country, Site Id and Investigator Id based on micro-ITT NTF-S Population.  
6.1.3. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, height/weight, BMI at 
screening and race will be summarized with descriptive statistics. In addition, the 
following age categories will be summarized: <18, 18-64 and >=65 based on the ITT and 
micro-ITT NTF-S populations. The listing of demographic characteristics will be 
produced as well.  
A summary of baseline characteristics will be provided as follows. Data will be listed and 
summarized using descriptive statistics or frequency counts and percentages as 
applicable.  


 
CONFIDENTIAL 
 
214144 
 
Page 58 of 93 
Analysis set 
Baseline characteristics 
ITT Population 
• 
Cardiovascular family history 
ITT, and micro-ITT 
NTF-S Populations 
• 
Actual randomization strata as per IRT system 
• 
Age category 
• 
Baseline acute cystitis recurrence 
• 
Age category as per cCRF (<=50 years, >50 years) 
• 
Baseline acute cystitis recurrence 
• 
The number of episodes of uncomplicated UTI in the past 3 months, 3-6 months 
and 6-12 months.  
• 
Baseline renal impairment category (refer to Section 6.2.2.2 for the details) 
• 
Baseline quantitative bacterial counts by uropathogen 
• 
Number of participants with at least one baseline qualifying uropathogen identified 
by uropathogen.  
• 
Number of baseline uropathogens identified per participant 
• 
Number of baseline qualifying uropathogens identified per participant 
• 
Baseline clinical symptom score 
Micro-ITT Population 
• 
Baseline qualifying uropathogens (including phenotypic and genotypic 
subcategories)  
• 
Baseline qualifying uropathogens by species and group (e.g. Klebsiella spp., other 
Enterobacterales, gram-negative nonfermenters, gram-positive species) 
The proportion in the above summaries is calculated using the total number of baseline 
qualifying uropathogens as denominator. Note that for the participants who have the same 
species of more than one baseline qualifying uropathogens (e.g. 2 E coli.), this will be 
counted multiple times. For example, suppose a participant has 2 identical E coli. and 
another participant has 1 E coli. and 1 Klebsiella spp. For the proportion of E coli over both 
patients is 0.75 (3/4). 
Past medical conditions and current medical conditions as of screening will be 
summarized respectively based on the ITT Population and micro-ITT NTF-S Population. 
If the reported medical condition was resolved before screening, this will be regarded as 
past medical condition. Otherwise, this will be regarded as current medical condition.  
Substance use, including smoking history, cigarettes per day, alcohol and caffeine 
consumption will be summarized based on the ITT Population.  
6.1.4. 
Protocol Deviations 
Important protocol deviations will be summarized based on ITT Population.  
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations (where possible without knowing the study intervention details) 
are captured and categorised in the protocol deviations dataset.  


 
CONFIDENTIAL 
 
214144 
 
Page 59 of 93 
• 
This dataset will be the basis for the summaries of important protocol deviations. 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced for important protocol deviations related to COVID-19 based on the 
ITT Population. Listings of important protocol deviations and subjects with 
inclusion/exclusions criteria deviations will be produced.  
6.1.5. 
Prior and Concomitant Medications 
The analysis is based on the ITT and micro-ITT NTF-S Populations.  
Prior and concomitant medications will be coded using WHO Drug dictionaries. The 
summary of concomitant medications will be provided by Anatomical Therapeutic 
Chemical (ATC) classification Level 1 and ingredient. Note that multi-ingredient 
medications will be summarized for a combination of ingredients. Listing of prior and 
concomitant medications will be produced.  
Separate summaries of prior and concomitant medications will be provided for systemic 
antibiotics as well. An antibiotic is considered systemic if the route is oral, subcutaneous, 
intramuscular, intravenous, or rectal.  
6.1.6. 
Study Intervention Compliance 
Refer to Section 4.6.1.  
6.1.7. 
Additional Analyses Due to the COVID-19 Pandemic 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
Numbers of participants with a suspected, probable or confirmed COVID-19 infection, 
and of COVID-19 test results will be summarized based on the Safety Population.  
Additionally, if greater than 30 participants have a suspected, probable of confirmed 
COVID-19 infection, the following data displays will be produced: 
• 
Summary of current (and/or past) medical conditions for participants with COVID-
19 adverse events. 
• 
Summary of baseline characteristics for participants with COVID-19 adverse events. 


 
CONFIDENTIAL 
 
214144 
 
Page 60 of 93 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Efficacy 
6.2.1.1. 
Microbiological Outcome and Response 
Microbiological response by Baseline Qualifying Uropathogen will be derived at On-
therapy, TOC and Follow-up Visits according to Table 7, Table 8 and Table 9. Only start 
date (not time) of antibiotics use will be considered when deriving the outcome and 
response.  
Participant-level microbiological outcome and response will be derived at On-therapy, 
TOC and Follow-up Visits according to Table 10.  
Microbiological outcome by New Qualifying Uropathogen will be derived at On-therapy 
Visit according to Table 11, Table 12 and Table 13.  
Table 7 
Microbiological Outcome by Baseline Qualifying Uropathogen at the 
On-Therapy Visit 
Defining Criteria 
Outcome 
A quantitative urine culture taken at the On-therapy Visit 
shows that the qualifying bacterial uropathogen 
recovered at Baseline is reduced to <103 CFU/mL, 
without the participant receiving other systemic 
antimicrobials before the On-therapy Visit 
Microbiological eradication 
A quantitative urine culture taken at the On-therapy Visit 
shows that the qualifying bacterial uropathogen 
recovered at Baseline grows  103 CFU/mL, without the 
participant receiving other systemic antimicrobials 
before the On-therapy Visit 
Microbiological persistence 
• 
The On-therapy urine culture result is missing, or  
• 
The participant received other systemic 
antimicrobials before the Ontherapy Visit 
Unable to determine 
CFU=colony-forming units. 
Table 8 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Test of Cure Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered microbiological failures at 
the Follow-up Visit. 
A quantitative urine culture taken at the TOC Visit 
shows reduction of the qualifying bacterial 
uropathogen recovered at Baseline to <103 CFU/mL, 
without the participant receiving other systemic 
antimicrobials before the TOC Visit 
Microbiological eradication 
Microbiological success 
A quantitative urine culture taken at the TOC Visit 
shows that the qualifying bacterial uropathogen 
recovered at Baseline, and which was also shown to 
persist or unable to determine at the On-therapy Visit, 
grows ≥103 CFU/mL, without the participant receiving 
other systemic antimicrobials before the TOC Visit  
Microbiological persistence 
Microbiological failure 


 
CONFIDENTIAL 
 
214144 
 
Page 61 of 93 
Defining Criteria 
Outcome 
Response 
A quantitative urine culture taken at the TOC Visit 
shows that the qualifying bacterial uropathogen 
recovered at Baseline, and which was also shown to 
be eradicated at the On-therapy Visit, grows ≥103 
CFU/mL, without the participant receiving other 
systemic antimicrobials before the TOC Visit 
Microbiological recurrence 
Microbiological failure 
• 
The TOC urine culture result is missing, or 
• 
The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to determine 
Microbiological failure 
CFU=colony-forming units; TOC=Test-of-Cure. 
Table 9 
Microbiological Outcome and Response by Baseline Qualifying 
Uropathogen at the Follow Up Visit 
Defining Criteria 
Outcome 
Response 
Participants considered microbiological failures at the TOC Visit will also be considered microbiological failures at 
the Follow-up Visit. 
A quantitative urine culture taken at the Follow-up Visit 
shows reduction of the qualifying bacterial uropathogen 
recovered at Baseline to <103 CFU/mL, following 
microbiological eradication at the TOC Visit, without the 
participant receiving other systemic antimicrobials before 
the Follow-up Visit 
Sustained microbiological 
eradication 
Microbiological success 
A quantitative urine culture taken at the Follow-up Visit 
shows that the qualifying bacterial uropathogen recovered 
at Baseline grows  103 CFU/mL, following 
microbiological eradication at the TOC Visit, without the 
participant receiving other systemic antimicrobials before 
the Follow-up Visit 
Microbiological recurrence 
Microbiological failure 
A quantitative urine culture taken at the Follow-up Visit 
shows that the qualifying bacterial uropathogen recovered 
at Baseline grows  103 CFU/mL, and also did not 
achieve an outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Microbiological persistence 
Microbiological failure 
A quantitative urine culture taken at the Follow-up Visit 
shows reduction of the qualifying bacterial uropathogen 
recovered at Baseline to <103 CFU/mL, and also did not 
achieve an outcome of microbiological eradication at the 
TOC Visit, without the participant receiving other systemic 
antimicrobials before the Follow-up Visit 
Delayed  
microbiological  
eradication 
Microbiological failure 
• 
The Follow-up urine culture result is missing, or 
• 
The participant received other systemic 
antimicrobials before the Follow-up Visit 
Unable to determine 
Microbiological failure 
CFU=colony-forming units; TOC=Test-of-Cure. 


 
CONFIDENTIAL 
 
214144 
 
Page 62 of 93 
Table 10 
Participant-Level Microbiological Outcome and Response 
Definitions per Study Visit 
Defining Criteria at the On-Therapy Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological outcome 
of eradication at On-therapy 
Microbiological 
eradication 
NA 
At least one qualifying baseline uropathogen has an outcome of 
persistence at On-therapy 
Microbiological 
persistence 
NA 
All qualifying baseline uropathogen outcomes are unable to 
determine at On-therapy  
Unable to determine 
NA 
Defining Criteria at the TOC Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological outcome 
of eradication at TOC 
Microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an outcome of 
persistence at TOC 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an outcome of 
recurrence and none have an outcome of persistence at TOC 
Microbiological 
recurrence 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at TOC 
Unable to determine 
Microbiological 
failure 
Defining Criteria at the Follow-up Visit 
Outcome 
Response 
All qualifying baseline uropathogens have a microbiological outcome 
of sustained eradication at Follow-up 
Sustained 
microbiological 
eradication 
Microbiological 
success 
At least one qualifying baseline uropathogen has an outcome of 
recurrence and none have an outcome of persistence at Follow-up 
Microbiological 
recurrence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an outcome of 
persistence at Follow-up 
Microbiological 
persistence 
Microbiological 
failure 
At least one qualifying baseline uropathogen has an outcome of 
delayed eradication and none have an outcome of persistence or 
recurrence at Follow-up 
Delayed microbiological 
eradication 
Microbiological 
failure 
All qualifying baseline uropathogen outcomes are unable to 
determine at Follow-up 
Unable to determine 
Microbiological 
failure 
NA=Not applicable; TOC=Test-of-Cure. 
Table 11 
Microbiological Outcome by New Qualifying Uropathogen at the On 
Therapy Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not identified at 
Baseline, is documented by quantitative urine culture at 
the On-therapy Visit 
New uropathogen 
Table 12 
Microbiological Outcome by New Qualifying Uropathogen at the 
Test-of-Cure Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not identified at 
Baseline, is documented by quantitative urine culture at 
the Test-of-Cure Visit in a participant who did not 
achieve a clinical outcome of clinical resolution at the 
Test-of-Cure Visit 
New infection 
A new qualifying bacterial uropathogen, not identified at 
Baseline, is documented by quantitative urine culture at 
the Test-of-Cure Visit in a participant who did achieve a 
clinical outcome of clinical resolution at the Test-of-Cure 
Visit 
Colonization 


 
CONFIDENTIAL 
 
214144 
 
Page 63 of 93 
Table 13 
Microbiological Outcome by New Qualifying Uropathogen at the 
Follow up Visit 
Defining Criteria 
Outcome 
A new qualifying bacterial uropathogen, not identified at 
Baseline, is documented by quantitative urine culture at 
the Follow-up Visit in a participant who did not achieve a 
clinical resolution at the Follow-up Visit 
New infection 
A new qualifying bacterial uropathogen, not identified at 
Baseline, is documented by quantitative urine culture at 
the Follow-up Visit in a participant who did achieve a 
clinical resolution at the Follow-up Visit 
Colonization 
6.2.1.2. 
Clinical Outcome and Response 
Clinical signs and symptoms of acute cystitis will be recorded based on participant 
interview per the SoA (Protocol Section 1.3) using the scoring system and instructions 
(Table 14). The total cumulative symptom score is derived by summing the score for 
each individual sign and symptom. If any individual sign and symptom scores are 
missing, then total symptom score will also be missing.  
At TOC, success is defined as normal presentation of signs and symptoms with a total 
cumulative symptom score of zero. Clinical outcome and response will be derived at On-
therapy (Table 15), TOC (Table 16) and Follow-up (Table 17) Visits. Note that 
“resolution”, “improvement” and “worsening or no change” in total symptom score as 
used in the tables below are defined as:  
• 
“Resolution”: Total cumulative symptom score is zero.  
• 
“Improvement”: Change from baseline in total cumulative symptom score is less 
than zero.  
• 
“Worsening or no change”: Change from baseline in total cumulative symptom score 
is greater than or equal to zero.  
Note that only start date of antibiotics use will be considered when deriving the outcome 
and response. 


 
CONFIDENTIAL 
 
214144 
 
Page 64 of 93 
Table 14 
Clinical Signs and Symptoms Scoring System 
Clinical Signs and 
Symptoms 
None 
 
Mild 
Symptom is easily 
tolerated, causing 
minimal discomfort 
and not interfering 
with everyday 
activities 
Moderate 
Symptom is 
sufficiently 
discomforting to 
interfere with normal 
everyday activities 
Severe 
Symptom prevents 
normal everyday 
activities 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
Dysuria 
 
 
 
 
Frequency 
 
 
 
 
Urgency 
 
 
 
 
Lower abdominal or 
suprapubic pain 
 
 
 
 
Table 15 
Clinical Outcome at the On-Therapy Visit 
Defining Criteria 
Outcomea 
Resolution of signs and symptoms of acute cystitis 
present at Baseline (and no new signs and symptoms), 
without the participant receiving other systemic 
antimicrobials not for the current infection before the 
On-therapy Visit and also without receiving an other 
systemic antimicrobials for the current infection prior to 
or at the On-therapy Visit.  
Clinical resolution 
Improvement in total symptom scores from Baseline, but 
not complete resolution, without the participant receiving 
other systemic antimicrobials (not for the current 
infection) before the On-therapy Visit and also without 
receiving an other systemic antimicrobials for the current 
infection prior to or at the On-therapy Visit.  
Clinical improvement 
Worsening or no change in total symptom scores from 
Baseline or the participant received other systemic 
antimicrobials for the current infection prior to or on the 
date of the On-therapy Visit (if the date of On-therapy 
Visit is missing, the end date of the analysis window will 
be used as the date of On-therapy visit) 
Clinical worsening 
• 
The Baseline score is missing (unless On-therapy 
score is 0 and no antibiotics use (either not for 
current infection or for current infection) then 
outcome will be clinical resolution OR unless 
Clinical Worsening outcome criteria were met then 
outcome will be Clinical worsening), or 
• 
The On-therapy assessment is missing, (unless 
clinical worsening outcome criteria were met then 
outcome is worsening) or 
• 
The participant received other systemic 
antimicrobials not for the current infection prior to 
Unable to determine 


 
CONFIDENTIAL 
 
214144 
 
Page 65 of 93 
Defining Criteria 
Outcomea 
the assessment (unless clinical worsening outcome 
criteria were met) 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Table 14), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
The text with underline is additional clarification to derive the clinical outcome in 
addition to the protocol table.  
Table 16 
Clinical Outcome and Response at the Test-of-Cure Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of acute cystitis 
present at Baseline (and no new signs or 
symptoms), without the participant receiving other 
systemic antimicrobials not for the current infection 
before the TOC Visit and also without receiving an 
other systemic antimicrobials for the current 
infection prior to or at the TOC Visit 
Clinical resolution 
Clinical success 
Improvement in total symptom scores from 
Baseline, but not complete resolution, without the 
participant receiving other systemic antimicrobials 
not for the current infection before the TOC Visit 
and also without receiving an other systemic 
antimicrobials for the current infection prior to or at 
the TOC Visit 
Clinical improvement  
Clinical failure 
Worsening or no change in total symptom scores 
from Baseline or the participant received other 
systemic antimicrobials for the current infection 
before or on the date of the TOC Visit (if the date 
of TOC Visit is missing, the end date of the 
analysis window will be used as the date of TOC 
visit) 
Clinical worsening 
Clinical failure 
• 
The Baseline score is missing (unless TOC 
score is 0 and no antibiotics use (either not 
for current infection or for current infection) 
then outcome will be clinical resolution OR 
unless Clinical worsening outcome criteria 
were met then outcome will be Clinical 
worsening), or 
• 
The TOC assessment is missing (unless 
clinical worsening outcome criteria were met 
then outcome is worsening), or 
• 
The participant received other systemic 
antimicrobials not for the current infection 
prior to the assessment (unless clinical 
worsening criteria were met) 
Unable to determine 
Clinical failure 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Table 14), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
The text with underline is additional clarification to derive the clinical outcome and 
response in addition to the protocol table.  


 
CONFIDENTIAL 
 
214144 
 
Page 66 of 93 
Table 17 
Clinical Outcome and Response at the Follow-up Visit 
Defining Criteria 
Outcomea 
Response 
Resolution of signs and symptoms of acute cystitis 
demonstrated at the TOC Visit persist at the 
Follow-up Visit (and no new signs and symptoms), 
without the participant receiving other systemic 
antimicrobials not for the current infection before 
the Follow-up Visit and also without receiving an 
other systemic antimicrobials for the current 
infection prior to or at the Follow Up Visit 
Sustained clinical resolution 
Clinical success 
Resolution of signs and symptoms of acute cystitis 
present at Baseline (and no new signs or 
symptoms), after clinical failure at TOC, without 
the participant receiving other systemic 
antimicrobials not for the current infection before 
the Follow-up Visit and also without receiving an 
other systemic antimicrobials for the current 
infection prior to or at the Follow-Up Visit 
Delayed clinical resolution 
Clinical failure 
Improvement in total symptom scores from 
Baseline, but not complete resolution after clinical 
failure at the TOC visit, without the participant 
receiving other systemic antimicrobials not for the 
current infection before the Follow-up Visit and 
also without receiving an other systemic 
antimicrobials for the current infection prior to or at 
the Follow-Up Visit 
Clinical improvement 
Clinical failure 
Worsening or no change in total symptom scores 
at Follow-up compared to Baseline after clinical 
failure at TOC, or the participant received other 
systemic antimicrobials for the current infection 
before or on the date of the Follow-up Visit (if the 
date of Follow-Up Visit is missing, the end date of 
the analysis window will be used as the date of 
Follow-Up visit) 
Clinical worsening 
Clinical failure 
Signs and symptoms of acute cystitis reoccur at 
the Follow-up Visit (can be improved (but not 
resolution) OR worsening or no change from 
baseline i.e., (1) change from baseline at Follow-
Up visit < 0 AND score is not 0 at Follow-Up Visit 
(2) change from baseline at the Follow-Up visit >= 
0) after clinical success at TOC without the 
participant receiving an other systemic 
antimicrobials for the current infection prior to or at 
the Follow-Up visit 
Clinical recurrence 
Clinical failure 
1) The Baseline score is missing (unless Follow-
Up score is 0 and no antibiotics use (either 
not for current infection or for current 
infection) then outcome will be clinical 
resolution (delayed or sustained as 
appropriate) OR unless Clinical worsening 
outcome criteria were met then outcome will 
be clinical worsening), or 
2) The Follow-up assessment is missing (unless 
clinical worsening outcome criteria were met 
then outcome is clinical worsening), or 
Unable to determine 
Clinical failure 


 
CONFIDENTIAL 
 
214144 
 
Page 67 of 93 
Defining Criteria 
Outcomea 
Response 
3) The participant received other systemic 
antimicrobials not for the current infection 
prior to the assessment (unless the clinical 
worsening or recurrence outcome criteria 
were met) 
TOC = Test-of-Cure 
a. 
A study physician or otherwise appropriately medically trained staff will determine the individual clinical signs 
and symptoms scores for acute cystitis (Table 14), which will then be used to programmatically determine the 
clinical outcome. The same scorer will be used at all assessment time points for each participant, on all 
occasions, whenever possible. 
The text with underline is additional clarification to derive the clinical outcome in 
addition to the protocol table.  
6.2.1.3. 
Fold change on susceptibility 
Fold change will be used to describe how much the MIC for gepotidacin and 
nitrofurantoin changes between baseline and subsequent visits for the same bacterial 
species from the same participant based on the broth microdilution results. Fold change 
will be calculated (in doubling dilutions) as the ratio of the MIC at the subsequent visit to 
the MIC at Baseline Visit. However, ratio of 1 will be reported as 0-fold ratio. Ratio less 
than 1 will be reported in reciprocal with negative sign (e.g. ratio of 0.5 will be reported 
as -2 fold). Examples:  
Baseline MIC (mcg/mL)  
Post-baseline MIC (mcg/mL)  
Fold-change 
1 
1 
0-fold 
1 
2 
2-fold 
1 
4 
4-fold 
1 
8 
8-fold 
1 
16 
16-fold 
1 
0.5 
- 2-fold 
1 
0.25 
- 4-fold 
1 
>32 
>/=64-fold 
1 
>/=32 
>/=32-fold 
1 
<0.125 
>/= - 16-fold 
1 
</=0.125 
>/= - 8-fold 
6.2.1.4. 
MIC50 and MIC90 
MIC50 and MIC90 are defined as the 50th and 90th percentile of the MIC values. They 
will only be reported if the number of uropathogens is larger or equal to 10. MICxx is 
defined as follows.  
𝑀𝐼𝐶𝑥𝑥= min
𝑗{𝑥𝑗; 𝐹̂(𝑥𝑗) ≥𝑥𝑥%} 
, 𝑤ℎ𝑒𝑟𝑒 𝑥𝑗 𝑖𝑠 𝑀𝐼𝐶 𝑣𝑎𝑙𝑢𝑒 𝑎𝑛𝑑 𝐹̂(∙) 𝑖𝑠 𝑒𝑚𝑝𝑖𝑟𝑖𝑐𝑎𝑙 𝑐𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛.  
For an even number of samples, the MIC50 is the next one above the median. Similar 
algorithm applied to MIC90.  


 
CONFIDENTIAL 
 
214144 
 
Page 68 of 93 
6.2.1.5. 
Investigator-Assessed Clinical Response 
Missing data will be handled based on the table below.  
Scenario 
Date of data 
at EW (early 
withdrawal) 
Visit 
Response at EW 
visit 
Reason for 
response at 
EW visit 
Start date of 
Antibiotics 
use for uUTI 
Derivation of data 
Missing at 
TOC 
Date < 17 days 
+ baseline 
Clinical Failure 
OR 
Indeterminate 
“Death” is 
contained 
NA 
Same as data at EW visit 
Missing at 
TOC 
Any date 
Clinical Failure 
“Use of 
additional 
systemic 
antibiotic(s) 
for the current 
infection” 
Baseline <= 
date <= 17 
days + 
baseline 
Same as data at EW visit 
Missing at 
Follow-Up 
Date < 31 days 
+ baseline 
Clinical Failure 
OR 
Indeterminate 
“Death” is 
contained 
NA 
Same as data at EW visit 
Missing at 
Follow-Up 
Any date 
Clinical Failure 
“Use of 
additional 
systemic 
antibiotic(s) 
for the current 
infection” 
Baseline <= 
date <= 31 
days + 
baseline 
Same as data at EW visit 
Any other missing other than the above 
Response: 
Indeterminate/missing 
Reason: Participant was 
lost to follow-up and/or the 
clinical assessment was not 
undertaken/missing 
Definitions 
Clinical Response 
Sufficient resolution of acute cystitis signs and symptoms such that no additional systemic 
antimicrobial therapy is required for the current infection 
Clinical Success 
Participant met any one of the criteria below:  
• 
No apparent response to treatment (persistence or progression of any pretreatment 
clinical signs and symptoms) 
• 
Use of additional systemic antibiotic(s) for the current infection  
• 
Death related to acute cystitis prior to the visit 
Clinical Failure 
Determination of clinical response could not be made at the visit for any of the following 
reasons: 
• 
Participant was lost to follow-up and/or the clinical assessment was not undertaken 
• 
Use of confounding systemic antibiotic(s) for another infection 
• 
Death prior to the visit where acute cystitis was clearly noncontributory 
Indeterminate 


 
CONFIDENTIAL 
 
214144 
 
Page 69 of 93 
6.2.2. 
Safety 
6.2.2.1. 
Adverse Events of Special Interest 
Cardiovascular (CV) AEs, gastrointestinal (GI) AEs, C. difficile AEs, and AEs related to 
Acetylcholinesterase Inhibition (AChE-I) as determined by algorithm will be considered 
AESIs.  
Clostridium difficile AESIs 
AEs will be regarded as C. difficile AESIs if the preferred terms are either Clostridium 
difficile infection or Clostridium difficile colitis.  
CCI


 
CONFIDENTIAL 
 
214144 
 
Page 70 of 93 
Cardiovascular and Gastrointestinal AESIs 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Degenerative aortic valve disease 
10075846 
Tachycardia 
10043071 
Supraventricular extrasystoles 
10042602 
Ventricular tachyarrhythmia 
10065341 
Rebound tachycardia 
10067207 
Torsade de pointes 
10044066 
Cardio-respiratory arrest neonatal 
10007618 
Fascicular block 
10086740 
Cardiac flutter 
10052840 
Lown-Ganong-Levine syndrome 
10024984 
Paroxysmal arrhythmia 
10050106 
Conduction disorder 
10010276 
Cardiac death 
10049993 
Congenital supraventricular tachycardia 
10082343 
Atrial conduction time prolongation 
10064191 
Pacemaker generated arrhythmia 
10053486 
Neonatal bradyarrhythmia 
10082054 
Wolff-Parkinson-White syndrome 
10048015 
Bradycardia foetal 
10006094 
Long QT syndrome 
10024803 
Neonatal sinus bradycardia 
10082188 
Parasystole 
10033929 
Sinus bradycardia 
10040741 
Cardiac arrest neonatal 
10007516 
Marshall-White syndrome 
10088084 
Foetal tachyarrhythmia 
10077575 
Junctional ectopic tachycardia 
10074640 
Neonatal sinus tachycardia 
10082191 
Ventricular fibrillation 
10047290 
Congenital tricuspid valve stenosis 
10010656 
Ventricular parasystole 
10058184 
Parachute mitral valve 
10064192 
Pulseless electrical activity 
10058151 
Stroke in evolution 
10059613 
Accessory cardiac pathway 
10067618 
Subarachnoid haemorrhage 
10042316 
Sinoatrial block 
10040736 
Ischaemic cerebral infarction 
10060840 
Paroxysmal atrioventricular block 
10077503 
Spinal subdural haematoma 
10050164 
Ogden syndrome 
10082376 
Thrombotic stroke 
10043647 
Familial atrial fibrillation 
10088317 
Pituitary infarction 
10035092 
Nodal rhythm 
10029470 
Cerebral haemorrhage neonatal 
10008112 
Bundle branch block left 
10006580 
Cerebral haemorrhage 
10008111 
Precerebral artery embolism 
10085250 
Claude's syndrome 
10085447 
Cerebral septic infarct 
10070671 
Vertebrobasilar stroke 
10082484 
Cerebellar ischaemia 
10068621 
Intraoperative cerebral artery occlusion 
10056382 
Pseudostroke 
10078090 
Cerebral gas embolism 
10070813 
Basal ganglia stroke 
10071043 
Brain stem thrombosis 
10062573 
Lacunar infarction 
10051078 
Basal ganglia haemorrhage 
10067057 
Ruptured cerebral aneurysm 
10039330 
Vertebral artery perforation 
10075735 
Malignant middle cerebral artery 
syndrome 
10086546 
Carotid artery perforation 
10075728 
Cerebral artery perforation 
10075734 
Ischaemic stroke 
10061256 


 
CONFIDENTIAL 
 
214144 
 
Page 71 of 93 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Spinal cord haemorrhage 
10048992 
Cerebral arteriovenous malformation 
haemorrhagic 
10008086 
Subarachnoid haematoma 
10076701 
Cerebrovascular disorder 
10008196 
Mitral valve disease 
10061532 
Myxomatous mitral valve degeneration 
10077377 
Pulmonary oil microembolism 
10069388 
Mitral valve stenosis 
10027733 
Heritable pulmonary arterial hypertension 
10085244 
Pulmonary tumour thrombotic 
microangiopathy 
10079988 
Cor pulmonale acute 
10010969 
Pulmonary venous thrombosis 
10037459 
Neonatal pulmonary hypertension 
10088909 
Cement embolism 
10050484 
Pulmonary hypertensive crisis 
10068726 
Pulmonary veno-occlusive disease 
10037458 
Pulmonary valve incompetence 
10037448 
Newborn persistent pulmonary 
hypertension 
10053592 
Transient aphasia 
10080106 
Pulmonary valve thickening 
10079337 
Subclavian steal syndrome 
10042335 
Capsular warning syndrome 
10067744 
Tricuspid valve thrombosis 
10088062 
Tricuspid valve incompetence 
10044640 
Tricuspid valve disease mixed 
10086096 
Transmyocardial revascularisation 
10059211 
Heart valve stenosis 
10061996 
Deep vein thrombosis postoperative 
10066881 
Peripheral revascularisation 
10053351 
Carotid revascularisation 
10072559 
Respiratory sinus arrhythmia magnitude 
increased 
10079115 
Progressive encephalopathy, 
hypsarrhythmia and optic atrophy 
syndrome 
10086607 
Renal artery revascularisation 
10087816 
Unicuspid aortic valve 
10081548 
Acute myocardial infarction 
10000891 
Aortic valve atresia 
10066801 
Aortic valve disease 
10061589 
Arrhythmia supraventricular 
10003130 
Congenital aortic valve incompetence 
10010370 
Reperfusion arrhythmia 
10058156 
Supravalvular aortic stenosis 
10042598 
Heart alternation 
10058155 
Arrhythmia neonatal 
10003124 
Timothy syndrome 
10079205 
Central bradycardia 
10078310 
Foetal heart rate disorder 
10061158 
Sinus arrest 
10040738 
Atrial parasystole 
10071666 
Cardiac fibrillation 
10061592 
Atrial tachycardia 
10003668 
Trifascicular block 
10044644 
Bifascicular block 
10057393 
Accelerated idioventricular rhythm 
10049003 
Sudden cardiac death 
10049418 
Ventricular tachycardia 
10047302 
Atrioventricular block complete 
10003673 
Bundle branch block right 
10006582 
Sinus node dysfunction 
10075889 
Bundle branch block bilateral 
10006579 
Sudden death 
10042434 
Bezold-Jarisch reflex 
10076999 
Cardio-respiratory arrest 
10007617 
Chronotropic incompetence 
10068627 
Neonatal tachyarrhythmia 
10082055 


 
CONFIDENTIAL 
 
214144 
 
Page 72 of 93 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Baseline foetal heart rate variability 
disorder 
10074638 
Bradycardia 
10006093 
Inherited cardiac conduction disorder 
10070294 
Congenital heart valve incompetence 
10077594 
Ventricular flutter 
10047294 
Mitral valve atresia 
10066800 
Straddling tricuspid valve 
10083223 
Congenital tricuspid valve incompetence 
10067887 
Extraischaemic cerebral haematoma 
10080347 
Congenital heart valve disorder 
10064086 
Central nervous system haemorrhage 
10072043 
Congenital tricuspid valve atresia 
10049767 
Vertebral artery thrombosis 
10057777 
Cerebral microembolism 
10078311 
Vertebral artery occlusion 
10048965 
Carotid aneurysm rupture 
10051328 
Pituitary haemorrhage 
10049760 
Cerebral artery occlusion 
10008089 
Thalamic infarction 
10064961 
Cerebellar infarction 
10008034 
Cerebellar artery occlusion 
10053633 
Cerebral microinfarction 
10083668 
Reversible ischaemic neurological deficit 
10050496 
Post stroke depression 
10070606 
Cerebral infarction foetal 
10008119 
Precerebral artery thrombosis 
10074717 
Brain stem haemorrhage 
10006145 
Brain stem infarction 
10006147 
Medullary compression syndrome 
10087065 
Basal ganglia haematoma 
10077031 
Lacunar stroke 
10076994 
Mitral valve incompetence 
10027727 
Embolic cerebellar infarction 
10084072 
Pulmonary thrombosis 
10037437 
Cerebral artery embolism 
10008088 
Pulmonary microemboli 
10037421 
Embolism arterial 
10014513 
Hoigne's syndrome 
10059393 
Mitral valve calcification 
10050558 
Post procedural pulmonary embolism 
10063909 
Systolic anterior motion of mitral valve 
10076976 
Cor pulmonale 
10010968 
Pulmonary embolism 
10037377 
Pulmonary arterial hypertension 
10064911 
Embolic pneumonia 
10065680 
Pulmonary artery wall hypertrophy 
10063561 
Cor pulmonale chronic 
10010970 
Right ventricular hypertension 
10074301 
Lambl's excrescences 
10083691 
Tricuspid valve disease 
10061389 
Arrhythmia prophylaxis 
10051305 
Cardiac valve rupture 
10068165 
ECG signs of myocardial infarction 
10075299 
Heart valve calcification 
10058968 
Bicuspid aortic valve 
10004552 
Cardiac valve discolouration 
10079467 
Arrhythmia 
10003119 
Cardiac valve vegetation 
10057651 
Atrioventricular node dysfunction 
10084085 
Cerebral revascularisation 
10071508 
Ventricular pre-excitation 
10049761 
Aortic valve stenosis 
10002918 
Supraventricular tachyarrhythmia 
10065342 
Tachyarrhythmia 
10049447 
Cardiac arrest 
10007515 
Sinus arrhythmia 
10040739 
Atrioventricular node dispersion 
10077893 
Atrioventricular conduction time shortened 
10068180 
Holiday heart syndrome 
10083709 
Postural orthostatic tachycardia syndrome 
10063080 
Anomalous atrioventricular excitation 
10002611 
Supraventricular tachycardia 
10042604 


 
CONFIDENTIAL 
 
214144 
 
Page 73 of 93 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Bundle branch block 
10006578 
Sinusoidal foetal heart rate pattern 
10074643 
Adams-Stokes syndrome 
10001115 
Bradyarrhythmia 
10049765 
Atrioventricular dissociation 
10069571 
Withdrawal arrhythmia 
10047997 
Atrial escape rhythm 
10085756 
Tachycardia paroxysmal 
10043079 
Atrial flutter 
10003662 
Wandering pacemaker 
10047818 
Cardiac failure congestive 
10007559 
Sinus tachycardia 
10040752 
Bicuspid pulmonary valve 
10063730 
Arrhythmic storm 
10067339 
Weber's syndrome 
10085448 
Ictal bradycardia syndrome 
10088979 
Cerebral haemorrhage foetal 
10050157 
Foetal heart rate acceleration abnormality 
10074642 
Spinal epidural haematoma 
10050162 
Pacemaker syndrome 
10051994 
Basal ganglia infarction 
10069020 
Atrial standstill 
10087237 
Cerebellar embolism 
10067167 
Congenital pulmonary valve disorder 
10061075 
Spinal subarachnoid haemorrhage 
10073564 
Congenital pulmonary valve atresia 
10052644 
Septic cerebral embolism 
10086435 
Congenital mitral valve stenosis 
10010548 
Intracranial tumour haemorrhage 
10022775 
Thalamic stroke 
10087626 
Post procedural stroke 
10066591 
Basilar artery perforation 
10075736 
Embolic cerebral infarction 
10060839 
Brain stem embolism 
10074422 
Meningorrhagia 
10052593 
Lateral medullary syndrome 
10024033 
Intraventricular haemorrhage neonatal 
10022841 
Occipital lobe stroke 
10089110 
Cerebellar haemorrhage 
10008030 
Intracranial haemorrhage neonatal 
10086946 
Internal capsule infarction 
10083408 
Pseudo-occlusion of internal carotid artery 
10085779 
Pituitary apoplexy 
10056447 
Cerebral vascular occlusion 
10076895 
Cerebellar artery thrombosis 
10008023 
Perinatal stroke 
10073945 
Brain stem stroke 
10068644 
Cerebral artery thrombosis 
10008092 
Mitral valve thickening 
10079336 
Periventricular haemorrhage neonatal 
10076706 
Ischaemic mitral regurgitation 
10077864 
Spinal epidural haemorrhage 
10049236 
Mitral perforation 
10068138 
Middle cerebral artery stroke 
10027580 
Portopulmonary hypertension 
10067281 
Intraventricular haemorrhage 
10022840 
Right-to-left cardiac shunt 
10076605 
Haemorrhagic cerebral infarction 
10019005 
Congenital pulmonary hypertension 
10050701 
Cerebral infarction 
10008118 
Pulmonary valve calcification 
10057464 
Thrombotic cerebral infarction 
10067347 
Pulmonary valve disease 
10061541 
Basilar artery thrombosis 
10063093 
Pulmonary valve sclerosis 
10057465 
Myocardial infarction 
10028596 
Pulmonary valve stenosis 
10037450 
Septic pulmonary embolism 
10083093 
Tricuspid valve prolapse 
10066862 
Alveolar capillary dysplasia 
10077023 
Prosthetic cardiac valve thrombosis 
10063176 
Coronary sinus dilatation 
10082615 
Heart valve incompetence 
10067660 
Pulmonary venous hypertension 
10085364 


 
CONFIDENTIAL 
 
214144 
 
Page 74 of 93 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Cardiac valve disease 
10061406 
Amaurosis fugax 
10001903 
Prosthetic cardiac valve regurgitation 
10087802 
Tricuspid valve sclerosis 
10057467 
Cardiac valve fatty infiltration 
10087637 
Tricuspid valve thickening 
10079338 
Deep vein thrombosis 
10051055 
Cardiac valve thickening 
10079587 
Periprocedural myocardial infarction 
10079319 
Silent myocardial infarction 
10049768 
Cerebrovascular pseudoaneurysm 
10084087 
Coronary revascularisation 
10049887 
Revascularisation procedure 
10084091 
Foetal cerebrovascular disorder 
10053601 
Angina unstable 
10002388 
Aortic annulus rupture 
10079586 
Aortic valve prolapse 
10057454 
Subvalvular aortic stenosis 
10042431 
Aortic valve thickening 
10075851 
Heart block congenital 
10019263 
Aortic valve sclerosis 
10002917 
Extrasystoles 
10015856 
Williams syndrome 
10049644 
Atrioventricular block second degree 
10003677 
Ventricular extrasystoles 
10047289 
Brugada syndrome 
10059027 
Ectopic atrial rhythm 
10088339 
Wolff-Parkinson-White syndrome 
congenital 
10049291 
Lenegre's disease 
10071710 
BRASH syndrome 
10084073 
Nodal arrhythmia 
10029458 
Ventricular arrhythmia 
10047281 
Foetal cardiac arrest 
10084280 
Early repolarisation syndrome 
10086230 
Rhythm idioventricular 
10039111 
Foetal heart rate deceleration abnormality 
10074636 
Atrioventricular block 
10003671 
Long QT syndrome congenital 
10057926 
Nonreassuring foetal heart rate pattern 
10074641 
Agonal rhythm 
10054015 
Ventricular asystole 
10047284 
Chronic atrial and intestinal dysrhythmia 
syndrome 
10086078 
Defect conduction intraventricular 
10012118 
Frederick's syndrome 
10082089 
Tachycardia foetal 
10043074 
Bradycardia neonatal 
10056471 
Atrial fibrillation 
10003658 
Shone complex 
10066802 
Foetal arrhythmia 
10016847 
Pulmonary valve stenosis congenital 
10037451 
Atrioventricular block first degree 
10003674 
Ebstein's anomaly 
10014075 
Neonatal tachycardia 
10049775 
Carotid artery occlusion 
10048964 
Mitral valve dysplasia 
10089005 
Cerebellar haematoma 
10061038 
Congenital mitral valve incompetence 
10010547 
Spinal cord infarction 
10058571 
Carotid blowout syndrome 
10088005 
Migrainous infarction 
10056237 
Brain stem haematoma 
10073230 
Cerebral haematoma 
10053942 
Spinal stroke 
10082031 
Haemorrhage intracranial 
10018985 
Putamen haemorrhage 
10058940 
Embolic stroke 
10014498 
Carotid artery thrombosis 
10007688 
Parietal lobe stroke 
10089109 
Spinal subdural haemorrhage 
10073563 
Spinal cord haematoma 
10076051 


 
CONFIDENTIAL 
 
214144 
 
Page 75 of 93 
Gastrointestinal AESIs are defined as 
AEs with a “Gastrointestinal disorders” 
SOC. AEs will be regarded as 
Cardiovascular AESIs if the preferred 
terms are any one of the following PTs 
below. Term 
Code 
Term 
Code 
Basilar artery occlusion 
10048963 
Haemorrhagic transformation stroke 
10055677 
Cerebellar stroke 
10079062 
Precerebral artery occlusion 
10036511 
Inner ear infarction 
10070754 
Brain stem ischaemia 
10006148 
Cerebral ischaemia 
10008120 
Cerebral aneurysm perforation 
10075394 
Benedikt's syndrome 
10085451 
Thalamus haemorrhage 
10058939 
Intracranial haematoma 
10059491 
Carotid arterial embolus 
10007684 
Haemorrhagic stroke 
10019016 
Subdural haemorrhage neonatal 
10042365 
Cerebral thrombosis 
10008132 
Subarachnoid haemorrhage neonatal 
10042317 
Mitral valve disease mixed 
10027724 
Haemorrhagic cerebellar infarction 
10085944 
Degenerative mitral valve disease 
10075847 
Cerebrovascular accident 
10008190 
Metastatic pulmonary embolism 
10069909 
Mitral valve sclerosis 
10051538 
Carcinoid heart disease 
10069010 
Mitral face 
10073380 
Cardiac valve replacement complication 
10053748 
Mitral valve prolapse 
10027730 
Degenerative multivalvular disease 
10081779 
Obstetrical pulmonary embolism 
10029925 
Cardiac valve sclerosis 
10061082 
Anaphylactoid syndrome of pregnancy 
10067010 
Cardiac valve abscess 
10064267 
Pulmonary artery thrombosis 
10037340 
Respiratory sinus arrhythmia magnitude 
10079114 
Pulmonary hypertension 
10037400 
Respiratory sinus arrhythmia magnitude 
abnormal 
10079117 
Transient ischaemic attack 
10044390 
Congenital aortic valve stenosis 
10010371 
Tricuspid valve stenosis 
10044642 
Aortic valve calcification 
10050559 
Degenerative tricuspid valve disease 
10078909 
Aortic valve incompetence 
10002915 
Tricuspid valve calcification 
10057466 
Heyde's syndrome 
10049251 
Post procedural myocardial infarction 
10066592 
Aortic valve disease mixed 
10002912 
Respiratory sinus arrhythmia magnitude 
decreased 
10079116 
- 
- 
Arterial revascularisation 
10084482 
Acetylcholinesterase Inhibition AESIs 
AEs will be regarded as Acetylcholinesterase Inhibition AESIs if the preferred terms are 
any one of the following PTs below.  
Term 
Code 
Term 
Code 
Atrioventricular block first degree 
10003674 
Convulsions local 
10010920 
Atonic seizures 
10003628 
Diarrhoea 
10012735 
Bradycardia foetal 
10006094 
Status epilepticus 
10041962 
Diarrhoea haemorrhagic 
10012741 
Laryngeal dyspnoea 
10052390 
Dysarthria 
10013887 
Prophylaxis against bronchospasm 
10054927 


 
CONFIDENTIAL 
 
214144 
 
Page 76 of 93 
Term 
Code 
Term 
Code 
Dyspnoea paroxysmal nocturnal 
10013974 
Post procedural diarrhoea 
10057585 
Retching 
10038776 
Procedural vomiting 
10066963 
Simple partial seizures 
10040703 
Idiopathic generalised epilepsy 
10071081 
Sinus bradycardia 
10040741 
Bradycardia 
10006093 
Vomiting projectile 
10047708 
Convulsive threshold lowered 
10010927 
Self-induced vomiting 
10048636 
Diarrhoea infectious neonatal 
10012744 
Hypoglycaemic seizure 
10048803 
Dyspnoea at rest 
10013969 
Lennox-Gastaut syndrome 
10048816 
Frequent bowel movements 
10017367 
Nocturnal dyspnoea 
10049235 
Haematemesis 
10018830 
Atypical benign partial epilepsy 
10056699 
Nausea 
10028813 
Hyponatraemic seizure 
10073183 
Tonic convulsion 
10043994 
Infantile vomiting 
10075315 
Frontal lobe epilepsy 
10049424 
Neonatal sinus bradycardia 
10082188 
Tonic clonic movements 
10051171 
Abdominal discomfort 
10000059 
Clonic convulsion 
10053398 
Defaecation urgency 
10012110 
Lafora's myoclonic epilepsy 
10054030 
Drooling 
10013642 
Psychogenic seizure 
10058895 
Epilepsy 
10015037 
Partial seizures 
10061334 
Flatulence 
10016766 
Seizure like phenomena 
10071048 
Heart rate decreased 
10019301 
Change in seizure presentation 
10075606 
Hyperkinesia 
10020651 
Idiopathic partial epilepsy 
10076552 
Petit mal epilepsy 
10034759 
Post stroke seizure 
10076981 
Psychomotor hyperactivity 
10037211 
Abdominal pain lower 
10000084 
Vomiting 
10047700 
Cold sweat 
10009866 
Myoclonic epilepsy 
10054859 
Diarrhoea infectious 
10012742 
Partial seizures with secondary 
generalisation 
10056209 
Dyspnoea exertional 
10013971 
Alcoholic seizure 
10056347 
Febrile convulsion 
10016284 
Therapeutic emesis 
10058324 
Generalised tonic-clonic seizure 
10018100 
Faecal vomiting 
10064670 
Night sweats 
10029410 
Psychogenic pseudosyncope 
10075190 
Presyncope 
10036653 
Central bradycardia 
10078310 
Sweat gland disorder 
10042653 
Gastrointestinal disorder 
10017944 
Bradyarrhythmia 
10049765 
Hyperemesis gravidarum 
10020614 
Convulsion in childhood 
10052391 
Lacrimation decreased 
10023642 
Prophylaxis of nausea and vomiting 
10054133 
Vomiting psychogenic 
10047709 
Increased bronchial secretion 
10062530 
Wheezing 
10047924 
Transfusion-associated dyspnoea 
10072266 
Viral diarrhoea 
10051511 
Hypocalcaemic seizure 
10072456 
Epigastric discomfort 
10053155 
Abdominal pain 
10000081 
Antidiarrhoeal supportive care 
10055660 
Abdominal pain upper 
10000087 
Bronchial hyperreactivity 
10066091 
Bronchospasm 
10006482 
Gastrointestinal tract irritation 
10070840 
Gastrointestinal pain 
10017999 


 
CONFIDENTIAL 
 
214144 
 
Page 77 of 93 
Term 
Code 
Term 
Code 
Focal dyscognitive seizures 
10079424 
Hyperhidrosis 
10020642 
Febrile infection-related epilepsy 
syndrome 
10079438 
Salivary hypersecretion 
10039424 
Neonatal epileptic seizure 
10082068 
Seizure 
10039906 
Gelastic seizure 
10082918 
Sweating fever 
10042666 
Abdominal tenderness 
10000097 
Syncope 
10042772 
Drug withdrawal convulsions 
10013752 
Bradycardia neonatal 
10056471 
Dyspnoea 
10013968 
Acetonaemic vomiting 
10058938 
Lacrimation increased 
10023644 
Abdominal symptom 
10060926 
Seizure anoxic 
10039907 
Cyclic vomiting syndrome 
10062937 
Autonomic seizure 
10049612 
Prophylaxis against diarrhoea 
10064065 
Benign familial neonatal convulsions 
10067866 
Post-tussive vomiting 
10066220 
Hyperglycaemic seizure 
10071394 
Procedural nausea 
10066962 
Unilateral bronchospasm 
10072338 
Seizure cluster 
10071350 
Faeces soft 
10074859 
Migraine-triggered seizure 
10076676 
Irregular breathing 
10076213 
Acute encephalitis with refractory, 
repetitive partial seizures 
10076948 
Asthma 
10003553 
Discoloured vomit 
10079120 
Bacterial diarrhoea 
10004016 
Epilepsy with myoclonic-atonic seizures 
10081179 
Bronchospasm paradoxical 
10006486 
Seizure prophylaxis 
10081601 
- 
- 
Neonatal seizure 
10082067 
6.2.2.2. 
Renal impairment 
The severity of renal impairment will be evaluated using estimated by creatinine 
clearance (Ccr).  
Severity of renal impairment will be categorized based on creatinine clearance as below 
(rounded to the nearest integer):  
• 
Normal (≥90 𝑚𝐿/𝑚𝑖𝑛) 
• 
Mild (≥60 𝑡𝑜 89 𝑚𝐿/𝑚𝑖𝑛) 
• 
Moderate (≥30 𝑡𝑜 59 𝑚𝐿/𝑚𝑖𝑛) 
• 
Severe (< 30 𝑚𝐿/𝑚𝑖𝑛) 


 
CONFIDENTIAL 
 
214144 
 
Page 78 of 93 
6.2.3. 
Criteria for Potential Clinical Importance 
6.2.3.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
N/A 
>450 
Absolute PR Interval 
msec 
< 110 
> 220 
Absolute QRS Interval 
msec 
< 75 
> 110 
6.2.3.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potentially Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Pulse Rate 
bpm 
< 40 
> 110 
 


 
CONFIDENTIAL 
 
214144 
 
Page 79 of 93 
6.2.4. 
Division of Microbiology and Infectious Diseases Adult Toxicity Tables for Adverse Event Assessment 
6.2.4.1. 
Laboratory Values 
For grading, only numerical criteria will be used in the derivation rules as follows.  
Adults:  
For adults, laboratory abnormalities will be graded according to the modified US National institute of Allergy and Infectious Diseases 
Division of Microbiology and Infectious Diseases (DMID) criteria, which is aligned with the global studies (204989 and 212390). 
Laboratory results are converted to SI units.  
HEMATOLOGY 
 
Laboratory 
parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
Hemoglobin 
Hemoglobin 
(Low) 
9.5 to 10.5 g/dL 
8.0 to 9.4 g/dL 
6.5 to 7.9 g/dL 
<6.5 g/dL 
Absolute Neutrophil Count 
Neutrophils 
Neutrophils 
(Low) 
1000 to 1500 /mm3 
750 to 999 /mm3` 
500 to 749 /mm3 
<500 /mm3 
Platelets 
Platelets 
Platelets 
(Low) 
75,000 to 99,999 /mm3 
50,000 to 74,999 /mm3 
20,000 to 49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
Leukocytes 
Leukocytes 
(High) 
11,000 to 13,000 /mm3 
13,001 to 15,000 /mm3 
15,001 to 30,000 /mm3 
>30,000 or <1000 /mm3 
% Polymorphonuclear Leukocytes 
+ Band Cells 
NA 
NA 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
NA 
NA 
Low: 100 to 200 mg/dL 
High: 400 to 
600 mg/dL 
Low: <100 mg/dL 
High: >600 mg/dL 
Low: <50 mg/dL 
High: N/A 
Fibrinogen associated 
with gross bleeding or 
with disseminated 
coagulation 
Fibrin Split Product 
NA 
NA 
20 to 40 mcg/mL 
41 to 50 mcg/mL 
51 to 60 mcg/dL 
>60 mcg/dL 
Prothrombin Time (PT) 
NA 
NA 
1.01 to 1.25 × ULN 
1.26 to 1.5 × ULN 
1.51 to 3.0 × ULN 
>3 × ULN 
Activated Partial Thromboplastin 
(APTT) 
NA 
NA 
1.01 to 1.66 × ULN 
1.67 to 2.33 × ULN 
2.34 to 3 × ULN 
>3 ×ULN 
Methemoglobin 
NA 
NA 
5.0 to 9.9% 
10.0 to 14.9% 
15.0 to 19.9% 
>20% 
N/A=not applicable; ULN=upper limit of normal. 


 
CONFIDENTIAL 
 
214144 
 
Page 80 of 93 
CHEMISTRIES 
 
Laboratory 
parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
Sodium 
Sodium (Low) 
130 to 135 mEq/L 
123 to 
129 mEq/L 
116 to 122 mEq/L 
<116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
Sodium 
Sodium (High) 
146 to 150 mEq/L 
151 to 
157 mEq/L 
158 to 165 mEq/L 
>165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
Potassium 
Potassium (Low) 
3.0 to 3.4 mEq/L 
2.5 to 2.9 mEq/L 
2.0 to 2.4 mEq/L or 
intensive replacement 
therapy of 
hospitalization required 
<2.0 mEq/L or abnormal 
potassium with paresis, ileus, or 
life-threatening arrhythmia 
Hyperkalemia 
Potassium 
Potassium (High) 
5.6 to 6.0 mEq/L 
6.1 to 6.5 mEq/L 
6.6 to 7.0 mEq/L 
>7.0 mEq/L or abnormal 
potassium with life-threatening 
arrhythmia 
Hypoglycemia 
Glucose 
Glucose (Low) 
55 to 64 mg/dL 
40 to 54 mg/dL 
30 to 39 mg/dL 
<30 mg/dL or abnormal glucose 
with mental status changes or 
coma 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
Glucose 
Glucose (High) 
116 to 160 mg/dL 
161 to 
250 mg/dL 
251 to 500 mg/dL 
>500 mg/dL or abnormal 
glucose with ketoacidosis or 
seizures 
Hypocalcemia 
(corrected for albumin) 
Calcium 
Calcium (Low) 
8.4 to 7.8 mg/dL 
7.7 to 7.0 mg/dL 
6.9 to 6.1 mg/dL 
<6.1 mg/dL or abnormal calcium 
with life-threatening arrhythmia 
or tetany 
Hypercalcemia 
(corrected for albumin) 
Calcium 
Calcium (High) 
10.6 to 11.5 mg/dL 
11.6 to 
12.5 mg/dL 
12.6 to 13.5 mg/dL 
>13.5 mg/dL or abnormal 
calcium with life-threatening 
arrhythmia 
Hypomagnesemia 
Magnesium 
Magnesium (Low) 
1.4 to 1.2 mEq/L 
1.1 to 0.9 mEq/L 
0.8 to 0.6 mEq/L 
<0.6 mEq/L or abnormal 
magnesium with life-threatening 
arrhythmia 
Hypophosphatemia 
Phosphate 
Phosphate (Low) 
2.0 to 2.4 mg/dL 
1.5 to 1.9 mg/dL 
or replacement 
Rx required 
1.0 to 1.4 mg/dL 
intensive therapy or 
hospitalization required 
<1.0 mg/dL or abnormal 
phosphate with life-threatening 
arrhythmia 


 
CONFIDENTIAL 
 
214144 
 
Page 81 of 93 
CHEMISTRIES 
 
Laboratory 
parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyperbilirubinemia (when 
accompanied by any 
increase in other liver 
function test) 
Bilirubin 
(when any of AST, 
ALT and ALP is 
greater than the 
upper limit of 
normal range at the 
same analysis visit) 
Bilirubin (High) 
1.1 to 
<1.25 × ULN 
1.25 to 
<1.5 × ULN 
1.5 to 1.75 × ULN 
>1.75 × ULN 
Hyperbilirubinemia (when 
other liver function tests are 
in the normal range) 
Bilirubin 
(when all of AST, 
ALT and ALP are 
within the normal 
range at the same 
analysis visit) 
Bilirubin (High) 
1.1 to <1.5 × ULN 
1.5 to 
<2.0 × ULN 
2.0 to 3.0 × ULN 
>3.0 × ULN 
Blood urea nitrogen  
Urea 
Urea Nitrogen 
(High) 
1.25 to 2.5 × ULN 
2.6 to 5 × ULN 
5.1 to 10 × ULN 
>10 × ULN 
Hyperuricemia (uric acid) 
NA 
NA 
7.5 to 10.0 mg/dL 
10.1 to 
12.0 mg/dL 
12.1 to 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
Creatinine 
Creatinine (High) 
1.1 to 1.5 × ULN 
1.6 to 3.0 × ULN 
3.1 to 6.0 × ULN 
>6 × ULN or dialysis required 
Rx=therapy; ULN=upper limit of normal 


 
CONFIDENTIAL 
 
214144 
 
Page 82 of 93 
ENZYMES 
 
Laboratory 
parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Aspartate 
aminotransferase 
(AST) 
Aspartate 
aminotransferase 
Aspartate aminotransferase (High) 
1.1 to <2.0 × ULN 
2.0 to <3.0 × ULN 
3.0 to 8.0 × ULN 
>8.0 × ULN 
Alanine 
aminotransferase 
(ALT) 
Alanine 
aminotransferase 
Alanine aminotransferase (High) 
1.1 to <2.0 × ULN 
2.0 to <3.0 × ULN 
3.0 to 8.0 × ULN 
>8.0 × ULN 
Gamma to glutamyl 
transferase (GGT) 
NA 
NA 
1.1 to <2.0 × ULN 
2.0 to <3.0 × ULN 
3.0 to 8.0 × ULN 
>8.0 × ULN 
Alkaline 
Phosphatase 
Alkaline 
Phosphatase 
Alkaline Phosphatase (High) 
1.1 to <2.0 × ULN 
2.0 to <3.0 × ULN 
3.0 to 8.0 × ULN 
>8.0 × ULN 
Amylase 
NA 
NA 
1.1 to 1.5 × ULN 
1.6 to 2.0 × ULN 
2.1 to 5.0 × ULN 
>5.1 × ULN 
Lipase 
NA 
NA 
1.1 to 1.5 × ULN 
1.6 to 2.0 × ULN 
2.1 to 5.0 × ULN 
>5.1 × ULN 
ULN=upper limit of normal. 
URINALYSIS 
 
Laboratory 
parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Proteinuria 
NA 
NA 
1+ or 
200 mg to 1 gm loss/day 
2 to 3+ or 
1 to 2 gm 
loss/day 
4+ or 
2 to 3.5 gm loss/day 
Nephrotic syndrome or 
>3.5 gm loss/day 
Hematuria 
NA 
NA 
Microscopic only 
<10 RBC/hpf 
Gross, no clots 
>10 RBC/hpf 
Gross, with or without clots, 
or red blood cells casts 
Obstructive or  
required transfusion 
HPF=high powered field; RBC=red blood cells. 


 
CONFIDENTIAL 
 
214144 
 
Page 83 of 93 
Adolescent Participants:  
For adolescent participants over 12 years of age and less than 18 years of age, the adult DMID will be applied for all parameters with the 
exception of serum creatinine which will be graded programmatically according to the modified DMID pediatric toxicity criteria , which 
is aligned with the global studies (204989 and 212390) . Laboratory results are converted to SI units.  
CHEMISTRIES 
 
Laboratory parameter 
Display label 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Creatinine 
Creatinine 
Creatinine (High) 
1.0 to 1.7 x ULN  
1.8 to 2.4 x ULN  
2.5 to 3.5 x ULN  
>3.5 x ULN  
ULN=upper limit of normal. 
 


 
CONFIDENTIAL 
 
214144 
 
Page 84 of 93 
6.2.5. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Pre-Intervention is defined as time prior to the first dose of study intervention. 
On-Intervention is defined as time from first dose to last date. If time of assessment or 
study intervention is not collected, the following assessment on the first dose date will be 
assumed to be taken prior to the first dose and therefore considered pre-intervention: 
ECG, Lab, and vital signs, and first dose date is considered on-intervention for AE and 
concomitant medication. 
Post-Intervention is defined as any time post on-intervention window, i.e. > last dose 
date. 
6.2.5.1. 
Study Phases for Concomitant medication 
Study Phase 
Definition 
Prior 
If medication started prior to the first dose date (or randomized date if first dose date is 
missing) 
Concomitant 
If medication ended after the first dose date or is ongoing regardless of the start date (or 
randomized date if first dose date is missing)  
Study phases for concomitant medication will be derived after handling of missing and 
partial dates for medication (see Section 6.2.9). If a single medication taken on the same 
date as the first dose date, time will be used to determine if it’s prior or concomitant. If 
time is missing, it will be considered concomitant.  
6.2.5.2. 
Treatment Emergent Flag for Adverse Events 
Adverse events are defined as treatment emergent AEs if AE onset date/time is on or 
after treatment start date/time. That is, study treatment start date/time <= AE start 
date/time. If time is missing, only date will be compared.  
6.2.5.3. 
Participant and Study Completion 
A participant is considered to have completed study treatment if she has taken all doses 
of the randomly assigned study treatment and also completed the ToC visit. A participant 
is considered to have completed the study if she has completed all study visits including 
the Follow-up Visit.  


 
CONFIDENTIAL 
 
214144 
 
Page 85 of 93 
6.2.6. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date (or randomization date if not 
dosed) and will be used to calculate study day for safety measures.  
The efficacy reference date is the study intervention start date (or randomization date if 
not dosed) and will be used to calculate study day for efficacy measures and baseline 
characteristics, as well as efficacy durations.  
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Date ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
6.2.7. 
Assessment Window  
Unscheduled and withdrawal visit data will be slotted into a target visit based on visit 
window defined in the table below. If there are multiple assessments within the same 
window, the closest one to the target day will be taken in the slotting. If multiple records 
are equally close to the target day, then the later record will be utilized. For post-baseline 
records collected outside the analysis visit window, a blank analysis visit label will be 
assigned.  
Analysis Set / 
Domain 
Parameter (if 
applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
All 
All 
Day 3 
Day 2 
Day 5 
On-therapy 
All 
All 
Day 12 
Day 9 
Day 16 
Test-of-Cure 
All 
All 
Day 28 
Day 21 
Day 31 
Follow-up 
The procedure of the analysis visit assignment is as follows.  
1. Calculate the analysis days for planned visit, unscheduled visit, and early withdrawal 
visit with non-missing outcome if applicable. The calculation of the analysis days is 
provided in Section 6.2.6.  
2. Slot the visits to each of analysis timepoint according to the above table.  
a. 
If there are multiple assessments within the same windows, the closest one to the 
target day will be taken in the slotting.  
b. If multiple records are equally close to the target day, then the later record will 
be utilized using the sequence number in SDTM dataset.  
c. 
For post-baseline records collected outside the analysis visit window, a blank 
analysis visit label will be assigned. Such assessments will not be included in 
any of the by visit summaries. Descriptive summaries that are shown for “any 
assessment post baseline” e.g. maximum/minimum/ worst case post baseline, 
will use all assessments irrespective of whether they fall in an analysis visit 
window. 


 
CONFIDENTIAL 
 
214144 
 
Page 86 of 93 
6.2.8. 
Multiple measurements at One Analysis Time Point 
Not applicable.  
6.2.9. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.  
• 
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only. In addition, partial dates may be imputed 
for ‘slotting’ data to study phases or for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., 
time since diagnosis). In addition, imputed dates are not used for deriving the last 
contact date in overall survival analysis dataset. 
Adverse Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start time 
(AChE-I only) 
Midnight 0:00:00 will be used for AEs with missing start time to 
determine if it’s AChE-I.  
Concomitant 
Medications/Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
Missing start day 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of study 
intervention start date, then 
• 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date= 1st of month. 
• 
Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e. participant did not 
start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start date, 
then 
• 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date = January 1. 
• 
Else set start date = study. intervention start 
date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the 
month. 


 
CONFIDENTIAL 
 
214144 
 
Page 87 of 93 
Element 
Reporting Detail 
Completely missing 
start/end date 
No imputation 
Age 
Age is derived using the date of first dose. When first dose date is missing, the informed 
consent date is used. Only year of birth is collected so Day and Month of birth are imputed 
as 30 June. Formula for deriving age is the integer component of:  
• 
(First Dose Date – 30 Jun of collected birth year + 1) / 365.25 
6.2.10. 
Qualifying Uropathogen Algorithm 
Qualifying Uropathogen Decision Tree: Single Uropathogen 
 
 


 
CONFIDENTIAL 
 
214144 
 
Page 88 of 93 
Qualifying Uropathogen Decision Tree: 2 Uropathogens 
 
Note: Since Enterococcus spp., beta-hemolytic streptococci, Gardnerella vaginalis and 
Aerococcus urinae must be present in pure culture to be considered a uropathogen, the 2 
or ≥3 uropathogens trees do not apply to these organisms. 
Qualifying Uropathogen Decision Tree: >= 3 Uropathogens 
 
Note: Since Enterococcus spp., beta-hemolytic streptococci, Gardnerella vaginalis and 
Aerococcus urinae must be present in pure culture to be considered a uropathogen, the 2 
or ≥3 uropathogens trees do not apply to these organisms. 


 
CONFIDENTIAL 
 
214144 
 
Page 89 of 93 
6.2.11. 
Uropathogen Phenotype Algorithm 
ESBL. Decision Tree:  
 
Note: ESBL not determined for other Gram-negative organisms.  
Methicillin* Decision Tree:  
 


 
CONFIDENTIAL 
 
214144 
 
Page 90 of 93 
*Cefoxitin is tested as a surrogate test for oxacillin to determine methicillin 
susceptibility/resistance. Methicillin-(oxacillin) resistant staphylococci are resistant to all 
currently available beta-lactams, cephalosporin and carbapenem antimicrobial agents, 
with the exception of ceftaroline. 
Multidrug Resistance (MDR):  
Definition 1: A uropathogen will be regarded as multidrug-resistant if the uropathogen is 
resistant to >= 1 drugs in each class among >= 2 antimicrobial classes (β-lactam, 
Fluoroquinolone, Fosfomycin and Aminoglycoside). This definition will be used for 
micro-ITT MDR Population.  
Definition 2: A uropathogen will be regarded as multidrug-resistant (3 or more) if the 
uropathogen is resistance to >= 1 drugs in each class among >= 3 antimicrobial classes 
(-lactam, Fluoroquinolone, Fosfomycin and Aminoglycoside). This phenotype will be 
included in the subgroup analyses.  
Below is the table of antimicrobial classes, susceptibility test and the guideline of 
susceptibility interpretation for the MDR definitions above.  
Antimicrobial class 
Antimicrobial 
Susceptibility test 
(MSMETHOD) 
Guideline  
(MSSCAT) 
Beta-lactam 
Ampicillin 
Micro Broth Dilution 
CLSI 
Mecillinam 
Disk diffusion 
CLSI 
Penicillin 
Disk diffusion 
CLSI 
Amoxicillin/clavulanic acid 
Micro Broth Dilution 
CLSI 
Ceftolozane/tazobactam 
Micro Broth Dilution 
CLSI 
Ceftazidime/avibactam 
Micro Broth Dilution 
CLSI 
Piperacillin/tazobactam 
Micro Broth Dilution 
CLSI 
Cefazolin 
Micro Broth Dilution 
CLSI 
Ceftriaxone 
Micro Broth Dilution 
CLSI 
Cefadroxil 
Disk diffusion 
EUCAST 
Cefoxitin  
Disk diffusion 
CLSI 
Meropenem 
Micro Broth Dilution 
CLSI 
Faropenem 
Disk diffusion 
[Fuchs, 1995]  
Aminoglycoside 
Amikacin 
Micro Broth Dilution 
CLSI 
Gentamicin 
Micro Broth Dilution 
CLSI 
Fluoroquinolone 
Ciprofloxacin 
Micro Broth Dilution 
CLSI 
Levofloxacin 
Micro Broth Dilution 
CLSI 
Fosfomycin 
Fosfomycin 
Agar dilution 
CLSI 
List of Antimicrobials Being Tested 
Antimicrobial Class 
Sub-class 
Antimicrobial 
β-lactam  
Penicillin 
Ampicillin 
Mecillinam 
Penicillin 
β-lactam combination 
Amoxicillin/clavulanic acid 
Ceftolozane/tazobactam 


 
CONFIDENTIAL 
 
214144 
 
Page 91 of 93 
Antimicrobial Class 
Sub-class 
Antimicrobial 
Ceftazidime/avibactam 
Piperacillin/tazobactam 
Cephalosporin 
Cefazolin 
Ceftriaxone 
Cefotaxime 
Ceftazidime 
Cefpodoxime 
Cefoxitin 
Cefadroxil 
Cefoxitin 
Carbapenem/Penem 
Meropenem 
Faropenem 
Monobactam 
Aztrenam 
Fluoroquinolone 
  
Ciprofloxacin 
Levofloxacin 
Fosfomycin 
  
Fosfomycin 
Aminoglycoside 
  
Amikacin 
Gentamicin 
Folate pathway Antagonist 
  
Trimethoprim-sulfamethoxazole 
Trimethoprim 
Sulfisoxazole 
Nitrofuran 
  
Nitrofurantoin 
Glycopeptide 
  
Vancomycin 
Nitroxoline 
  
Nitroxoline 
Antimicrobial-Resistant Phenotypes:  
Antimicrobial class 
Antimicrobial 
Drug 
relevant to 
Gram-
negatives 
Drug 
relevant to 
Gram-
positives 
Resistant 
phenotype to 
be reported by 
GCL if 
interpretation is 
resistant* 
 
Penicillin 
Ampicillin 
X 
X 
AMP-R 
Mecillinam 
X 
 
MEC-R 
Penicillin 
 
X 
PEN-R 
B-lactam combination 
Amoxicillin/clavulanic acid 
X 
 
AUG-R 
Ceftolozane/tazobactam 
X 
 
C/T-R 
Ceftazidime/avibactam 
X 
 
CZA-R 
Piperacillin/tazobactam 
X 
 
P/T-R 
Cephalosporin 
Cefazolin 
X 
 
FAZ-R 
Ceftriaxone 
X 
 
AXO-R 
Cefadroxil 
X 
 
CFR-R 
Cefoxitin** 
 
X 
See methicillin 
resistance tree 


 
CONFIDENTIAL 
 
214144 
 
Page 92 of 93 
Antimicrobial class 
Antimicrobial 
Drug 
relevant to 
Gram-
negatives 
Drug 
relevant to 
Gram-
positives 
Resistant 
phenotype to 
be reported by 
GCL if 
interpretation is 
resistant* 
 
Carbapenem/Penem 
Meropenem 
X 
 
MERO-R 
Faropenem 
X 
X 
FPM-R 
Aminoglycoside 
Amikacin 
X 
 
AMI-R 
Gentamicin 
X 
 
GEN-R 
Folate Pathway 
Antagonist 
Trimethoprim-sulfamethoxazole 
X 
X 
SXT-R 
Trimethoprim 
X 
X 
TMP-R 
Sulfisoxazole 
X 
X 
SFX-R 
Fluoroquinolone 
Ciprofloxacin 
X 
X 
CIP-R 
Levofloxacin 
X 
X 
LEVO-R 
Nitrofuran 
Nitrofurantoin 
X 
X 
NIT-R 
Glycopeptide 
Vancomycin 
 
X 
VAN-R 
Fosfomycin 
Fosfomycin 
X 
X 
FOF-R 
Nitroxoline 
Nitroxoline 
X 
X 
NOX-R 
*Resistant phenotype based on CLSI M100 interpretations with the exception of nitroxoline and cefadroxil which are 
based on EUCAST interpretations and faropenem which is based on [Fuchs, 1995].  
** Surrogate test for oxacillin to determine methicillin susceptibility/resistance.  
R=resistant 
6.2.12. 
Trademarks 
Trademarks of the [GlaxoSmithKline / ViiV 
Healthcare] Group of Companies 
 
Trademarks not owned by the [GlaxoSmithKline 
/ ViiV Healthcare] Group of Companies 
ADVAIR 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 


 
CONFIDENTIAL 
 
214144 
 
Page 93 of 93 
7. 
REFERENCES 
Crowe B, Brueckner A, Beasley C, Kulkarni P. Current Practices, Challenges, and 
Statistical Issues With Product Safety Labeling 2013;5(3): 180-193. Statistics in 
Biopharmaceutical Research. 2013;5(3):180-193.  
Fuchs PC, Barry AL, Sewell DL. Antibacterial activity of WY-49605 compared with 
those of six other oral agents and selection of disk content for disk diffusion susceptibility 
testing. Antimicrob Agents Chemother. 1995;39:1472-9.  
SAS Institute Inc. SAS/STAT User’s Guide. Version 15.1 ed. Cary, NC:SAS; 2018.  
Schmidli HS, Gsteiger S, Roychoudhury S, O'Hagan A, Spiegelhalter D, 
Neuenschwander B. Robust meta-analytic-predictive priors in clinical trials with 
historical control information. Biometrics. 2014;70:1023-1032.