A Phase III, Randomized, Multicenter, Open-Label Study in Adolescent and Adult Participants Comparing the Efficacy and Safety of Gepotidacin to Ceftriaxone Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae
Phase: PHASE3
Conditions: Gonorrhea
Sponsor: GlaxoSmithKline

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GSK group of companies 
 
BTZ116577 
 
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TITLE PAGE 
Protocol Title:  A Phase III, Randomized, Multicenter, Open-Label Study in Adolescent 
and Adult Participants Comparing the Efficacy and Safety of Gepotidacin to Ceftriaxone 
Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by 
Neisseria gonorrhoeae 
Protocol Number:  BTZ116577 / Amendment 3 
Short Title:  Phase III, Comparator-Controlled, Efficacy and Safety Study of 
Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea; Efficacy of 
Antibacterial Gepotidacin Evaluated (EAGLE-1) 
Compound 
Number: 
GSK2140944 
Sponsor Name and Legal Registered Address:  
GSK Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Contact Address: 
GSK 
1250 South Collegeville Road 
PO Box 5089 
Collegeville, PA 19426-0989 
USA 
Medical monitor name and contact information can be found in local study contact 
information documents 
Regulatory Agency Identifying Numbers: 
IND 111885 
EudraCT 2018-001780-23 
Protocol Amendment Number:  3 
Sponsor Signatory: 
Salim Janmohamed, BSc, MBBS (Hons), FRCP, FACE 
Clinical Development Lead 
GSK  
Pharmaceutical Research and Development 
Approval Date: 10 Aug 2023 
Copyright 2019 the GSK group of companies. All rights reserved. Unauthorized copying 
or use of this information is prohibited.

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
DNG Number 
Amendment 3 
10 Aug 2023 
TMF-16433266 
Amendment 2 
16 December 2022 
TMF-15064686 
Amendment 1 
14 December 2021 
TMF-14342295 
Original Protocol 
12 April 2019 
2017N317989_00 
Amendment 3 (10 Aug 2023) 
This global amendment is considered to be non-substantial. 
Overall rationale for the current Amendment:  
This global amendment revised the definition of the Microbiological ITT (micro-ITT) 
population to align with the reporting and analysis plan; reference to EUCAST 
breakpoints was deleted from this population definition in accordance with regulatory 
agency feedback. The amendment includes wording edits based on the above changes. 
Minor editorial edits have been done. Reference list has been updated as one reference 
was erroneously missed. 
 List of main change in the protocol and their rationale: 
Section # and Name 
Description of Change 
Brief Rationale 
10.3 Populations for 
Analyses  
The definition of the 
Microbiological Intent-to-Treat 
Population has been updated. 
Revisions were made to support 
the planned efficacy analyses 
per the reporting and analysis 
plan.  
11 References 
Reference list for erroneously 
missed reference has been 
updated  
Reference list has been updated 
as one reference was 
erroneously missed. 
 

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TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 6 
2. 
SCHEDULE OF ACTIVITIES ................................................................................. 10 
3. 
INTRODUCTION .................................................................................................... 13 
3.1. 
Study Rationale .......................................................................................... 13 
3.2. 
Background ................................................................................................ 14 
3.3. 
Benefit/Risk Assessment ............................................................................ 15 
3.3.1. 
Risk Assessment ......................................................................... 16 
3.3.2. 
Benefit Assessment ..................................................................... 23 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 23 
4. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS ..................................................... 24 
5. 
STUDY DESIGN .................................................................................................... 30 
5.1. 
Overall Design ............................................................................................ 30 
5.2. 
Number of Participants ............................................................................... 33 
5.3. 
Participant and Study Completion ............................................................... 33 
5.4. 
Scientific Rationale for Study Design .......................................................... 33 
5.5. 
Dose Justification ........................................................................................ 35 
6. 
STUDY POPULATION ........................................................................................... 37 
6.1. 
Inclusion Criteria ......................................................................................... 37 
6.2. 
Exclusion Criteria ........................................................................................ 38 
6.3. 
Lifestyle Restrictions ................................................................................... 41 
6.3.1. 
Meals and Dietary Restrictions .................................................... 41 
6.4. 
Screen Failures........................................................................................... 41 
7. 
TREATMENTS ....................................................................................................... 42 
7.1. 
Treatments Administered ............................................................................ 42 
7.2. 
Dose Modification ....................................................................................... 43 
7.3. 
Method of Treatment Assignment ............................................................... 43 
7.4. 
Blinding ....................................................................................................... 44 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 44 
7.6. 
Treatment Compliance ................................................................................ 45 
7.7. 
Concomitant Therapy.................................................................................. 45 
7.7.1. 
Permitted Medications and Nondrug Therapies ........................... 46 
7.7.2. 
Prohibited Medications and Nondrug Therapies........................... 46 
7.8. 
Treatment After the End of the Study .......................................................... 47 
8. 
DISCONTINUATION CRITERIA ............................................................................. 48 
8.1. 
Discontinuation of Study Treatment ............................................................ 48 
8.1.1. 
Liver Chemistry Evaluation Criteria .............................................. 48 
8.1.2. 
QTc Stopping Criteria .................................................................. 49 
8.1.3. 
Gastrointestinal Evaluation Criteria .............................................. 50 
8.2. 
Withdrawal From the Study ......................................................................... 50 
8.3. 
Lost to Follow-Up ........................................................................................ 51 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 51 

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9.1. 
Efficacy Assessments ................................................................................. 54 
9.1.1. 
Bacteriology Samples for Culture ................................................. 54 
9.1.2. 
NAAT Assay ................................................................................ 55 
9.2. 
Adverse Events........................................................................................... 57 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 57 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 58 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 58 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................. 58 
9.2.5. 
Adverse Events of Special Interest .............................................. 59 
9.2.6. 
Cardiovascular and Death Events ................................................ 59 
9.2.7. 
Pregnancy ................................................................................... 59 
9.3. 
Treatment of Overdose ............................................................................... 59 
9.4. 
Safety Assessments ................................................................................... 60 
9.4.1. 
Physical Examinations ................................................................. 60 
9.4.2. 
Vital Signs .................................................................................... 60 
9.4.3. 
Electrocardiograms ...................................................................... 61 
9.4.4. 
Clinical Safety Laboratory Assessments ...................................... 61 
9.5. 
Pharmacokinetics ....................................................................................... 62 
9.6. 
Pharmacodynamics .................................................................................... 62 
9.7. 
Genetics ..................................................................................................... 62 
9.8. 
Biomarkers ................................................................................................. 62 
9.9. 
Health Economics or Medical Resource Utilization and Health 
Economics .................................................................................................. 62 
10. STATISTICAL CONSIDERATIONS ........................................................................ 63 
10.1. 
Statistical Hypothesis .................................................................................. 63 
10.2. 
Sample Size Determination ........................................................................ 63 
10.2.1. 
Justification of Sample Size ......................................................... 63 
10.2.2. 
Sample Size Sensitivity ................................................................ 64 
10.3. 
Populations for Analyses ............................................................................ 65 
10.4. 
Statistical Analyses ..................................................................................... 66 
10.4.1. 
General Considerations ............................................................... 66 
10.4.2. 
Efficacy Analyses ......................................................................... 66 
10.4.3. 
Safety Analyses ........................................................................... 67 
10.4.4. 
Other Analyses ............................................................................ 68 
10.5. 
Interim Analysis .......................................................................................... 68 
10.6. 
Data Monitoring Committee or Other Review Board ................................... 68 
11. REFERENCES ....................................................................................................... 69 
12. APPENDICES ........................................................................................................ 71 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 71 
12.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 74 
12.3. 
Appendix 3: Study Governance Considerations .......................................... 76 
12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 82 
12.5. 
Appendix 5: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment........................................... 87 
12.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 95 
12.7. 
Appendix 7: Genetics .................................................................................. 98 

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12.8. 
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 99 
12.9. 
Appendix 9: Additional Guidance on Permitted and Prohibited 
Medications and Crediblemeds.org ........................................................... 103 
12.10. Appendix 10: Clostridium Difficile Testing Procedure and Algorithm ......... 106 
12.11. Appendix 11: COVID-19 Protocol Information ........................................... 107 
12.11.1. Overall Rationale for this Appendix ............................................ 107 
12.11.2. Study Procedures During the COVID-19 Pandemic ................... 107 
12.12. Appendix 12: Protocol Amendment History ............................................... 109 
 

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1. 
SYNOPSIS 
Protocol Title:  A Phase III, Randomized, Multicenter, Open-Label Study in Adolescent 
and Adult Participants Comparing the Efficacy and Safety of Gepotidacin to Ceftriaxone 
Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by 
Neisseria gonorrhoeae 
Short Title:  Phase III, Comparator-Controlled, Efficacy and Safety Study of 
Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea; Efficacy of 
Antibacterial Gepotidacin Evaluated (EAGLE-1) 
Rationale: 
Gonorrhea is the second most prevalent bacterial sexually transmitted infection globally 
and remains an important clinical and public health problem throughout the world. A 
variety of antimicrobial agents have been used over the years for the treatment of 
gonorrhea; however, effective treatment options for gonorrhea have diminished rapidly 
because of the emergence and worldwide spread of antimicrobial resistance to many 
drugs previously used or considered first line. Gepotidacin is a first-in-class, novel 
triazaacenaphthylene antibacterial that has demonstrated in vitro activity against 
Neisseria gonorrhoeae (NG) with gepotidacin MIC90 values of 0.25 and 1 µg/mL for 
ciprofloxacin-susceptible and -resistant strains, respectively. In a Phase II study of 
urogenital gonorrhea caused by NG, microbiological success (bacterial eradication) was 
demonstrated for 97% and 95% of participants treated orally with single doses of 
1500 and 3000 mg gepotidacin, respectively. This Phase III study aims to evaluate oral 
gepotidacin compared to intramuscular (IM) ceftriaxone plus oral azithromycin, a 
currently recommended treatment regimen, for the treatment of uncomplicated urogenital 
infection caused by NG in adolescent and adult participants. 

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Objectives and Estimands/Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat 
participants with uncomplicated 
urogenital gonorrhea caused by NG 
• 
Culture-confirmed bacterial eradication of 
NG from the urogenital body site (i.e., 
microbiological success) at the TOC 
(Day 4 to 8) Visit  
Secondary 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat 
participants with rectal gonorrhea caused 
by NG 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat 
participants with pharyngeal gonorrhea 
caused by NG 
• 
To evaluate the safety and tolerability of 
oral gepotidacin compared to IM 
ceftriaxone plus oral azithromycin 
• 
Culture-confirmed bacterial eradication of 
NG from the rectal body site (i.e., 
microbiological success) at the TOC 
(Day 4 to 8) Visit 
• 
Culture-confirmed bacterial eradication of 
NG from the pharyngeal body site (i.e., 
microbiological success) at the TOC 
(Day 4 to 8) Visit 
• 
Treatment-emergent adverse events and 
serious adverse events and change from 
baseline results for clinical laboratory 
tests and vital sign measurements 
Note: Exploratory objectives are described in the main protocol text. 
Estimands: 
The primary clinical question of interest is: What is the treatment effect on the culture-
confirmed bacterial eradication of NG from the urogenital body site (i.e., microbiological 
success) at the TOC (Day 4 to 8) Visit after treatment with oral gepotidacin compared to 
IM ceftriaxone plus oral azithromycin in participants with uncomplicated urogenital 
gonorrhea and have confirmed NG isolated from baseline culture of their urogenital 
specimen, regardless of treatment discontinuation for any reason.  
The primary estimand is described by the following attributes: 
• 
Population: Participants with uncomplicated urogenital gonorrhea caused by culture-
confirmed NG.  
• 
Treatment condition: Gepotidacin 2×3000 mg versus ceftriaxone 500 mg plus 
azithromycin 1 g, regardless of adherence. 
• 
Variable: Microbiological success: Participants with culture-confirmed bacterial 
eradication of NG from the urogenital body site (i.e., urogenital microbiological 
success) at the TOC (Day 4 to 8) Visit without the participant receiving other 
systemic antimicrobials before this visit. 

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• 
Summary measure: Difference in proportions (microbiological success rate in the 
gepotidacin treatment group - ceftriaxone plus azithromycin treatment group).  
• 
Intercurrent events: 
− Participants who receive systemic antimicrobials before the TOC Visit will be 
considered microbiological failures (composite strategy). 
− For study treatment discontinuation, the data will be analyzed as collected 
(treatment policy strategy). 
Components of estimands for all secondary endpoints are provided in Table 3.  
The rationale for a treatment policy intercurrent event strategy of study treatment 
discontinuation is that interest lies in the treatment effect irrespective of whether the full 
course of treatment was taken or not, this is reflective of how patients may be treated in 
clinical practice. 
The rationale for using a composite strategy for the intercurrent event of antimicrobial 
use is because usage could affect bacterial culture response; thus, a conservative 
approach has been adopted and if a participant receives systemic antimicrobials before 
the TOC Visit, the participant will be assumed to be a microbiological failure. Note: The 
intercurrent event of antimicrobial use is not applicable for the safety estimands. 
Overall Design: 
• 
BTZ116577 is a Phase III, open-label (sponsor-blinded), parallel-group, multicenter, 
comparator-controlled, noninferiority study in adolescent and adult participants 
comparing the efficacy and safety of oral gepotidacin to IM ceftriaxone plus oral 
azithromycin in the treatment of uncomplicated urogenital gonorrhea caused by NG. 
• 
Participants will be stratified by sex and sexual orientation combination and age; and 
will be randomly assigned to receive either oral gepotidacin or IM ceftriaxone plus 
oral azithromycin. 
• 
Appropriate safety and microbiological assessments will be conducted at the 
Baseline (Day 1) Visit and repeated at the TOC (Day 4 to 8) and Follow-up (Day 14 
to 21) Visits. 
• 
“Test-of-Cure” microbiological success will be defined by body site (i.e., urogenital 
and, as appropriate, pharyngeal and/or rectal) as culture-confirmed bacterial 
eradication of NG observed at the TOC (Day 4 to 8) Visit. 

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Number of Participants: 
Approximately 620 participants will be screened and randomized to achieve 
approximately 400 participants with culture-confirmed urogenital gonorrhea in the 
Microbiological Intent-to-Treat (micro-ITT) Population, for an estimated total of 
200 participants per treatment group in the micro-ITT Population. Enrollment will 
continue until the target number of participants in the micro-ITT Population has been 
reached. 
Treatment Groups and Duration: 
• 
Participants will receive 1 of the following treatments: 
− Gepotidacin: 3000 mg administered orally at the study site during the Baseline 
(Day 1) Visit followed by self-administration of a second oral 3000-mg dose as 
an outpatient 10 to 12 hours after the first dose; however, for participants who 
weigh <50 kg or have moderate renal impairment, the second dose should be 
taken approximately 12 hours after the first dose). (Note: Each dose should be 
taken after food consumption and with water to assist with tolerability.) 
− Ceftriaxone plus azithromycin: A single IM 500-mg dose of ceftriaxone plus a 
single oral 1-g dose of azithromycin administered at the study site during the 
Baseline (Day 1) Visit. (Note: Azithromycin should be taken after food 
consumption and with water.) 
• 
The duration of study participation is approximately 21 days with 3 planned study 
visits: 
− Baseline (Day 1) Visit 
− TOC (Day 4 to 8) Visit 
− Follow-up (Day 14 to 21) Visit 
Data Monitoring or Other Committee: Yes; an internal GSK Safety Review Team will 
monitor blinded safety data and an internal Microbiology Review Team will monitor 
blinded microbiological data instream. No external data monitoring review committees 
are planned for the study. 
 

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2. 
SCHEDULE OF ACTIVITIES 
Table 1 
Schedule of Activities 
Visita 
Baseline 
TOCb 
Follow-upc 
Early Withdrawal 
Study Day 
1 
4 to 8 
14 to 21 
NA 
Procedure 
Predose 
Postdose 
NA 
NA 
NA 
Written informed consent/assent 
X 
 
 
 
 
IRT – Screening module 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
Participant demography 
X 
 
 
 
 
Participant social and sexual historyd 
X 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
Diagnosis of presumptive uncomplicated urogenital gonorrhea 
X 
 
 
 
 
Bacteriology samplese 
X 
 
X 
X 
X 
NAAT assay samplesf 
X 
 
X 
X 
X 
Physical examination (including height and weight at Baseline only)g 
X 
 
X 
 
 
12-lead electrocardiogramh 
X 
 
 
 
 
Vital sign measurementsi 
X 
 
X 
 
 
Hematology, chemistry, and urinalysis 
X 
 
X 
 
 
Serology (hepatitis B and C and HIV)j 
X 
 
 
 
 
Urine pregnancy testk 
Xk 
 
X 
 
X 
Drug and alcohol screen 
X 
 
 
 
 
IRT – Randomization module 
X 
 
 
 
 
Administer oral gepotidacinl 
 
Xl 
 
 
 
Administer IM ceftriaxone plus oral azithromycinm 
 
Xm 
 
 
 
Sexual history since last visitd 
 
 
X 
X 
X 
Serious adverse eventsn 
X 
X 
X 
X 
X 
Adverse eventso 
 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
Schedule TOC and Follow-up Visits 
Xp,q 
 
Xq 
Xp 
 
Treatment for CT and/or Mgen infectionr 
 
 
X 
X 
X 
Genetic samples 
X 
 
 
 
 
CT=Chlamydia trachomatis; HIV=human immunodeficiency virus; IM=intramuscular; IRT; interactive response technology; Mgen=Mycoplasma genitalium; NA=not applicable; 
NAAT=nucleic acid amplification test; TOC=Test-of-Cure. 

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a. 
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.  
b. 
TOC (Day 4 to 8) Visit: Participants will be instructed to return to the study site within 3 to 7 days after study treatment administration. This visit may occur earlier if 
participants experience an adverse event. 
c. 
Participants will be instructed to return to the study site from Day 14 to 21 for a Follow-up Visit. The investigator and/or study site staff should make every effort to ensure the 
participant returns for this visit. If the participant is unable to return to the study site, the visit assessments may be completed via telephone, with the exception of 
assessments requiring sample collection for laboratory testing. 
d. 
Refer to the Study Reference Manual for information to collect for social and sexual history. 
e. 
See Table 2 for collection of bacteriology samples. Also refer to the laboratory manual. 
f. 
See Table 2 for collection of NAAT assay samples. Also refer to the laboratory manual.  
g. 
A complete physical examination will be performed at the Baseline Visit and a gonorrhea-focused examination will be performed at the TOC Visit (see Section 9.4.1). Height 
and weight will only be measured and recorded at the Baseline Visit (before dosing). 
h. 
See Section 6.2 for electrocardiogram exclusion criterion for participants aged ≥12 to <18 years. For additional details see Section 8.1.2 and Section 9.4.3.  
i. 
Take measurement of temperature, blood pressure, and pulse rate. See Section 9.4.2. 
j. 
If serology testing was performed within 3 months prior to the first dose of study treatment and results were positive, testing at Baseline is not required. If testing was 
performed within 3 months and any result was negative, testing at Baseline is required. 
k. 
For women of childbearing potential, a negative urine pregnancy test is sufficient for eligibility. See Appendix 6 for Baseline urine test sensitivity requirements and associated 
contraception requirements. 
l. 
During the Baseline Visit, participants randomly assigned to gepotidacin will receive their first oral dose (3000 mg) at the study site. Participants will self-administer their 
second dose (3000 mg) as an outpatient 10 to 12 hours after the first dose; however, for participants who weigh <50 kg or have moderate renal impairment, the second dose 
should be taken approximately 12 hours after the first dose). See Section 7.1. Each dose should be taken after food consumption and with water to assist with tolerability. 
Participants will be contacted to confirm that they took their second gepotidacin dose. See Section 7.6. 
m. During the Baseline Visit, participants randomly assigned to ceftriaxone plus azithromycin will receive a single IM dose of ceftriaxone (500 mg) plus a single oral dose of 
azithromycin (1 g). See Section 7.1. Azithromycin should be taken after food consumption and with water. 
n. 
Record serious adverse events from the time of consent/assent in order to fulfill international regulatory requirements. 
o. 
Record adverse events from the time of the first dose of study treatment. 
p. 
Confirm return day/time for the TOC and Follow-up Visits. 
q. 
Previsit reminder: Study site staff will contact the participant 24±4 hours before the respectively scheduled Baseline (if applicable), TOC, or Follow-up Visit. 
r. 
Participants who tested positive for CT and/or Mgen per NAAT results at the Baseline Visit should be treated per local standard of care at or after the TOC Visit or at the 
Follow-up Visit (if treatment has not already been initiated), as required, after all study procedures at the visit have been completed. 
s. 
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; however, it can 
be collected at any time during the study. 

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Table 2 
Collection of Bacteriology and NAAT Microbiological Specimens 
Visit 
Baseline 
TOCa 
Follow-up 
Early Withdrawal 
Study Day 
1 
4 to 8 
14 to 21 
NA 
Collection Type 
Anatomical Siteb – Organism  
Predose 
NA 
NA 
NA 
Bacteriology sample collectionb 
Urogenital – NGc  
X 
X 
 
X 
Pharyngeal – NGd 
X 
X 
Xe 
X 
Rectal – NGd 
X 
X 
 
X 
NAAT assay sample collectionf 
Urogenital – NG and CTg  
X 
Xh 
 
X 
Urogenital – Mgeng  
X 
 
Xi 
X 
Pharyngeal – NG and CTj 
X 
X 
Xk 
X 
Rectal – NG and CTj 
X 
X 
 
X 
CT=Chlamydia trachomatis; Mgen=Mycoplasma genitalium; NA=not applicable; NAAT=nucleic acid amplification test; NG=Neisseria gonorrhoeae; TOC=Test-of-Cure. 
a. 
Any participant that withdraws before TOC should have all bacteriology and NAAT assay collections performed as indicated at the TOC Visit. 
b. 
Multiple swab specimens and types may need to be obtained from each anatomical site; refer to the laboratory manual. 
c. 
Collect a pretreatment urogenital swab specimen from all participants for Gram stain (males and females), bacterial culture, and in vitro susceptibility testing at Baseline. At 
TOC, a urogenital swab specimen will be collected for Gram stain, bacterial culture, and in vitro susceptibility testing. Note: All urogenital swab specimens will be processed 
for Gram stain testing following inoculation of the culture plates. 
d. 
Pretreatment rectal and pharyngeal swab specimens for bacterial culture and in vitro susceptibility testing will be obtained from participants who are willing to provide such 
specimens, regardless of known exposure. At TOC, swab specimens will be collected from pharyngeal and/or rectal sites that were collected at Baseline for bacterial culture 
and in vitro susceptibility testing. Note: None of the rectal or pharyngeal swab specimens will be processed for Gram stain testing. 
e. 
At Follow-up, pharyngeal swab specimens will be obtained for bacterial culture and in vitro susceptibility testing from participants who had a positive NAAT assay for 
pharyngeal NG at both Baseline and TOC. Results from the NAAT assay will be available to the study sites by the Follow-up Visit.  
f. 
See the laboratory manual for local versus central laboratory details and the number and type of specimens to collect. 
g. 
Pretreatment baseline urogenital specimens will be obtained from all participants for detection of NG, Mgen, and CT by NAAT. At Baseline, while detection of NG and CT by 
NAAT may be performed using the same urogenital sample, 2 separate samples must be obtained (1 for the local laboratory and 1 for the central laboratory). 
h. 
Urogenital specimens will be obtained from all participants for detection of NG and CT by NAAT at the TOC Visit.  
i. 
At Follow-up, a urogenital specimen will be collected for the detection of Mgen only by NAAT from participants who had a positive NAAT assay for Mgen at Baseline. Results 
from the NAAT assay will be available to the study sites by the Follow-up Visit.  
j. 
Pretreatment baseline pharyngeal and rectal specimens for detection of NG and CT by NAAT will be obtained from participants who are willing to provide such specimens, 
regardless of known exposure. At TOC, a specimen will be collected from pharyngeal and/or rectal sites that were collected at Baseline.  
k. 
At Follow-up, a pharyngeal specimen will be collected for detection of NG and CT by NAAT from participants whose NAAT assay had the presence of nucleic acid for NG at 
both Baseline and TOC. NAAT assay results will be available to the study sites by the Follow-up Visit.  
 

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3. 
INTRODUCTION 
Gepotidacin (GSK2140944) is a novel, bactericidal, first-in-class triazaacenaphthylene 
antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action 
[Gibson, 2019; Bax, 2010] and equally and independently binds to 2 different type II 
topoisomerase enzymes [Oviatt, 2022]. 
This provides activity against most strains of Escherichia coli and Staphylococcus 
saprophyticus, including isolates resistant to current antibiotics [Biedenbach, 2016; 
Mushtaq, 2019]. Due to the equal and independent binding at both enzymes, mutations in 
both enzymes are needed to significantly affect gepotidacin susceptibility [Oviatt, 2022]. 
Gepotidacin has been evaluated in Phase II studies for the treatment of ABSSSIs, 
uncomplicated urogenital gonorrhea, and uncomplicated UTI. Phase III studies are 
ongoing to evaluate oral gepotidacin for the treatment of uncomplicated urogenital 
gonorrhea and uncomplicated UTI (acute cystitis). 
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. 
3.1. 
Study Rationale 
This study is being conducted based on the need to identify new and effective antibiotic 
treatment options for gonorrhea as antimicrobial resistance continues to rise worldwide 
(see Section 3.2) and based on the results of an open-label, dose-ranging Phase II study of 
gepotidacin for the treatment of adults with uncomplicated urogenital gonorrhea caused 
by NG. 
Study BTZ116576 was a Phase II, randomized, multicenter, open-label, dose-ranging 
study evaluating the efficacy, safety, and tolerability of gepotidacin therapy in adult 
participants with uncomplicated urogenital gonorrhea caused by NG. Participants were 
administered single oral doses (1500 or 3000 mg) of gepotidacin on Day 1 with a 
Test-of-Cure (TOC) (Day 4 to 8) Visit. A total of 69 participants (1500 mg: 
30 participants; 3000 mg: 39 participants) were included in the Microbiologically 
Evaluable Population. The primary aim of the study was to provide evidence for 
95% bacterial eradication of urogenital NG in the Microbiologically Evaluable 
Population at the TOC Visit (cure rate) and to exclude the null hypothesis that the cure 
rate was 80% or less. Microbiological success was achieved by 97% and 95% of 
participants (lower 1-sided exact 95% confidence interval [CI] bound, 85.1% and 84.7%, 
respectively) in the 1500- and 3000-mg treatment groups, respectively. Microbiological 
success (bacterial eradication) was also evaluated for pharyngeal and rectal NG, with 
1 of the 2 participants with pharyngeal NG and all 3 participants with rectal NG 
achieving microbiological success. In Study BTZ116576, gepotidacin was active in vitro 

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against the 69 baseline urogenital NG isolates recovered, with a gepotidacin minimum 
inhibitory concentration (MIC) range of ≤0.06 to 1 µg/mL and 50th and 90th percentile 
minimum inhibitory concentration (MIC50 and MIC90) values of 0.12 and 0.5 µg/mL, 
respectively. Additional study results demonstrated that some baseline urogenital NG 
isolates were resistant to ciprofloxacin, penicillin, and/or tetracycline. 
This Phase III study (BTZ116577) aims to evaluate oral gepotidacin compared to 
intramuscular (IM) ceftriaxone plus oral azithromycin, a currently recommended 
treatment regimen, for the treatment of uncomplicated urogenital infection caused by NG 
in adolescent and adult participants. 
3.2. 
Background 
Gonorrhea is the second most prevalent bacterial sexually transmitted infection globally 
and remains an important clinical and public health problem throughout the world. In 
2012, an estimated 78 million cases of gonorrhea occurred among 15- to 49-year-olds 
worldwide with a global incidence rate of 19 per 1000 females and 24 per 1000 males 
[WHO, 2016]. Gonococcal infections following sexual and perinatal transmission are a 
major source of morbidity worldwide [Barry, 2009]. Infections can involve cervicitis, 
proctitis, urethritis, pelvic inflammatory disease, and pharyngitis. Complications include 
infertility, ectopic pregnancy, chronic pelvic pain, adverse outcomes of pregnancy, 
disseminated gonococcal infection, and increased susceptibility to and transmission of 
human immunodeficiency virus [Workowski, 2008; Barry, 2009]. 
A variety of antimicrobial agents have been used over the years for the treatment of 
gonorrhea; however, effective treatment options for gonorrhea have diminished rapidly 
because of the emergence and worldwide spread of antimicrobial resistance to many 
drugs previously used or considered first line, i.e., penicillins, narrow-spectrum 
cephalosporins, tetracyclines, macrolides, and fluoroquinolones [Workowski, 2008; 
Barry, 2009]. At the start of the present study, the recommended treatment for urogenital 
gonorrhea per the European Union, United States (Centers for Disease Control and 
Prevention [CDC]), and World Health Organization (WHO) guidelines is an IM injection 
of ceftriaxone combined with a single oral dose of azithromycin [Bignell, 2013; CDC, 
2015; WHO, 2016]. As of Dec 2020, the CDC now recommends an IM injection of 
ceftriaxone based on body weight and an oral regimen of doxycycline if chlamydia 
infection has not been ruled out [CDC, 2021]. While these guidelines may help delay the 
emergence of cephalosporin-resistant gonorrhea by using combination antibacterial 
therapy, they are not able to eliminate this impending threat. Therefore, drug-resistant 
NG has been labeled at a threat level of urgent by the CDC and as a high priority by 
WHO; both agencies have urged scientists and private sector drug developers to prioritize 
the identification and study of new, effective antibiotic treatment options for gonorrhea 
[CDC, 2019; CDC, 2015; WHO, 2017]. 

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Gepotidacin is a first-in-class, novel triazaacenaphthylene antibacterial that has 
demonstrated in vitro activity against NG with gepotidacin MIC90 values of 0.25 and 
1 µg/mL for ciprofloxacin-susceptible and -nonsusceptible strains, respectively (see 
Section 4.2.1.3 in the investigator’s brochure [IB]). In a Phase II study of uncomplicated 
urogenital gonorrhea caused by NG, microbiological success (bacterial eradication) was 
demonstrated for 97% and 95% of participants treated orally with single doses of 
1500 and 3000 mg gepotidacin, respectively. 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 in order to address an unmet 
medical need by providing a new and effective oral treatment option for gonorrhea.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the IB. Details on the active comparator in this study, 
ceftriaxone plus azithromycin, may be found in locally approved prescribing information. 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) may be found in the IB for gepotidacin and in 
locally approved prescribing information for ceftriaxone and azithromycin. 
 

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3.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Gepotidacin (GSK2140944) 
Cardiovascular Effects 
Based on nonclinical data, cardiovascular 
effects were reversible increase in heart rate 
and blood pressure (dog and monkey); 
reversible 10 to 21 msec (4% to 9%) increase 
in QTc (monkey); and at the highest dose, a 
reversible 2 to 3 msec (6% to 8%) increase in 
QRS (monkey). 
Based on a thorough QTc clinical study, 
gepotidacin may cause mild, reversible heart 
rate effects and QT prolongation. 
In a thorough QTc study, infusion of gepotidacin 
at doses of 1000 and 1800 mg over 2 hours 
caused a mild increased heart rate effect of 
approximately 6 to 10 bpm and QT prolongation 
measured as ∆∆QTcF of 12 to 22 msec. The QT 
prolongation evolved during the infusion and was 
quickly reversed over 2 hours after the end of the 
infusion (see Section 5.2.6 and Section 6 of the 
IB). 
In Phase I and II studies, 
concentration-dependent QT prolongation has 
been observed during clinical trials with 
gepotidacin; however, this increase has not 
translated into medically significant QTc values or 
changes from baseline (QTcF >500 msec or 
change from baseline >60 msec) or 
cardiovascular safety concerns.  
In Phase I and II studies, gepotidacin did not have 
a clinically relevant effect on cardiac conduction 
(PR and QRS intervals). 
See Section 6.2 for excluded cardiac 
conditions. Close monitoring of clinical 
parameters and AEs (Section 2, Table 1) will 
be conducted, and treatment monitoring and 
evaluation criteria (Section 8.1.2) will be 
utilized to mitigate cardiovascular effects. 
Participants taking medications known to 
increase QT or potent CYP3A4 inhibitors will 
be excluded (Section 7.7.2). 
See also the Hepatic and Renal sections 
within this table below. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Gastrointestinal Effects 
Based on nonclinical data, gastrointestinal 
effects were mild ulceration of the nonglandular 
mucosa and minimal erosion and/or mural 
inflammation of the glandular mucosa in 
stomach (rat, oral study); moderate cecal 
ulceration and minimal colonic erosion (rat, IV 
study); and vomiting (dog). 
Lower gastrointestinal effects (soft stools, 
flatulence, and diarrhea) are among the most 
common AEs reported in gepotidacin clinical 
studies. Nausea and vomiting AEs have also 
been commonly observed in gepotidacin 
clinical studies. 
See also the Acetylcholinesterase Inhibition 
section within this table below. 
Clostridium difficile-associated diarrhea has been 
observed in clinical trials with gepotidacin. 
See Section 6.2 for excluded medical 
conditions. Close monitoring of clinical 
parameters and AEs (Section 2, Table 1) will 
be conducted to mitigate and assess 
gastrointestinal effects.  
Suspected C. difficile infection will be 
managed according to a prespecified 
algorithm provided in Appendix 10. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Acetylcholinesterase Inhibition 
In vitro testing showed gepotidacin to be a 
rapidly reversible inhibitor of 
acetylcholinesterase in the clinical plasma 
concentration range. 
Based on clinical data, caution should be used 
in participants who have a condition requiring 
treatment with anticholinergic medications or 
who have certain medical conditions that may 
be exacerbated by the acetylcholinesterase 
inhibition activity of gepotidacin. 
Increased cholinergic effects can potentially be 
associated with more severe symptoms including 
atrioventricular block, seizure/convulsions, 
bronchospasm, and vasovagal syncope. No 
causal relationship between these events and the 
use of gepotidacin has been established during 
clinical trials to date. 
Adverse events possibly 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.  
The majority of these AEs have been mild and 
transient and have been reported in clinical trials 
with comparable Cmax levels expected in this 
study. 
Participants who have medical conditions or 
require medications that may be impacted by 
inhibition of acetylcholinesterase will be 
excluded from participation in this study. See 
Section 6.2, for excluded medical conditions 
and Section 7.7.2, Prohibited Medications and 
Nondrug Therapies, for prohibited 
medications. 
Close monitoring of clinical parameters and 
AEs will be conducted to assess effects 
potentially related to acetylcholinesterase 
inhibition (Section 2, Table 1). 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Hepatic Effects 
In preclinical studies, increases in ALT, GLDH, 
alkaline phosphatase, and total bilirubin were 
observed in some rat studies of varying 
exposure. 
 
Elevations in ALT have occurred in a few 
participants with pre-existing hepatitis C infection, 
but none were felt related to study treatment. The 
type and pattern of elevation in liver 
transaminases observed has not been suggestive 
of an adverse effect of gepotidacin and none were 
considered related to study treatment. 
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in volunteer 
participants with severe hepatic impairment. 
Participants with severe hepatic impairment 
are excluded from Phase III trials. See 
Section 6.2 for excluded medical conditions. 
Monitoring and stopping criteria liver events 
have been implemented. 
Renal Effects 
In preclinical trials, mild to moderate tubular 
degeneration was noted in the rat and 
proteinuria in the dog. Proteinuria was also 
observed in humans. 
No clinical evidence of renal toxicity has been 
seen in clinical trials to date.  
A substantial increase in Cmax and AUC and 
decrease in clearance was observed in severe 
renal impairment/ESRD participants not on 
hemodialysis and in ESRD participants requiring 
hemodialysis (note: gepotidacin may have been 
administered at any time other than when 
receiving dialysis). 
Participants with severe renal 
impairment/ESRD (including those who may 
require dialysis) are excluded from Phase III 
trials. See Section 6.2 for excluded medical 
conditions. Monitoring criteria have been 
implemented. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Reproductive System Effects 
Preclinical studies demonstrated that 
gepotidacin was not genotoxic and no 
drug-related malformations were observed. 
Although positive in vitro findings for 
clastogenicity, consistent with a mechanism 
related to mammalian topoisomerase II 
inhibition were found, in vivo data from rat 
micronucleus and COMET assays suggest that 
gepotidacin does not pose a genotoxic hazard 
to humans. 
Gepotidacin effects on embryofetal 
development were limited to decreased fetal 
weights for male and female fetuses in rats and 
decreased fetal weights and increased fetal 
resorptions (fetal deaths) in mice, both at 
maternally toxic doses. These occurred at 
clinically relevant exposures (65 µg.h/mL in rat 
and 35 µg.h/mL in mouse). 
There are no data on the use of gepotidacin in 
pregnant women.  
Gepotidacin is not recommended in pregnant 
or nursing mothers. Pregnancy testing 
requirements in this study minimize the risk of 
exposure to a fetus. See Appendix 6 for 
contraceptive measures and for required 
pregnancy testing. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Other 
Ceftriaxone 
Intramuscular administration of ceftriaxone may 
be associated with local injection site reactions, 
including pain, warmth or induration, or 
tenderness. 
Some of the risks summarized for gepotidacin 
also apply to ceftriaxone, including the occurrence 
of gastrointestinal effects (diarrhea or loose 
stools) and the need to monitor for C. difficile-
associated diarrhea. Other adverse effects 
include hepatic (AST and ALT elevations) and 
hematologic (eosinophilia, thrombocytosis, and 
leukopenia). 
Additionally, ceftriaxone should not be 
reconstituted using diluents containing calcium, 
such as Ringer’s solution or Hartmann’s solution, 
because a precipitate can form.  
Refer to the locally approved ceftriaxone 
prescribing information for specific details relating 
to ceftriaxone. 
Close monitoring of clinical parameters and 
AEs (Section 2, Table 1) will be conducted, 
and treatment monitoring and evaluation 
criteria (Section 8.1.1) will be utilized to 
mitigate hepatic effects. 
Participants with a history of sensitivity to 
ceftriaxone, or components thereof, will not be 
allowed to enroll in the study (Section 6.2). 
Participant’s medical history will be carefully 
evaluated for a history of hypersensitivity. 
Suspected C. difficile infection will be 
managed according to a prespecified 
algorithm provided in Appendix 10. 
Precautions related to ceftriaxone solution 
preparation are included in Section 7.5 and 
summarized in detail in the Study Reference 
Manual.  

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Azithromycin 
Some of the risks summarized for gepotidacin 
also apply to azithromycin, including the 
occurrence of gastrointestinal effects (diarrhea or 
loose stools) and the need to monitor for 
C. difficile-associated diarrhea and prolongation of 
the QT interval.  
Azithromycin may also exacerbate muscle 
weakness in participants with myasthenia gravis. 
Other adverse effects include allergic and skin 
reactions and hepatotoxicity, which may be 
serious (including fatal).  
Close monitoring of clinical parameters and 
AEs (Section 2, Table 1) will be conducted. 
Suspected C. difficile infection will be 
managed according to a prespecified 
algorithm provided in Appendix 10. 
See Section 6.2 for excluded cardiac 
conditions. Monitoring and evaluation criteria 
(Section 8.1.2) will be utilized to mitigate 
cardiovascular effects. In addition, 
participants taking QT-prolonging drugs or 
strong CYP3A4 inhibitors will be excluded. 
Participants with myasthenia gravis will be 
excluded. 
Participants with a history of sensitivity to 
azithromycin, erythromycin, and any 
macrolide or ketolide drug will be excluded 
(Section 6.2). Participant’s medical history will 
be carefully evaluated for a history of 
hypersensitivity. Participants with a history of 
cholestatic jaundice or hepatic dysfunction 
associated with prior use of azithromycin will 
be excluded (Section 6.2). Treatment 
monitoring and evaluation criteria (Section 
8.1.1) will be utilized to mitigate hepatic 
effects. 
bpm=beats per minute; ABSSSI=acute bacterial skin and skin structure infection; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AUC=area 
under the drug concentration-time curve; Cmax=maximum concentration; CYP3A4=cytochrome P450 enzyme 3A4; ECG=electrocardiogram; ESRD=end-stage renal disease; 
GLDH=glutamate dehydrogenase; IC50=inhibitory concentration inhibiting 50% of microbial isolates; IB=investigator’s brochure; IV=intravenous; ΔΔQTcF=placebo-corrected change 
from baseline in corrected QT interval using the Fridericia formula; QTc=corrected QT interval; QTcB=QT interval corrected for heart rate according to Bazett; QTcF=interval corrected 
for heart rate according to Fridericia.  

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3.3.2. 
Benefit Assessment 
Given the results of the previous Phase II study in adult participants with uncomplicated 
urogenital gonorrhea and the demonstrated in vitro activity of gepotidacin against NG, 
including ciprofloxacin-resistant strains (see Section 3.1 and Section 4.2.1.1 in the IB), as 
well as human safety data and the pharmacokinetic (PK) profile, it is anticipated that 
gepotidacin will benefit participants with uncomplicated urogenital gonorrhea.  
The active comparator in this study is ceftriaxone plus azithromycin, both of which are 
marketed antibiotics that have demonstrated effectiveness for eradication of NG and 
Chlamydia trachomatis (CT), respectively (refer to locally approved ceftriaxone and 
azithromycin prescribing information). Participants randomly assigned to this treatment 
group are also expected to experience treatment benefits. 
It is expected that gepotidacin will have a similar efficacy profile to ceftriaxone plus 
azithromycin and may have a better tolerability profile, as gepotidacin will be 
administered orally and ceftriaxone will be administered IM, possibly resulting in fewer 
treatment-related AEs associated with oral gepotidacin dose administration.  
Overall, all participants in this study will not only receive routine medical monitoring for 
uncomplicated urogenital gonorrhea, but they will also receive heightened monitoring, 
including detection and treatment of any co-occurring infections caused by CT or 
Mycoplasma genitalium (Mgen), to ensure safety when participating in a clinical study. 
3.3.3. 
Overall Benefit:Risk Conclusion 
The ability of NG to develop resistance to antimicrobials has complicated the 
management of treatment for gonorrhea, leading to an urgent need for new treatment 
options [CDC, 2015; WHO, 2016]. However, even in the face of increasing drug 
resistance to existing agents, few new antibiotics with novel mechanisms of action are 
being developed. Gepotidacin selectively inhibits bacterial DNA replication by a means 
not utilized by any currently approved human therapeutic agent. Clinical results from a 
Phase II study in adult participants showed that gepotidacin is an effective treatment for 
uncomplicated urogenital gonorrhea, including most ciprofloxacin-resistant strains. 
Gepotidacin, therefore, represents a potential new oral treatment option for gonorrhea and 
an opportunity to address an unmet medical need.  
None of the potential or identified risks seen to date in participants dosed with 
gepotidacin preclude further clinical development. Mitigation strategies have been 
implemented to promptly identify and appropriately address risks in order to protect 
participant safety and to better characterize the safety profile of the study treatments (see 
Section 3.3.1). Furthermore, an internal GSK Safety Review Team (SRT) will monitor 
blinded safety data instream. Careful safety monitoring should also identify any emerging 
safety issues for gepotidacin and contribute to the benefit-risk profile of ceftriaxone plus 
azithromycin. 
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with gepotidacin and ceftriaxone 
plus azithromycin are justified by the anticipated benefits that may be afforded to 
participants with uncomplicated urogenital gonorrhea caused by NG. 

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4. 
OBJECTIVES AND ESTIMANDS/ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat participants 
with uncomplicated urogenital gonorrhea 
caused by NG 
• 
Culture-confirmed bacterial eradication 
of NG from the urogenital body site (i.e., 
microbiological success) at the TOC 
(Day 4 to 8) Visit  
Secondary 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat participants 
with rectal gonorrhea caused by NG 
• 
To evaluate the efficacy of oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin to treat participants 
with pharyngeal gonorrhea caused by NG 
• 
To evaluate the safety and tolerability of 
oral gepotidacin compared to IM 
ceftriaxone plus oral azithromycin 
• 
Culture-confirmed bacterial eradication 
of NG from the rectal body site (i.e., 
microbiological success) at the TOC 
(Day 4 to 8) Visit 
• 
Culture-confirmed bacterial eradication 
of NG from the pharyngeal body site 
(i.e., microbiological success) at the 
TOC (Day 4 to 8) Visit 
• 
Treatment-emergent AEs and serious 
AEs (SAEs) and change from baseline 
results for clinical laboratory tests and 
vital sign measurements 
Exploratory 
• 
To assess the clearance or persistence of 
NG nucleic acid (by nucleic acid 
amplification test [NAAT] assay) from 
urogenital specimens for oral gepotidacin 
compared to IM ceftriaxone plus oral 
azithromycin 
• 
Urogenital NG NAAT results at the TOC 
(Day 4 to 8) Visit 
• 
To assess the clearance or persistence of 
NG nucleic acid (NAAT assay) from 
pharyngeal specimens for oral 
gepotidacin compared to IM ceftriaxone 
plus oral azithromycin 
• 
Pharyngeal NG NAAT results at the 
TOC (Day 4 to 8) and Follow-up (Day 14 
to 21) Visits, where only participants 
who did not receive other systemic 
antimicrobials at or after the TOC (Day 4 
to 8) Visit will be evaluated at the 
Follow-up Visit 
• 
To assess the clearance or persistence of 
NG nucleic acid (NAAT assay) from rectal 
specimens for oral gepotidacin compared 
to IM ceftriaxone plus oral azithromycin 
• 
Rectal NG NAAT results at the TOC 
(Day 4 to 8) Visit 

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Objectives 
Endpoints 
• 
To assess the clearance or persistence of 
Mgen nucleic acid (by NAAT assay) from 
urogenital specimens for oral gepotidacin 
compared to IM ceftriaxone plus oral 
azithromycin 
• 
Urogenital Mgen NAAT results at the 
Follow-up (Day 14 to 21) Visit, where 
only participants who did not receive 
other systemic antimicrobials at or after 
the TOC (Day 4 to 8) Visit will be 
evaluated 
• 
To evaluate the microbiological 
characteristics and antimicrobial 
susceptibility profile of NG from 
urogenital, pharyngeal, or rectal 
specimens 
• 
Gram stain (urogenital specimens only), 
bacterial culture, and in vitro 
susceptibility test results from urogenital, 
pharyngeal, or rectal specimens at the 
Baseline (Day 1), TOC (Day 4 to 8), and 
Follow-up (Day 14 to 21) Visits, as data 
permit 
Estimands: 
The primary clinical question of interest is: What is the treatment effect on the 
culture-confirmed bacterial eradication of NG from the urogenital body site (i.e., 
microbiological success) at the TOC (Day 4 to 8) Visit after treatment with oral 
gepotidacin compared to IM ceftriaxone plus oral azithromycin in participants with 
uncomplicated urogenital gonorrhea and have confirmed NG isolated from baseline 
culture of their urogenital specimen, regardless of treatment discontinuation for any 
reason. 
Prespecified estimands with related attributes are presented in Table 3 for the primary 
and key secondary objectives. 
 

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Table 3 
Estimands 
Estimand 
Category  
Estimand 
Variable/Endpoint 
Population 
Treatment Condition 
Summary Measure 
Intercurrent Event Strategy 
Primary Objective: To evaluate the efficacy of oral gepotidacin compared to IM ceftriaxone plus oral azithromycin to treat participants with uncomplicated 
urogenital gonorrhea caused by NG 
Primary  
Microbiological success: 
Participants with 
culture-confirmed bacterial 
eradication of NG from the 
urogenital body site (i.e., 
urogenital microbiological 
success) at the TOC 
(Day 4 to 8) Visit without 
the participant receiving 
other systemic 
antimicrobials 
Refer to Table 5 for further 
details on the endpoint 
definition, including the 
missing data strategy for 
participants who do not 
return for the TOC Visit 
Participants with 
uncomplicated 
urogenital gonorrhea 
caused by 
culture-confirmed 
NG 
Gepotidacin 2×3000 mg 
versus  
Ceftriaxone 500 mg plus 
azithromycin 1 g,  
regardless of adherence 
Difference in proportions  
(microbiological success 
rate in the gepotidacin 
treatment group - 
ceftriaxone plus 
azithromycin treatment 
group) 
Participants who receive 
systemic antimicrobials 
before the TOC Visit will be 
considered microbiological 
failures (composite strategy) 
For study treatment 
discontinuation, the data will 
be analyzed as collected 
(treatment policy strategy) 

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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population 
Treatment Condition 
Summary Measure 
Intercurrent Event Strategy 
Secondary Objective: To evaluate the efficacy of oral gepotidacin compared to IM ceftriaxone plus oral azithromycin to treat participants with rectal gonorrhea 
caused by NG 
Secondary 
Participants with 
culture-confirmed bacterial 
eradication of NG from the 
rectal body site (i.e., rectal 
microbiological success) at 
the TOC (Day 4 to 8) Visit 
without the participant 
receiving other systemic 
antimicrobials 
Refer to Table 5 for further 
details on the endpoint 
definition, including missing 
data strategy for 
participants who do not 
return for the TOC Visit 
Participants with 
uncomplicated 
urogenital and rectal 
gonorrhea caused 
by culture-confirmed 
NG 
Gepotidacin 2×3000 mg 
versus  
Ceftriaxone 500 mg plus 
azithromycin 1 g,  
regardless of adherence 
Difference in proportions  
(microbiological success 
rate in the gepotidacin 
treatment group - 
ceftriaxone plus 
azithromycin treatment 
group) 
Participants who receive 
systemic antimicrobials 
before the TOC Visit will be 
considered microbiological 
failures (composite strategy) 
For study treatment 
discontinuation, the data will 
be analyzed as collected 
(treatment policy strategy) 

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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population 
Treatment Condition 
Summary Measure 
Intercurrent Event Strategy 
Secondary Objective: To evaluate the efficacy of oral gepotidacin compared to IM ceftriaxone plus oral azithromycin to treat participants with pharyngeal 
gonorrhea caused by NG 
Secondary 
Participants with 
culture-confirmed bacterial 
eradication of NG from the 
pharyngeal body site (i.e., 
pharyngeal microbiological 
success) at the TOC (Day 
4 to 8) Visit without the 
participant receiving other 
systemic antimicrobials 
 
Refer to Table 5 for further 
details on the endpoint 
definition, including the 
missing data strategy for 
participants who do not 
return for the TOC Visit 
Participants with 
uncomplicated 
urogenital and 
pharyngeal 
gonorrhea caused 
by culture-confirmed 
NG 
Gepotidacin 2×3000 mg 
versus  
Ceftriaxone 500 mg plus 
azithromycin 1 g,  
regardless of adherence 
Difference in proportions  
(microbiological success 
rate in the gepotidacin 
treatment group - 
ceftriaxone plus 
azithromycin treatment 
group) 
Participants who receive 
systemic antimicrobials 
before the TOC Visit will be 
considered microbiological 
failures (composite strategy) 
For study treatment 
discontinuation, the data will 
be analyzed as collected 
(treatment policy strategy) 

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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population 
Treatment Condition 
Summary Measure 
Intercurrent Event Strategy 
Secondary Objective: To evaluate the safety and tolerability of oral gepotidacin compared to IM ceftriaxone plus oral azithromycin 
Secondary 
(Safety) 
Treatment-emergent AEs 
and serious AEs and 
change from baseline 
results for clinical 
laboratory tests and vital 
sign measurements 
Participants with 
uncomplicated 
urogenital gonorrhea 
Gepotidacin 2×3000 mg 
versus  
Ceftriaxone 500 mg plus 
azithromycin 1 g,  
regardless of adherence 
The proportions for 
treatment-emergent AEs 
and serious AEs will be 
produced for each arm 
separately. The means for 
change from baseline 
results (clinical laboratory 
results and vital sign 
measurements) will be 
produced for each arm 
separately. 
For study treatment 
discontinuation, the data will 
be analyzed as collected 
(treatment policy strategy) 
AE=adverse events; NG=Neisseria gonorrhoeae; TOC=Test-of-Cure. 
 

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The rationale for a treatment policy intercurrent event strategy of study treatment 
discontinuation is that interest lies in the treatment effect irrespective of whether the full 
course of treatment was taken or not, this is reflective of how patients may be treated in 
clinical practice. 
The rationale for using a composite strategy for the intercurrent event of antimicrobial 
use is because usage could affect bacterial culture response; thus, a conservative 
approach has been adopted and if a participant receives systemic antimicrobials before 
the TOC Visit, the participant will be assumed to be a microbiological failure. Note: The 
intercurrent event of antimicrobial use is not applicable for the safety estimands. 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
• 
BTZ116577 is a Phase III, open-label (sponsor-blinded), parallel-group, multicenter, 
comparator-controlled, noninferiority study in adolescent and adult participants 
comparing the efficacy and safety of oral gepotidacin to IM ceftriaxone plus oral 
azithromycin in the treatment of uncomplicated urogenital gonorrhea caused by NG. 
• 
Participants will be stratified by sex and sexual orientation combination (men who 
have sex with men [MSM], men who have sex with women [MSW], or female) and 
age (<18 years, ≥18 to 65 years, or >65 years). The MSM category will include 
MSM and bisexual males (i.e., male participants who have sex with both males and 
females). Participants will be randomly assigned to receive 1 of the following 
treatments (see Section 7.1): 
− 
Gepotidacin: 3000 mg administered orally at the study site during the Baseline 
(Day 1) Visit followed by self-administration of a second oral 3000-mg dose as 
an outpatient 10 to 12 hours after the first dose; however, for participants who 
weigh <50 kg or have moderate renal impairment, the second dose should be 
taken approximately 12 hours after the first dose. (Note: Each dose should be 
taken after food consumption and with water to assist with tolerability.) 
− 
Ceftriaxone plus azithromycin: A single IM 500-mg dose of ceftriaxone plus a 
single oral 1-g dose of azithromycin administered at the study site during the 
Baseline (Day 1) Visit. (Note: Azithromycin should be taken after food 
consumption and with water.) 
• 
Appropriate safety and microbiological assessments will be conducted at the 
Baseline (Day 1) Visit and repeated at the TOC (Day 4 to 8) and Follow-up (Day 14 
to 21) Visits. 
• 
“Test-of-Cure” microbiological success will be defined by body site (i.e., urogenital 
and, as appropriate, pharyngeal and/or rectal) as culture-confirmed bacterial 
eradication of NG observed at the TOC (Day 4 to 8) Visit, which is 3 to 7 days 
posttreatment per Food and Drug Administration (FDA) guidance [DHHS, 2015]. 
• 
Participants may return to the study site before the TOC Visit due to AEs. 

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• 
Participants who test positive for a CT and/or Mgen infection per baseline NAAT 
results should be treated per local standard of care at or after the TOC Visit or at the 
Follow-up Visit (if treatment has not already been initiated), as required, after all 
study procedures at the visit have been completed (see Section 7.8). 
• 
Participants will be instructed to return to the study site anytime from Day 14 to 21 
for a Follow-up Visit. The investigator and/or study site staff should make every 
effort to ensure a participant returns for this visit. If it is determined that the 
participant is unable to return to the study site, the Follow-up Visit assessments may 
be completed via telephone, with the exception of assessments requiring sample 
collection for laboratory testing (see Table 1). 
• 
The duration of study participation is approximately 21 days with 3 planned study 
visits (see Section 9 for study visit details): 
− 
Baseline (Day 1) Visit 
− 
TOC (Day 4 to 8) Visit 
− 
Follow-up (Day 14 to 21) Visit 
A study design schematic is depicted in Figure 1. 
Refer to Appendix 11 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 Study Reference 
Manual (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. 

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Figure 1 
Study Design Schematic 
  
a. 
Refer to Inclusion Criterion #2 for details regarding urogenital gonococcal infection eligibility requirements. 
b. 
Stratification will be performed before randomization to ensure that treatment groups are balanced with regard to sex and sexual orientation combination and age. 
c. 
Study treatment will be administered under open-label conditions. All doses of oral study treatment should always be taken after food consumption and with water. 
d. 
Participants randomly assigned to gepotidacin will self-administer their second dose (3000 mg) as an outpatient 10 to 12 hours after the first dose; however, for participants who 
weigh <50 kg or have moderate renal impairment, the second dose should be taken approximately 12 hours after the first dose. 
e. 
Participants will return to the study site anytime from Day 14 to 21 for a Follow-up Visit. The investigator and/or study site staff should make every effort to ensure a participant 
returns for this visit. If it is determined that a participant is unable to return to the study site, the Follow-up Visit assessments may be completed via telephone, with the exception of 
assessments requiring sample collection for laboratory testing. 

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5.2. 
Number of Participants 
Approximately 620 participants will be screened and randomized to achieve 
approximately 400 participants with culture-confirmed urogenital gonorrhea in the 
Microbiological Intent-to-Treat (micro-ITT) Population, for an estimated total of 
200 participants per treatment group in the micro-ITT Population. Enrollment will 
continue until the target number of participants in the micro-ITT Population has been 
reached. 
5.3. 
Participant and Study Completion 
A participant is considered to have completed study treatment if he or she has taken all 
doses of the randomly assigned study treatment and completed the TOC Visit. A 
participant is considered to have completed the study if he or she has completed all study 
visits including the Follow-up Visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4. 
Scientific Rationale for Study Design 
The study design follows the FDA guidance for industry for developing drug treatments 
for uncomplicated gonorrhea [DHHS, 2015] and the European Medicines Agency (EMA) 
guideline on the evaluation of medicinal products indicated for treatment of bacterial 
infections [EMA, 2011]. 
The selected gepotidacin dose in this study (oral 3000-mg dose taken twice, with the 
second dose administered 10 to 12 hours after the first dose) was informed by the safety 
and efficacy results in the Phase II study, where single doses of 1500 and 3000 mg 
gepotidacin were efficacious against NG with gepotidacin MICs <1 µg/mL, including 
isolates resistant to ciprofloxacin (see Section 3.1). A comparison of gepotidacin MICs 
and the corresponding gepotidacin dose against NG demonstrated 100% microbiological 
success rate in both treatment groups for participants with baseline urogenital NG isolates 
with gepotidacin MICs ≤0.5 µg/mL. There were no unexpected safety signals at either 
dose in this study. As further described in Section 5.5, based on PK modeling, 
gepotidacin will be administered as 2 single oral 3000-mg doses, with 10 to 12 hours 
between doses, to provide higher daily systemic exposures that allow coverage of NG 
isolates with higher gepotidacin MIC values, which are likely to be observed in this 
global Phase III study, and reduce the risk of resistance emergence.  
Both adult and adolescent (≥12 to <18 years) eligible participants will be enrolled in this 
open-label (sponsor-blinded) study. 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 ethic committees and local country/national guidelines and enrollment 
will be contingent upon such approvals. Adolescent assent forms and adult consent forms 
will be developed with oversight from local governing institutional review boards 
(IRBs)/independent ethics committees (IECs) (see Appendix 3). Randomization by sex 
and sexual orientation combination (MSM, MSW, or females) and age will be employed 
in this study. The effectiveness of gepotidacin is not expected to be different for the 

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participants in the stratification categories, but the randomization has been planned such 
that the treatment groups are balanced within each category. 
Given the method of study treatment administration (oral gepotidacin versus IM 
ceftriaxone plus oral azithromycin) blinding of the study was not feasible. A 
double-blind, double-dummy design would require all participants randomized to oral 
gepotidacin to receive a placebo IM injection, which is considered unnecessary because 
the primary endpoint is based on objective microbiological laboratory assessments rather 
than subjective clinical assessments. 
Ceftriaxone plus azithromycin was chosen as the comparator based on the recommended 
treatment regimen for uncomplicated gonorrhea by authoritative bodies. At the time of 
study start, both the CDC and WHO recommend a dual antibiotic regimen consisting of a 
single IM 250-mg dose of ceftriaxone and a single oral 1-g dose of azithromycin 
[CDC, 2015; WHO, 2016], while in Europe and Australia the recommended dose of 
ceftriaxone is a single IM 500-mg dose and either a single oral 2-g (Europe) or 1-g 
(Australia) dose of azithromycin [Bignell, 2013; ASHA, 2016]. As of Dec 2020, the CDC 
now recommends an IM injection of ceftriaxone based on body weight (500-mg IM if 
<150 kg and 1-g IM if ≥150 kg) and an oral regimen of doxycycline if chlamydia 
infection has not been ruled out [CDC, 2021]. For this study, a single IM 500mg- dose of 
ceftriaxone with a single oral 1-g dose of azithromycin has been chosen (for dose 
justification see Section 5.5). 
In this study, participants who test positive for CT and/or Mgen infection per baseline 
NAAT results should be treated per local standard of care at or after the TOC Visit or at 
the Follow-up Visit, as required, after all study procedures at the visit have been 
completed. Treatment with alternate antibiotic therapy for these co-infections is needed, 
as gepotidacin and ceftriaxone are not active in vitro against CT, not all participants will 
receive azithromycin study treatment (an effective treatment for CT), and the study 
treatment regimen may be insufficient for treatment of Mgen infection. At study entry, 
any participant suspected or confirmed to have a CT infection will not be allowed to 
enroll in the study if, per the investigator’s judgement, standard-of-care treatment for this 
infection cannot be safely postponed until the TOC Visit.  
Participants meeting eligibility criteria will be treated prior to the availability of culture 
data to confirm infection. Culture-confirmed bacterial eradication of NG will be assessed 
3 to 7 days after the initial treatment per FDA guidelines [DHHS, 2015]. Problems in 
studies of gonococcal infection include lower culture-confirmed pathogen recovery rates 
from NG cultures in certain patient populations and the risk for participants to not return 
for the TOC Visit. In order to maximize the efficiency of this study while minimizing 
discomfort and inconvenience to participants consenting to this protocol, an internal GSK 
SRT will monitor blinded safety data instream, while an internal Microbiology Review 
Team will monitor blinded pathogen identification and susceptibility data instream.  

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5.5. 
Dose Justification 
In the Phase II study, both single oral doses of 1500 and 3000 mg gepotidacin were ≥95% 
efficacious (bacterial eradication) against urogenital NG with no unexpected safety 
signals at either dose. A total of 3 participants failed therapy at the urogenital body site 
(all with a baseline gepotidacin MIC of 1 μg/mL, which was among the highest MIC for 
gepotidacin), and analysis of the posttreatment cultures identified 2 isolates that had 
become resistant to gepotidacin (TOC gepotidacin MICs ≥32 μg/mL). Further analysis 
revealed that both isolates also had a pre-existing D86N polymorphism in the 
topoisomerase IV gene at Baseline. Following treatment, both isolates showed a second 
mutation, an A92T substitution in the DNA gyrase enzyme, which resulted in reduced 
susceptibility to gepotidacin. Of the 8 participants in the study with D86N-positive 
baseline urogenital NG isolates, 5 were microbiological successes (bacterial eradication), 
including 2 that were infected with baseline organisms with the higher gepotidacin MIC 
of 1 μg/mL. These data suggest that the 3000-mg single dose may provide close to an 
effective exposure and that this genotype may be overcome with appropriate dosing. 
In the current study, gepotidacin will be administered as 2 oral 3000-mg doses. The two 
3000-mg doses, administered 10 to 12 hours apart, compared with the single 3000-mg 
dose used in the Phase II study, is expected to provide 2-fold higher systemic exposures 
that allow coverage of NG isolates with higher gepotidacin MIC values, which are likely 
to be observed in this global Phase III study, and also to reduce the risk of resistance 
emergence. 
Previous studies with antibacterials have shown that attaining a target exposure that 
correlates with bacterial reduction endpoints in preclinical models is predictive of good 
clinical outcome in participants with bacterial infections [Ambrose, 2007]. However, due 
to lack of validated preclinical models for NG, the PK/pharmacodynamic (PD) parameter 
and magnitude predictive of gepotidacin efficacy has not been established in preclinical 
models for this infection or pathogen. In the Phase II study, the bacterial cure rate was 
100% when the free drug area under the concentration-time curve/MIC (fAUC/MIC) was 
approximately 48 or higher and the free mean time above the MIC (fT>MIC) was ≥42% 
(10 hours) for NG isolates with gepotidacin MICs up to 0.5 µg/mL. Based on PK 
modeling, including PK data in adults and adolescents (Study 209611), the dosing 
strategy of 2 gepotidacin 3000-mg doses (administered 10 to 12 hours apart) is expected 
to limit the occurrence of maximum plasma exposures ≥14 μg/mL, which is necessary 
from a safety perspective due to corrected QT interval (QTc) increases and 
acetylcholinesterase inhibition. This dosing strategy also supports an fAUC/MIC of 
40 with an fT>MIC of 58% to 63% (14 to 15 hours), which will maximize the probability 
for efficacy against NG isolates with gepotidacin MICs up to 1 μg/mL. A set of duplicate 
10-day hollow fiber infection model studies was also completed using a NG isolate with a 
gepotidacin MIC of 1 μg/mL and a D86N mutation in ParC to determine if the exposure 
achieved by 2 gepotidacin 3000-mg doses (administered 8 or 12 hours apart) prevented 
amplification of a resistant subpopulation when a pre-existing single step mutation was 
already present. An inverted-U shaped function described the relationship between drug 
resistance amplification and gepotidacin dose with total daily gepotidacin doses 
≥4500 mg (including the 2 gepotidacin 3000-mg doses [administered either 8 or 12 hours 
apart]) preventing resistance amplification to gepotidacin for NG in the hollow fiber 

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infection model. Therefore, 2 gepotidacin 3000-mg doses (administered 8 or 12 hours 
apart) are expected to prevent amplification of resistance against NG isolates with 
gepotidacin MICs up to 1 μg/mL. However, it should be noted, any emergence of 
resistance to gepotidacin is not expected to limit or affect standard-of-care treatment for 
gonorrhea or a participant’s future treatment options in this study. 
At the start of this study, both the CDC and WHO recommend a dual antibiotic regimen 
that includes a single 250-mg IM ceftriaxone dose plus a single 1-g oral dose of 
azithromycin for the treatment of uncomplicated gonococcal infections [CDC, 2015; 
WHO, 2016]. The CDC now recommends an IM injection of ceftriaxone based on body 
weight and an oral regimen of doxycycline only if chlamydia infection has not been ruled 
out [CDC, 2021]. The selected ceftriaxone dose in this study is 500 mg IM. This higher 
ceftriaxone dose was selected because this dose allows for higher systemic exposures, 
which are predicted to offer additional coverage of NG isolates with higher ceftriaxone 
MIC values, should the prevalence of such isolates increase and be observed in this 
global Phase III study. A single 500-mg IM dose of ceftriaxone is within the prescribing 
limits, which states the total daily dose for ceftriaxone should not exceed 4000 mg, and is 
consistent with treatment guidance for Europe and from the Australian regulatory 
authority [Bignell, 2013; ASHA, 2016]. The selected azithromycin dose in this study is 
1 gm administered orally. The azithromycin dose is in alignment with the CDC, WHO, 
and Australian uncomplicated gonorrhea treatment recommendations [CDC, 2015; 
WHO, 2016; ASHA, 2016]. Lastly, with approximately 99% efficacy [CDC, 2021], the 
dual-therapy comparator arm of 500 mg ceftriaxone plus a single 1 g dose of 
azithromycin is expected to be at least as efficacious as 500 mg ceftriaxone monotherapy. 

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6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age and Weight 
1. The participant is ≥12 years at the time of signing the informed consent/assent and 
has a body weight >45 kg.  
Note: Although participants as young as 12 years may enroll in the study, study sites 
must follow their institutional ethics committee and local country/national regulatory 
guidelines and enrollment will be contingent upon such approvals regarding the 
allowed lower age limit for clinical study participants. 
Type of Participant and Disease Characteristics 
2. The participant has clinical suspicion of a urogenital gonococcal infection (which 
can include sexual contact within the past 14 days with a partner who has a 
confirmed gonococcal infection) with or without pharyngeal and/or rectal 
gonococcal infection and has 1 of the following:  
− 
male participants with purulent yellow, green, or white urethral discharge or 
female participants with abnormal cervical or vaginal mucopurulent discharge 
upon physical examination 
OR 
− 
a prior positive culture for NG from up to 5 days before Screening (as long as 
the participant has not received any treatment for this infection), or 
− 
a Gram or equivalent stain (urogenital specimens only) positive or presumptive 
for intracellular diplococci from up to 5 days before Screening (as long as the 
participant has not received any treatment for this infection), or  
− 
a prior positive NAAT assay for NG from up to 7 days before Screening (as long 
as the participant has not received any treatment for this infection). 
Note:  A urogenital specimen will be taken from all participants (males and females) 
for NG culture at the Baseline Visit; however, these results will not be used to 
determine participant eligibility for enrollment in the study. The culture results will 
be used to identify the primary analysis population. 
3. The participant must be willing to abstain from anal, oral, and vaginal sexual 
intercourse or use condoms for all forms of intercourse from the Baseline Visit 
through the TOC Visit. 

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Sex 
4. Male or female and must have his or her original urogenital anatomy at birth 
a. Male participants: 
A male participant must agree to use contraception as detailed in Appendix 6 of this 
protocol from the Baseline Visit through completion of the TOC Visit. 
b. Female participants:  
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 text at Baseline (Day 1) regardless of current or prior contraception 
use or abstinence, is not breastfeeding, or is not a WOCBP. Note:  Pregnancy 
testing requirements, contraceptive guidance, and WOCBP definitions are provided 
in Appendix 6. 
Informed Consent 
5. The participant is capable of giving signed informed consent/assent as described in 
Appendix 3, which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF)/assent form and in this protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions and History 
1. The participant is a male with a current diagnosis of epididymitis and/or orchitis at 
the time of the Baseline Visit. 
2. The participant is suspected or confirmed to have a CT infection and per the 
investigator’s judgement standard-of-care treatment for this infection cannot be 
safely postponed until the TOC Visit. 
3. The participant has a body mass index ≥40 kg/m2 or has a body mass index 
≥35.0 kg/m2 and is experiencing obesity-related health conditions such as 
uncontrolled high blood pressure or uncontrolled diabetes. 
4. The participant has a history of sensitivity to the study treatments, or components 
thereof, or a history of a drug (including erythromycin and any macrolide or ketolide 
drug) or other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates his or her participation. 
5. 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., participants with 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 

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≥10 mg/day for >6 weeks]). Participants with a known CD4 count of <200 cells/mm3 
should not be enrolled. 
Note: Participants taking pre-exposure prophylactics for human immunodeficiency 
virus (HIV) are allowed to enroll. HIV-infected participants are allowed to enroll, as 
long as their CD4 count is ≥200 cells/mm3. Use of strong cytochrome P450 enzyme 
3A4 (CYP3A4) inhibitors during the study is prohibited (see Exclusion 
Criterion 15). 
6. The participant has any of the following: 
− 
Medical condition that requires medication that may be impacted by inhibition 
of acetylcholinesterase, such as: 
− Poorly controlled asthma or chronic obstructive pulmonary disease at the 
Baseline Visit and, in the opinion of the investigator, not stable on current 
therapy 
− 
Acute severe pain, uncontrolled with conventional medical management 
− 
Active peptic ulcer disease 
− 
Parkinson disease 
− 
Myasthenia gravis 
− A history of seizure disorder requiring medications for control (this does not 
include a history of childhood febrile seizures) 
OR  
− Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study treatment 
(e.g., ileostomy or malabsorption syndrome). 
7. The participant has known anuria, oliguria, or severe impairment of renal function 
(creatinine clearance <30 mL/min or clinically significant elevated serum creatinine 
as determined by the investigator). 
8. The participant, in the judgment of the investigator, would not be able or willing to 
comply with the protocol or complete study follow-up. 
9. 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. 
Cardiac Exclusions 
10. The participant has congenital long QT syndrome or known prolongation of QTc. 
11. The participant has uncompensated heart failure. 
12. The participant has severe left ventricular hypertrophy. 
13. The participant has a family history of QT prolongation or sudden death. 
14. The participant has a recent history of vasovagal syncope or episodes of 
symptomatic bradycardia or bradyarrhythmia within the last 12 months. 

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15. 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 his or her Baseline Visit, which cannot be safely discontinued 
from the Baseline Visit to the TOC Visit; or the participant is taking a strong 
CYP3A4 inhibitor.  
Cardiac ECG Exclusions 
16. For any participant ≥12 to <18 years, the participant has an abnormal ECG reading. 
17. 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. 
18. The participant has a documented or recent history of uncorrected hypokalemia 
within the past 3 months.  
Hepatic Exclusions 
19. The participant has a known history of cholestatic jaundice or hepatic dysfunction 
associated with prior use of azithromycin. 
20. The participant has a known alanine aminotransferase (ALT) value >2 × upper limit 
of normal (ULN). 
21. The participant has a known bilirubin value >1.5 × ULN (isolated bilirubin >1.5 × 
ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
22. The participant has a current or chronic history of liver disease, or known hepatic or 
biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones), including symptomatic viral hepatitis or moderate-to-severe liver 
insufficiency (Child Pugh class B or C).  
Note:  Participants with asymptomatic viral hepatitis are eligible for study 
participation. 
Prior/Concurrent Clinical Study Experience Exclusions 
23. The participant has been previously randomized in this study or has previously been 
treated with gepotidacin. 
24. The participant has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer. 

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Gonococcal Infection Exclusions 
25. The participant has any of the following gonococcal infections that require a 
different dose or duration of treatment: 
− 
Suspected or confirmed pelvic inflammatory disease 
− 
Suspected or confirmed gonococcal arthritis 
− 
Suspected or confirmed gonococcal conjunctivitis 
− 
Suspected or confirmed gonococcal endocarditis 
− 
Other evidence of disseminated gonococcal infection 
Prior Antibiotic/Antifungal Use and Concomitant Medication Exclusions 
26. The participant has received any antibacterial therapy for the treatment of a 
gonococcal infection within 14 days before the Baseline Visit. 
27. The participant has received any systemic, topical, or intravaginal antibiotics or any 
systemic antifungals within 7 days before the Baseline Visit. 
28. The participant must not use St John’s wort or ergot derivatives from within 14 days 
before the Baseline Visit through the TOC Visit. 
6.3. 
Lifestyle Restrictions 
Participants will be instructed to abstain from sexual activity from the Baseline Visit 
through the TOC Visit to prevent possible re-infection with NG. If a participant refuses to 
abstain and is sexually active, male participants as well as male partners of female 
participants, of both childbearing and nonchildbearing potential, must use a male condom 
during intercourse from the Baseline Visit through completion of the TOC Visit. Details 
for contraception requirements are included in Appendix 6. 
6.3.1. 
Meals and Dietary Restrictions 
Gepotidacin and azithromycin should be taken with food (a meal or snack) (see 
Section 7.1). 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. Participants who are screen failures are not allowed 
to be rescreened for the same infection episode; however, participants who were screen 
failures for an earlier infection episode may be newly screened for a second infection 
episode ≥4 weeks later and participate in the study if they meet all of the inclusion and 
exclusion criteria. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 

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7. 
TREATMENTS 
All doses of oral study treatment should always be taken after food consumption and with 
water. Study treatment is defined as any investigational treatments or marketed products 
intended to be administered to a study participant according to the study protocol. 
7.1. 
Treatments Administered 
Study Treatment 
Name: 
Gepotidacin 
Ceftriaxone 
Azithromycina 
Dosage 
Formulation: 
Tablets containing 
gepotidacin and inactive 
formulation excipients 
Sterile powder for 
reconstitution with 
appropriate diluent 
Tabletsa 
Unit Dose 
Strengths/ 
Dosage Levels: 
4 × 750-mg tablets 
500-mg equivalent 
2 × 500-mg tabletsa 
Route of 
Administration: 
Oral 
IM 
Oral 
Dosing 
Instructions: 
Administer first oral dose 
at the study site. 
Participant 
self-administers the 
second dose as an 
outpatient 10 to 12 hours 
after the first dose; 
however, for participants 
who weigh <50 kg or 
have moderate renal 
impairment, the second 
dose should be taken 
approximately 12 hours 
after the first dose 
Dose 1: 3000 mg – 
4 tablets 
Dose 2: 3000 mg – 
4 tablets 
Each dose should be 
taken after food 
consumption and with 
water. 
Administer one 500-mg 
IM dose at the study site 
(volume administered will 
be dependent on the 
amount of diluentb added 
and resulting 
concentration; see Study 
Reference Manual). 
Administer one 1-gm 
oral dose at the study 
site. 
Dose should be taken 
after food consumption 
and with water. 

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Study Treatment 
Name: 
Gepotidacin 
Ceftriaxone 
Azithromycina 
Packaging and 
Labeling: 
Gepotidacin tablets will 
be provided in bottles. 
Each bottle will be 
labeled as required per 
country requirement. 
Ceftriaxone will be 
provided by PPD and 
labeled as required per 
country requirement. 
Azithromycin tabletsa 
will be provided by PPD 
and labeled as required 
per country 
requirement. 
Manufacturer: 
May be sourced locally 
or centrally within 
individual countries but 
will be supplied by PPD 
and labeled as per the 
regulatory requirements 
in all participating 
countries. 
May be sourced locally 
or centrally within 
individual countries but 
will be supplied by PPD 
and labeled as per the 
regulatory requirements 
in all participating 
countries. 
IM=intramuscular. 
a. 
The total oral dose of azithromycin must be 1 gm. Based on locally or centrally sourced available supplies 
and tablet/capsule strengths, the number of tablet/capsules may be adjusted to reach the 1-gm dose of 
azithromycin. 
b. Study sites will be responsible for procurement of diluent and injection supplies. 
The labeling, distribution, procurement, and/or drug returns for comparator investigative 
products were supported by Almac US, Almac UK, PPD Athlone (Germany and Spain), 
Flinders (Australia), World Courier Mexico, Clinigen (Australia, EMEA, and US), 
Bionical LTDA (UK), and Oncomedic (Mexico). 
7.2. 
Dose Modification 
The study design does not allow for dose modifications.  
7.3. 
Method of Treatment Assignment 
Participants will be stratified by sex and sexual orientation combination (MSM, MSW, or 
females) and age (<18 years, ≥18 to 65 years, or >65 years) to ensure that treatment 
groups are balanced within each category. The MSM category will include MSM and 
bisexual males (i.e., male participants who have sex with both males and females). 
Within each stratum, participants will be centrally randomized in a 1:1 ratio to either 
gepotidacin or ceftriaxone plus azithromycin using an interactive response technology 
(IRT) in accordance with the randomization schedule generated by or under the direction 
of GSK’s Clinical Statistics. Before the study is initiated, information and directions for 
the IRT will be provided to each study site.  
Each participant scheduled to receive study treatment will receive a randomization 
number at the time of randomization. This randomization number will be used to identify 
the participant and indicate the treatment to be administered to that participant. 
For those participants randomly assigned to gepotidacin, the first dose will be 
administered at the study site during the Baseline Visit and the second dose will be 
dispensed to participants during this visit for self-administration 10 to 12 hours after the 
CCI

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first dose (see Section 7.1). Participants randomly assigned to ceftriaxone plus 
azithromycin will be administered a single IM dose of ceftriaxone plus a single oral dose 
of azithromycin during the Baseline Visit. 
Returned gepotidacin should not be re-dispensed to other participants. 
7.4. 
Blinding 
This is an open-label (sponsor-blinded) randomized study. The specific treatment to be 
taken by a participant will be assigned using an IRT using central randomization. The 
study site will contact the IRT prior to the start of study treatment administration for each 
participant. The study site will record the treatment assignment on the applicable 
electronic case report form (eCRF), if required. Potential bias will be reduced by the use 
of central randomization. 
The GSK SRT, which will monitor safety data instream, will remain blinded to 
participant treatment assignment throughout the study (see Appendix 3). A Microbiology 
Review Team will monitor blinded pathogen identification and susceptibility data 
instream as well as the number of participants eligible for the micro-ITT Population. 
Blinded monitoring of pathogens will be conducted, to determine whether end-of-study 
targets are likely to be achieved. Provision will be made for a limited degree of 
unblinding of a minority of participant sample data should this be viewed as appropriate 
for planning closure of trial enrollment. Procedures will be described in a separate 
microbiology sample monitoring plan, and no impact on trial integrity is expected. 
7.5. 
Preparation/Handling/Storage/Accountability 
No special preparation of gepotidacin or azithromycin is required. 
A pharmacist or other qualified professional will prepare the ceftriaxone solution using a 
fixed volume of an appropriate diluent to reconstitute the ceftriaxone powder. Full details 
of the methods and materials required for ceftriaxone solution preparation are provided in 
the SRM. 
The following considerations must be made with regard to study treatment preparation, 
handling, storage, and accountability in this study: 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment and only 
authorized study site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized study site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 

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4. Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to the study site staff. For ceftriaxone solution, take 
adequate precautions to avoid direct eye or skin contact and the generation of aerosols or 
mists. In the case of unintentional occupational exposure, notify the monitor, medical 
monitor, and/or GSK study contact. 
A Material Safety Data Sheet or equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, where 
this is required by local laws, or is available upon request from GSK. 
7.6. 
Treatment Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 
• 
Participants dosed at the study site will receive study treatment (oral dose of 
gepotidacin or single IM dose of ceftriaxone plus an oral dose of azithromycin) 
directly from 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 and reported in the eCRF. The dose of study treatment and study 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment. 
• 
Participants will self-administer the second oral dose of gepotidacin as an outpatient 
(see Section 7.1). Compliance with gepotidacin will be assessed by contacting the 
participant via telephone, email, or text message. The participants should confirm 
that the second dose was taken. Study site staff will also query the participant during 
the TOC Visit and document whether the second dose was taken. A record of the 
number of gepotidacin tablets dispensed to each participant must be recorded and 
reconciled with study treatment and compliance records. The date and time of each 
dose will also be recorded in the eCRF. 
7.7. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving within 30 days prior 
to the Baseline Visit or receives during the study must be recorded in the eCRF. In 
addition, any antibiotic use within 6 months prior to the Baseline Visit or during the study 
must be recorded in the eCRF. The concomitant therapy name must be recorded in the 
eCRF along with the following: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 

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7.7.1. 
Permitted Medications and Nondrug Therapies 
Participants testing positive for CT and/or Mgen per NAAT results at the Baseline Visit 
will be permitted to receive local standard of care at or after the TOC Visit or at the 
Follow-up Visit (if treatment has not already been initiated), as required, after all study 
procedures at the visit have been completed. Note: If at Baseline a participant is 
suspected or confirmed to have a CT infection and per the investigator’s judgement 
standard-of-care treatment for this infection cannot be safely postponed until the TOC 
Visit, the participant should not be enrolled in the study (see Section 6.2).  
The use of H1 antihistaminics not associated with QT prolongation is allowed (e.g., 
loratadine, cetirizine, ebastine, and fexofenadine). Use of pre-exposure prophylaxis for 
HIV is allowed. The use of nonsystemic antifungals (e.g., topical, intravaginal) is allowed 
throughout the study. Please also refer to Appendix 9. 
A list of permitted medications commonly used for nausea, vomiting, pain, and diarrhea 
per investigator discretion is provided in Appendix 9. 
A further detailed list of medications will be provided in the SRM. 
7.7.2. 
Prohibited Medications and Nondrug Therapies 
At the time of enrollment and/or during the study, 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 
Baseline Visit. 
• 
Any antibacterial therapy for the treatment of a gonococcal infection within 14 days 
before the Baseline Visit. 
• 
Any systemic, topical, or intravaginal antibiotics or any systemic antifungals within 
7 days before the Baseline Visit. 
• 
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). 
• 
With the exception of azithromycin study treatment, QT-prolonging drugs or drugs 
with known TdP risk, per the www.crediblemeds.org “Known Risk of TdP” 
category, at the time of their Baseline Visit, which cannot be safely discontinued 
from the Baseline Visit to the TOC Visit. Details regarding website access are 
provided in the SRM; additional guidance is provided in Appendix 9. Of note, 
ondansetron is not allowed from the Baseline Visit to the TOC Visit due to its known 
TdP risk. Alternative antiemetics that are permitted per investigator discretion are 
listed in Appendix 9. 
Note: Crediblemeds.org categorizes drugs into 4 categories. The only category for 
exclusion in this study is the “Known Risk of TdP” category; participants taking 
drugs that meet criteria of other categories are NOT excluded from participation. 

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• 
St John’s wort or other strong CYP3A4 inhibitors within 14 days before the Baseline 
Visit through the TOC Visit (a list of strong CYP3A4 inhibitors is provided in the 
SRM). 
• 
Ergot derivatives from within 14 days before the Baseline Visit through the TOC 
Visit. 
Due to the gepotidacin’s property of acetylcholinesterase inhibition, the concomitant use 
of succinylcholine or other nondepolarizing paralytic agents is also prohibited. Caution 
should be used in participants who have a condition requiring medication that may 
exacerbate the inhibition of acetylcholinesterase, or neuromuscular blocking agents. 
7.8. 
Treatment After the End of the Study 
Participants testing positive for CT and/or Mgen per NAAT results at the Baseline Visit 
should be treated per local standard of care at or after the TOC or at Follow-up Visit (if 
treatment has not already been initiated), as required, after all study procedures at the 
visit have been completed. Treatment with alternate antibiotic therapy for these 
co-infections is needed, as gepotidacin and ceftriaxone are not active in vitro against CT, 
not all participants will receive azithromycin study treatment (an effective treatment for 
CT), and the study treatment regimen may be insufficient for treatment of Mgen 
infection. Note: If at Baseline a participant is suspected or confirmed to have a CT 
infection and per the investigator’s judgement standard-of-care treatment for this 
infection cannot be safely postponed until the TOC Visit, the participant should not be 
enrolled in the study (see Section 6.2).  
Participants with culture-confirmed bacterial persistence of urogenital and, as 
appropriate, pharyngeal and/or rectal NG at the TOC Visit should receive appropriate 
alternative therapy per the investigator’s choice. 
Participants will not receive any additional treatment for urogenital, pharyngeal, and/or 
rectal NG from GSK after they discontinue or complete the study (i.e., after the 
Follow-up Visit). However, the investigator is responsible for ensuring that consideration 
has been given to the poststudy care of the participant’s medical condition, whether or 
not GSK is providing specific poststudy treatment. 

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8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Participants may voluntarily discontinue study treatment at any time. The investigator 
may also, at his or her discretion, discontinue the participant from study treatment at any 
time and initiate appropriate alternative therapy. 
Reasons for study treatment discontinuation may include the following: 
• 
Adverse event 
• 
Protocol deviation 
• 
Termination of the study by GSK 
• 
Investigator discretion 
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 return to the study site to complete the TOC and Follow-up 
Visits (see Table 1). 
8.1.1. 
Liver Chemistry Evaluation Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
The stopping criteria for discontinuing dosing of study treatment due to liver chemistry 
parameters have limited application in this study, as study treatment is administered as 
2 oral doses of gepotidacin over a 24-hour period starting on Day 1 or as a single dose IM 
dose of ceftriaxone plus an oral dose of azithromycin on Day 1. However, if participants 
are found to have values consistent with the usual stopping parameters, it is appropriate 
to institute evaluation and monitoring criteria according to standard GSK criteria. 
Therefore, liver function tests should be evaluated according to stopping criteria and 
laboratory evaluation instituted if defined parameters are reached.  
Phase III liver chemistry evaluation criteria are presented in Table 4. 

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Table 4 
Liver Chemistry Evaluation Criteria 
Liver Chemistry Evaluation Criteria – Liver Event 
ALT Absolute 
ALT ≥8 × ULN 
ALT Increase 
ALT ≥5 x ULN but <8 x ULN persists for ≥2 weeks 
ALT ≥3 x ULN but <5 x ULN persists for ≥4 weeks 
Bilirubin 
ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) 
INR 
ALT ≥3 × ULN and INR >1.5, if INR measured 
Cannot Monitor 
ALT ≥5 x ULN but <8 x ULN and cannot be monitored weekly for ≥2 
weeks 
ALT ≥3 x ULN but <5 x ULN and cannot be monitored weekly for ≥4 
weeks 
Symptomatic 
ALT ≥3 × ULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity 
ALT=alanine aminotransferase; INR=international normalized ratio; ULN=upper limit of normal. 
Liver safety required actions and follow-up assessments section can be found in 
Appendix 8. 
8.1.2. 
QTc Stopping Criteria 
• 
This protocol only requires an ECG evaluation at the Baseline Visit. Should further 
ECG monitoring or evaluation be needed for an individual participant, per 
investigator discretion, the following should be considered: 
• 
Further monitoring and/or evaluation should be considered in any participant who 
meets either of the bulleted criteria below: 
− 
QTc >500 msec OR uncorrected QT >600 msec 
− 
Change from baseline of QTc >60 msec 
For participants with underlying bundle-branch block, follow the evaluation criteria listed 
below: 
Baseline QTc With Bundle-Branch Block 
Criteria for Further Evaluation and 
Monitoring of QTc With Bundle-Branch 
Block 
<450 msec 
>500 msec 
450 to 480 msec 
≥530 msec 

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• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for the study and whether further evaluation and/or monitoring 
are necessary. This formula may not be changed or substituted once the participant 
has been enrolled. (Note: Ideally, all ECGs for a participant should be performed 
with the same ECG machine.) 
− For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well. 
− Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other nonprotocol-specified 
ECGs are an exception. 
• 
The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5- to 10-minute) recording period. 
8.1.3. 
Gastrointestinal Evaluation Criteria 
If a participant meets the clinical criteria outlined in Appendix 10, Clostridium difficile 
toxin detection should be conducted and the specific eCRF page completed. C. difficile 
infection or colitis is considered an AE of special interest (Section 9.2.5). 
8.2. 
Withdrawal From the Study 
• 
A participant may withdraw from the study at any time at his or her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. 
• 
Reasons for study withdrawal include: 
− 
Participant lost to follow-up 
− 
Participant withdrew consent 
− 
Termination of the study by GSK 
− 
Investigator discretion 
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, he or she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• 
Participants who withdraw from the study should be encouraged to return for the 
TOC and/or Follow-up Visits. Refer to Table 1 for data to be collected at these visits. 
• 
The reason for participant withdrawal will be recorded in the eCRF. Participants who 
were randomly assigned to gepotidacin should return all unused study treatment. 

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8.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the study site for a 
required study visit: 
• 
The study site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in Table 1. 
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment (only applicable to participants randomly assigned to 
gepotidacin). 
• 
Adherence to the study design requirements, including those specified in Table 1, is 
essential and required for study conduct. 
• 
All baseline screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility 
or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in Table 1. 
• 
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 
150 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 

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The study will comprise the following 3 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 Table 1, including the following: 
− 
If applicable, the Baseline 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. 
− 
Demographic data such as year of birth, sex, sexual orientation, race, and 
ethnicity will be recorded in the participant’s eCRF. The collection of sex, 
sexual orientation, race, and ethnicity data is necessary to assess and monitor the 
diversity of the trial participants, and to determine if the trial participants are 
truly representative of the impacted population. The year of birth is collected to 
stratify the population. 
− 
The participant’s medical/surgical history will be obtained by interviewing the 
participant and/or the participant's legally authorized representative and/or 
review of the participant’s medical records. Any pre-existing conditions, signs 
and/or symptoms present prior to the first dose of study treatment will be 
recorded in the eCRF. 
− 
Pretreatment baseline specimens for microbiological testing will be collected as 
described in Section 9.1 and Table 2. 
− 
Following completion of all pretreatment assessments, eligible participants will 
be randomly assigned to treatment as described in Section 7.3. 
− 
The first oral gepotidacin dose (3000 mg) or the IM ceftriaxone dose (500 mg) 
plus the oral azithromycin dose (1 g) will be administered at the study site. Oral 
study treatment (gepotidacin and azithromycin) should be taken after food 
consumption and with water to assist with tolerability. After dose 
administration, Day 1 posttreatment assessments will be performed, as shown in 
Table 1. Any AEs or clinically significant changes should be followed 
accordingly. 
− 
Participants randomly assigned to gepotidacin will self-administer the second 
3000-mg oral dose as an outpatient 10 to 12 hours after the first dose; however, 
for participants who weigh <50 kg or have moderate renal impairment, the 
second dose should be taken approximately 12 hours after the first dose. 
Gepotidacin study treatment should be taken after food consumption and with 
water to assist with tolerability. Note: The second dose may occur on Day 1 or 
Day 2, depending on the time at which the first dose was taken. Participants 
randomly assigned to gepotidacin will be contacted to confirm that they took 
their second gepotidacin dose (see Section 7.6). 

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− 
The TOC and Follow-up Visits should be scheduled before the participant 
leaves the study site on Day 1 (as indicated in Table 1); the planned return 
day/time should be at the convenience of the participant and also the availability 
of the study site staff. 
• 
TOC (Day 4 to 8) Visit: Participants will be instructed to return to the study site 3 to 
7 days following study treatment administration at Baseline in order to complete the 
TOC Visit. Assessments will be performed as shown in Table 1, 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 9.1 and Table 2. 
− 
Participants may return to the study site before the scheduled TOC Visit due to 
AEs.  
− 
Participants testing positive for a CT and/or Mgen infection per baseline NAAT 
results should be treated, as required, per local standard of care at the TOC Visit 
only after completion of all visit procedures or at any point after the TOC Visit. 
− 
Participants with culture-confirmed bacterial persistence of urogenital and, as 
appropriate, pharyngeal and/or rectal NG should receive appropriate alternative 
therapy per the investigator’s choice either on or after the TOC Visit, based on 
availability of results. 
• 
Follow-up (Day 14 to 21) Visit: Participants will be instructed to return to the study 
site 14 to 21 days following study treatment administration at Baseline in order to 
complete the Follow-up Visit. Assessments will be performed as shown in Table 1, 
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. 
− 
The investigator and/or study site staff should make every effort to ensure a 
participant returns for this visit. If it is determined that the participant is unable 
to return to the study site, the Follow-up Visit assessments may be completed 
via telephone, with the exception of assessments requiring sample collection for 
laboratory testing. 
− 
Specimens for microbiological testing will be collected as described in 
Section 9.1 and Table 2. 
− 
Participants may return to the study site before the scheduled Follow-up Visit 
due to AEs or if they feel they are not responding to any alternative therapy 
started after the TOC Visit. 

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− 
Participants testing positive for a CT and/or Mgen infection per baseline NAAT 
results should be treated, as required, per local standard of care (if treatment has 
not already been initiated) only after completion of all Follow-up Visit 
procedures. 
9.1. 
Efficacy Assessments 
Microbiological efficacy laboratory assessments were performed at PPD Global Clinical 
Laboratory and JMI Laboratories. Addresses for the central laboratories, as well as all 
local laboratories, are provided in the List of Clinical Laboratories Used for Human 
Biological Sample Analysis, which will be stored in the trial master file. 
9.1.1. 
Bacteriology Samples for Culture 
Multiple swab specimens and types may need to be obtained from each anatomical site; 
refer to the laboratory manual. See Table 2 for collection of bacteriology samples. 
At the Baseline Visit, a pretreatment urogenital swab specimen must be obtained from all 
participants for Gram stain (male and females) and bacteriological culture for NG. 
Pretreatment pharyngeal and rectal swab specimens will also be obtained from 
participants who are willing to provide such specimens, regardless of known exposure, 
for bacteriological culture for NG.  
At the TOC Visit, specimens will be obtained for Gram stain (urogenital specimens only) 
and bacteriological culture for NG only from all body sites collected at Baseline.  
At the Follow-up Visit, only pharyngeal swab specimens will be obtained for 
bacteriological culture for NG from participants who had a positive NAAT assay for 
pharyngeal NG at both Baseline and TOC. 
Gram stain and bacteriological cultures will be performed at a designated laboratory(ies). 
Confirmation of identification and susceptibility testing by agar dilution will be 
conducted at a designated laboratory(ies) for all isolates of NG recovered at all visits 
from all body sites. Instructions for sample collection, processing, and shipment are 
provided in the SRM and the laboratory manual. Laboratories should follow the 
Microbiology Procedures section of the laboratory manual to minimize potential 
contamination of the specimens or isolates. 
Only those participants who have NG confirmed by a designated laboratory(ies) from 
their baseline bacteriology specimen will be evaluated for microbiological outcome and 
response. The microbiological outcome and response to the study treatment will be 
determined programatically at GSK before breaking of the study blind. (Note: The 
sponsor is blinded to participant treatment assignment; see Section 7.4.) 
The microbiological outcome is determined by comparing the baseline culture results to 
the respective culture results at each subsequent visit. The corresponding microbiological 
response (success or failure) “by participant” will then be assigned, as shown in Table 5. 

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Table 5 
Determining Microbiological Outcome and Response at the TOC 
Visit 
Defining Criteria 
Microbiological 
Outcome 
Microbiological 
Response 
Culture-confirmed elimination of baseline NG 
pathogen from a bacteriology sample taken at 
the TOC Visit, without the participant 
receiving other systemic antimicrobials before 
this visit 
Bacterial eradication 
Microbiological 
success 
Culture-confirmed persistence of baseline NG 
pathogen from a bacteriology sample taken at 
the TOC Visit, without the participant 
receiving other systemic antimicrobials before 
this visit 
Bacterial persistence 
Microbiological failure 
1) A determination of the TOC NG pathogen 
microbiological outcome cannot be made 
(e.g., no bacteriology sample taken for 
culture, sample lost, visit did not occur) 
2) The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to determine 
Microbiological failure 
NG=Neisseria gonorrhoeae; TOC=Test-of-Cure. 
Note: A bacteriological specimen refers to either a urogenital, pharyngeal, or rectal sample obtained for 
bacteriological culture. Microbiological outcomes are determined on a per-pathogen and per-specimen source 
basis. 
9.1.2. 
NAAT Assay 
Refer to the laboratory manual for local versus central laboratory details and the number 
and type of specimens to collect for NAAT assay. See Table 2 for collection of NAAT 
assay samples. 
Pretreatment urogenital specimens will be obtained from all participants for NAAT assay 
to detect the presence of NG, Mgen, and CT nucleic acids at the Baseline Visit. 
Urogenital specimens will also be obtained from all participants for NAAT assay to 
detect the presence of NG and CT nucleic acids at the TOC Visit. At the Follow-up Visit, 
a urogenital specimen for NAAT assay will be collected for detection of Mgen only from 
participants who had a positive NAAT assay for Mgen at Baseline. 
In addition, pretreatment baseline pharyngeal and rectal specimens for NAAT assay for 
detection of NG and CT will be obtained from participants who are willing to provide 
such specimens, regardless of known exposure. Specimens will also be collected for 
NAAT assay for detection of NG and CT at the TOC Visit from all body sites collected at 
the Baseline Visit. At the Follow-up Visit, a pharyngeal specimen for NAAT assay will 
be collected for detection of NG and CT from participants whose NAAT assay had the 
presence of nucleic acid for NG at both Baseline and TOC.  

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The NAAT assay will be performed at a designated laboratory(ies). Participants testing 
positive for CT or Mgen nucleic acid by NAAT assay at the Baseline Visit should be 
treated per local standard of care at or after the TOC Visit or at the Follow-up Visit (if 
treatment has not already been initiated), as required, after all study procedures for the 
visit have been completed.  
Only those participants who have NG or Mgen nucleic acid detected from their baseline 
NAAT specimen will be evaluated for NAAT outcome and response. The NAAT 
outcome and response to study treatment will be determined by an algorithm at GSK 
before breaking of the study blind (Note: Sponsor is blinded to participant treatment 
assignment; see Section 7.4). 
For the exploratory objectives, the NAAT outcome is determined by comparing the 
baseline NAAT result with the respective NAAT result at each subsequent visit. The 
corresponding NAAT response (success or failure) “by participant” will then be assigned, 
as shown in Table 6 and Table 7. 
Table 6 
Determining NAAT Outcome and Response at the Test-of-Cure Visit 
(NG Only) 
Defining Criteria 
NAAT Outcome 
NAAT Response  
Clearance of baseline pathogen nucleic acid 
from a specimen taken at the TOC Visit, without 
the participant receiving other systemic 
antimicrobials before this visit 
Nucleic acid 
clearance 
NAAT success 
Persistence of baseline pathogen nucleic acid 
from a specimen taken at the TOC Visit, without 
the participant receiving other systemic 
antimicrobials before this visit 
Nucleic acid 
persistence 
NAAT failurea 
1) A determination of the nucleic acid 
outcome from a specimen taken at the 
TOC Visit cannot be made (e.g., no 
sample taken, sample lost, visit did not 
occur) 
2) The participant received other systemic 
antimicrobials before the TOC Visit 
Unable to determine 
NAAT failurea 
NAAT=nucleic acid amplification test; NG=Neisseria gonorrhoeae; TOC = Test-of-Cure. 
Note: Specimen refers to either a urogenital, pharyngeal, or rectal specimen obtained for NAAT. The NAAT 
outcomes are determined on a per-pathogen basis.  
a. 
Participants who are a “NAAT failure” at the TOC Visit assessment yet are not switched to other systemic 
antimicrobials are evaluable at subsequent time points. 

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Table 7 
Determining NAAT Outcome and Response at the Follow-Up Visit 
(Pharyngeal NG and Mgen Only) 
Defining Criteria 
NAAT Outcome 
NAAT Response  
Clearance of baseline pathogen nucleic acid 
from a specimen taken at the Follow-up Visit, 
without the participant receiving other systemic 
antimicrobials before this visit 
Nucleic acid 
clearance 
NAAT success 
Persistence of baseline pathogen nucleic acid 
from a specimen taken at the Follow-up Visit, 
without the participant receiving other systemic 
antimicrobials before this visit 
Nucleic acid 
persistence 
NAAT failure 
A determination of the nucleic acid outcome 
from a specimen taken at the Follow-up Visit 
cannot be made (e.g., no sample taken, sample 
lost, visit did not occur) 
Note: Any participants who received other 
systemic antimicrobials before the Follow-up 
Visit will not be evaluated for NAAT outcome or 
response at the Follow-up Visit 
Unable to determine 
NAAT failure 
Mgen=Mycoplasma genitalium; NAAT=nucleic acid amplification test; NG=Neisseria gonorrhoeae. 
Note: Specimen refers to either a urogenital or pharyngeal specimen obtained for NAAT. The NAAT outcomes are 
determined on a per-pathogen basis and will only be conducted if both the Baseline (NG and Mgen) and TOC 
(NG only) NAAT assay showed the presence of nucleic acid for the respective pathogen and specimen.  
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or from the study (see 
Section 8). PPD was responsible for the safety oversight for this study. 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the ICF until the Follow-up Visit at 
the time points specified in Table 1 (Section 2).  
• 
All AEs will be collected from the start of treatment until the Follow-up Visit at the 
time points specified in Table 1 (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the medical history/current medical conditions 
section of the eCRF and not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstances should this exceed 24 hours, as indicated in Appendix 4. The 

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investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. 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 or she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4. 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest 
(as defined in Section 9.2.5) will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 4. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements. 

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9.2.5. 
Adverse Events of Special Interest 
Predefined AEs of special interest for this study are cardiovascular (CV) events, 
gastrointestinal events, C. difficile infection or colitis events, and AEs related to 
acetylcholinesterase inhibition (see Section 3.3.1), which will be identified by a 
prespecified list of coded terms or determined by algorithm, as described in the reporting 
and analysis plan (RAP). Additional details are provided in Appendix 4. 
C. difficile specimens were analyzed at IHMA, Inc. Addresses for the central laboratories, 
as well as all local laboratories, are provided in the List of Clinical Laboratories Used for 
Human Biological Sample Analysis, which will be stored in the trial master file. 
9.2.6. 
Cardiovascular and Death Events 
For any CV events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific CV and death sections of the eCRF will be required to be 
completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death.  
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific CV section of the eCRF within 1 week of receipt of a CV event 
data query prompting its completion. 
The death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
9.2.7. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start of 
study treatment and through the Follow-up Visit. 
• 
If a pregnancy is reported, the investigator should inform GSK/PPD within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 6. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
9.3. 
Treatment of Overdose 
In the ceftriaxone plus azithromycin treatment group, only 1 dose of ceftriaxone and 
1 dose of azithromycin are administered during the study, and both are administered at 
the study site. Although 2 doses of gepotidacin will be administered in the study, 
participants will not have access to more than the required gepotidacin dose at each 
dosing time point. At the Baseline Visit, the first gepotidacin dose is administered at the 
study site and the study site staff will dispense to the participant only the number of 
tablets required for the second dose (self-administered as an outpatient 10 to 12 hours 
after the first dose). Therefore, overdoses of either study treatment are not anticipated in 
this study.  

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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. 
There is no specific antidote for an overdose of ceftriaxone or azithromycin. Treatment of 
an overdose should be symptomatic (refer to the locally approved ceftriaxone and 
azithromycin prescribing information). 
9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in Table 1. 
9.4.1. 
Physical Examinations 
• 
A complete physical examination will be performed at the Baseline Visit and a 
gonorrhea-focused physical examination will be performed at the TOC Visit. At 
Baseline, the complete physical examination will include assessments of the 
respiratory, CV, abdominal, gastrointestinal, and urogenital systems, as well as 
pharyngeal and rectal examinations with collections of microbiology specimen(s) as 
appropriate (see Section 9.1). Height and weight will only be measured and recorded 
at the Baseline Visit (before dosing). The gonorrhea-focused physical examination at 
the TOC visit will include urogenital systems, as well as pharyngeal and rectal 
examinations with collections of microbiology specimen(s) as appropriate (see 
Section 9.1). 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• 
Clinically significant changes from baseline or clinically significant new clinical 
signs will be reported as AEs. 
9.4.2. 
Vital Signs 
• 
Vital signs will be measured at the time points indicated in Table 1. 
• 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse rate. 
− Vital sign measurements should be obtained before any blood draws scheduled 
on the same assessment day. 
− Clinically significant changes from baseline will be reported as AEs. 

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9.4.3. 
Electrocardiograms 
• 
Triplicate 12-lead ECGs (over an approximate 5- to 10-minute period) will be 
performed at the Baseline Visit using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2 
for QTc withdrawal criteria and additional QTc readings that may be necessary. 
• 
This protocol only requires an ECG evaluation at the Baseline Visit. Ideally, ECGs 
will be obtained before any vital sign measurements or blood draws scheduled on the 
same assessment day; however, sites may perform procedures in an order per their 
standard of care, as long as participants return to a resting state prior to the start of 
the ECG collections. Subsequent ECGs only need to be triplicate if the initial one is 
prolonged. 
• 
If clinically significant changes occur during the study, they will be reported as AEs. 
• 
Equipment provided qualified ECG machines and supportive maintenance during the 
study to sites that required provision.  
9.4.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to 
Table 1 for the timing and frequency.  
• 
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered significantly abnormal by the investigator or 
medical monitor.  
• 
If such values do not return to normal or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and Table 1.  
• 
All safety laboratory tests will be performed at PPD Global Clinical Laboratory. 
Addresses for the central laboratories, as well as all local laboratories, are provided 
in the List of Clinical Laboratories Used for Human Biological Sample Analysis, 
which is stored in the trial master file. 

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9.5. 
Pharmacokinetics 
No PK samples will be collected in this study except as potentially required for liver 
safety follow-up assessments as described in Appendix 8. Any PK samples will be 
performed by PPD Bioanalytical Lab. 
9.6. 
Pharmacodynamics 
Microbiological assessments will include the determination of gepotidacin MICs and 
other antibacterial MICs for urogenital, pharyngeal, and rectal NG isolates in this study. 
The MIC values will be used in the PD analysis. 
9.7. 
Genetics 
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 Appendix 7. 
9.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
9.9. 
Health Economics or Medical Resource Utilization and 
Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 

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10. 
STATISTICAL CONSIDERATIONS 
Full details of all data handling conventions and statistical analyses conducted for this 
study will be provided in the RAP. 
10.1. 
Statistical Hypothesis 
The study is designed to demonstrate that gepotidacin administered orally is noninferior 
compared to ceftriaxone plus azithromycin on the primary efficacy endpoint of 
culture-confirmed eradication of NG from the urogenital body site (i.e., microbiological 
success) at the TOC Visit. 
The following are null and alternative hypotheses for the primary analysis of the 
microbiological success rates at the prespecified noninferiority margin of -10%: 
H0: Microbiological success rate of gepotidacin – Microbiological success rate of 
ceftriaxone plus azithromycin ≤-10.0% 
H1: Microbiological success rate of gepotidacin – Microbiological success rate of 
ceftriaxone plus azithromycin >-10.0% 
Gepotidacin will be declared noninferior to treatment with ceftriaxone plus azithromycin 
if the lower limit of the 2-sided 95% CI for the difference between the microbiological 
success rate of gepotidacin and ceftriaxone plus azithromycin at the TOC Visit is 
above -10.0%. Superiority of gepotidacin will be declared if the lower end of the CI is 
above 0%. 
The difference in the microbiological success rate between the 2 treatment groups and the 
corresponding CI will be computed using the Miettinen and Nurminen method 
[Miettinen, 1985]. 
10.2. 
Sample Size Determination 
10.2.1. 
Justification of Sample Size 
Approximately 400 participants will be needed for the primary analysis population (i.e., 
the micro-ITT Population, as defined in Section 10.3) to demonstrate efficacy of 
gepotidacin in this study.  
A conservative estimate of a 90% microbiological success rate has been assumed for 
ceftriaxone 500 mg IM plus azithromycin 1 g orally. Participants not returning for TOC 
will be considered a microbiological failure in this study. 

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Assuming a 90% microbiological success rate of ceftriaxone plus azithromycin and the 
same value for the actual success rate of gepotidacin, a sample size of 400 urogenital 
microbiological evaluable participants (200 participants in each treatment) will provide 
approximately 91% power to demonstrate noninferiority of gepotidacin and ceftriaxone 
plus azithromycin in adolescents and adults with uncomplicated gonorrhea caused by NG 
with a 0.025 one-sided significance level and a -10% noninferiority margin.  
Approximately 620 participants will be enrolled and randomized 1:1 to gepotidacin and 
ceftriaxone plus azithromycin in order to identify approximately 400 participants that 
meet the definition of the micro-ITT Population.  
10.2.2. 
Sample Size Sensitivity 
Sensitivity of the sample size has been explored considering various microbiological 
success rates. The assumed reference microbiological success rate affects the power for a 
target number of participants in the study. Table 8 shows the power with the target 
number of participants in this clinical trial under different assumptions of the 
microbiological success rate.  
Table 8 
Power of the Study for the Target Microbiological Intent-to-Treat 
Population at Various Microbiological Success Rates 
Microbiological 
Success Rate of 
Ceftriaxone Plus 
Azithromycin 
Microbiological 
Success Rate of 
Gepotidacin 
Total Number of 
Participants in 
the Primary 
Analysis 
Number of 
Participants in the 
Primary Analysis in 
Each Treatment Group 
Power 
92% 
92% 
400 
200 
95% 
90% 
90% 
400 
200 
91% 
89% 
89% 
400 
200 
89% 
88% 
88% 
400 
200 
86% 
87% 
87% 
400 
400 
84% 
The power of the study will remain above 84% if the true microbiological success rate in 
the 2 treatment groups is the same and 87% or higher. 

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10.3. 
Populations for Analyses 
For purposes of analysis, the following key populations are defined: 
Population 
Description 
Screened Population 
All participants who were screened for eligibility. 
Intent-to-Treat (ITT) 
Population 
All participants randomly assigned to study treatment.  
Participants will be analyzed according to their randomized study 
treatment arm. 
Microbiological ITT 
(micro-ITT) Population 
All participants randomly assigned to study treatment who 
receive at least 1 dose of study treatment and have confirmed 
NG isolated that is ceftriaxone-susceptible from baseline culture 
of their urogenital specimen. 
Participants will be analyzed according to their randomized study 
treatment arm. 
This is the primary analysis population. 
Micro-ITT Rectal 
Population 
Participants who meet the definition of the micro-ITT Population 
and have confirmed NG isolated that is ceftriaxone-susceptible 
from baseline culture of their rectal specimen. 
Participants will be analyzed according to their randomized study 
treatment arm. 
Micro-ITT Pharyngeal 
Population 
Participants who meet the definition of the micro-ITT Population 
and have confirmed NG isolated that is ceftriaxone-susceptible 
from baseline culture of their pharyngeal specimen. 
Participants will be analyzed according to their randomized study 
treatment arm. 
Microbiologically Evaluable 
(ME) Population 
Participants who meet the definition of the micro-ITT Population 
and follow important components of the study (i.e., [1] receive all 
planned doses as randomized and actual treatment is the same 
as randomized, [2] have a urogenital specimen collected at the 
TOC Visit, with available culture results, [3] have not taken any 
other systemic antibiotic prior to the TOC Visit, unless it was 
taken for the current infection, and [4] have no major deviation 
that prevents evaluation of efficacy). 
Participants will be analyzed according to their randomized study 
treatment arm. 
Safety Population 
All participants who receive at least 1 dose of study treatment.  
Participants will be analyzed according to their actual treatment 
received. 
 Mgen=Mycoplasma genitalium; NG=Neisseria gonorrhoeae; TOC=Test-of-Cure. 

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10.4. 
Statistical Analyses 
10.4.1. 
General Considerations 
Any additional analysis populations or supplemental analyses will be detailed in the 
RAP. Any additional analyses or outputs needed as a result of COVID-19 on the study 
will be detailed in the RAP. 
10.4.2. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis will be performed using the micro-ITT Population. 
• The primary efficacy endpoint is culture-confirmed bacterial eradication 
of NG from the urogenital body site (i.e., microbiological success) at the 
TOC (Day 4 to 8) Visit. For this analysis, participants who do not return 
for the TOC (Day 4 to 8) Visit will be treated as failures. 
• The number and percentage of participants with culture-confirmed 
bacterial eradication of NG from the urogenital body site (i.e., 
microbiological success) will be summarized, along with 95% CIs, at the 
TOC (Day 4 to 8) Visit by treatment group. 
• The difference in microbiological success rates between gepotidacin and 
ceftriaxone plus azithromycin for culture-confirmed bacterial eradication 
of urogenital NG at the TOC Visit will be summarized, along with 95% 
CIs. 
• Gepotidacin will be declared noninferior to treatment with ceftriaxone plus 
azithromycin if the lower limit of the 2-sided 95% CI for the difference 
between the microbiological success rate of gepotidacin and ceftriaxone 
plus azithromycin at the TOC Visit is above -10.0%. Superiority of 
gepotidacin will be declared if the lower end of the CI is above 0%. The 
Miettinen and Nurminen method will be used for the analysis adjusting for 
treatment and stratification factors of sex and sexual orientation 
combination (i.e., MSM, MSW, or female). 
• A further supplementary analysis on the primary endpoint may be 
performed based on the Microbiologically Evaluable Population. 
Additional sensitivity analysis, if warranted, will be described in the RAP.  
• The microbiological success in each treatment group along with the 
difference in microbiological success rates for culture-confirmed bacterial 
eradication of urogenital NG at the TOC Visit between gepotidacin and 
ceftriaxone plus azithromycin will be summarized (along with 95% CI) by 
subgroups based on sex and sexual orientation combination (MSM, 
MSW, or female). Further analyses may be performed based on the 
observed differences between the treatment groups in these subgroups; 
additional details will be provided in the RAP. 

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Endpoint 
Statistical Analysis Methods 
Secondary 
Secondary analyses will be performed using the micro-ITT Population subset 
to only include participants with confirmed NG isolated from baseline culture 
of their rectal/pharyngeal specimen, respectively, unless otherwise specified. 
• The microbiological success rates for culture-confirmed bacterial 
eradication of rectal NG at the TOC Visit will be summarized by 
treatment group and sex and sexual orientation combination. 
• The microbiological success rates for culture-confirmed bacterial 
eradication of pharyngeal NG at the TOC Visit will be summarized by 
treatment group and sex and sexual orientation combination. 
• Additional details will be provided in the RAP. 
Exploratory 
• 
Gram stain (urogenital specimens only), bacterial culture, and in vitro 
susceptibility test results and NAAT results at the Baseline, TOC (Day 4 
to 8), and Follow-up (Day 14 to 21) Visits will be summarized as data 
permit. 
• 
Details regarding exploratory analyses, including additional exploratory 
analyses not defined in the protocol, will be described in the RAP. 
PPD, in conjunction with GSK, will perform the analysis of the primary and secondary 
endpoints. 
10.4.3. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. The severity of AEs and 
SAEs will be determined by the investigator according to the US National Institute of 
Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases 
(DMID) criteria for adult toxicity assessment [DMID, 2007a], with the exception of 
serum creatinine adolescent laboratory data, which will be assessed using pediatric 
toxicity criteria [DMID, 2007b] (Appendix 5). All reported AEs will be coded using 
MedDRA and summarized by system organ class and preferred terms. 

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Endpoint 
Statistical Analysis Methods 
Secondary 
• 
The number and percentage of treatment-emergent AEs, study treatment 
related AEs, deaths, SAEs, and AEs leading to study treatment or study 
withdrawal will be provided. 
• 
Treatment-emergent AEs will be summarized by severity. 
• 
Change from baseline over time in laboratory parameters 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 postbaseline value will be provided. Abnormal 
liver chemistry results will be determined using increases above the upper 
limit of normal. Changes from baseline values will be summarized with 
descriptive statistics. 
• 
The severity of specified AEs and laboratory abnormalities will be graded 
according to the modified DMID toxicity grading system (Appendix 5). 
Data will be tabulated and reported by absolute grade for Grades 3 and 
higher and shift tables, as appropriate. 
• 
Adverse events of special interest will include CV, gastrointestinal, and 
C. difficile infection or colitis events. In addition, AEs associated with 
acetylcholinesterase inhibition are also considered special interest. As 
described in the RAP, manual and programmatic reviews of AEs/preferred 
terms will be used to assess these events. 
• 
Baseline ECG results will be provided in a listing. 
10.4.4. 
Other Analyses 
Pharmacodynamic analysis will be performed to examine the potential relationship 
between MIC values for the treatment/isolate pairings in this study and microbiological 
response at the TOC Visit. The full details will be described in the RAP. 
10.5. 
Interim Analysis 
No interim analysis is planned for this study. 
10.6. 
Data Monitoring Committee or Other Review Board 
An internal GSK Safety Review Team will monitor blinded safety data and an internal 
Microbiology Review Team will monitor blinded microbiological data instream. No 
external data monitoring review committees are planned for the study. For details on 
these internal review teams, refer to Appendix 3. 

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11. 
REFERENCES 
Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, et al. 
Pharmacokinetics–pharmacodynamics of antimicrobial therapy: it's not just for mice 
anymore. Clin Infect Dis. 2007;44(4):79-86. 
Australian Sexual Health Alliance (ASHA). Australian STI management guidelines for 
use in primary care: gonorrhoea. http://www.sti.guidelines.org.au/sexually-transmissible-
infections/gonorrhoea. Last updated June 2016. Accessed 05-Apr-2017. 
Barry PM, Klausner JD. The use of cephalosporins for gonorrhea: the impending problem 
of resistance. Expert Opin Pharmacother. 2009;10(4):555-77. 
Bax BD, Chan PF, Eggleston DS, et al. Type IIA topisomerase inhibition by a new class 
of antibacterial agents. Nature. 2010;466(7309:935-40. 
Biedenbach DJ, Bouchillon SK, Hackel M et al. In vitro activity of gepotidacin, a novel 
triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of 
bacterial pathogens. Antimicrob Agents Chemother. 2016;60(30):1918-23. 
Bignell C, Unemo M; European STI Guidelines Editorial Board. 2012 European 
guideline on the diagnosis and treatment of gonorrhoeae in adults. Int J STD AIDS. 
2013;24(2):85-92. 
Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the 
United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-
threats-report-508.pdf. Accessed 01-Aug-2021. 
Centers for Disease Control and Prevention (CDC). Morbidity and Mortality Weekly 
Report (MMWR): Neisseria gonorrhoeae Antimicrobial Susceptibility Surveillance — 
The Gonococcal Isolate Surveillance Project, 27 Sites, United States, 2014. 
https://www.cdc.gov/mmwr/volumes/65/ss/ss6507a1.htm?s_cid=ss6507_w. Last updated 
15-Jul-2016. Accessed 14-Mar-2017. 
Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases 
treatment guidelines, 2015. MMWR Recomm Rep 2015;64(No. RR-3):1-137. 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm. Accessed 03-Dec-2021. 
Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases 
treatment guidelines, 2021. https://www.cdc.gov/std/treatment-guidelines/gonorrhea-
adults.htm#:~:text=Although%20clinical%20data%20confirm%20that%20a%20single%
20injection,necessary%20for%20isolates%20with%20elevated%20MICs%20%28880%2
C%20881%29. Last updated 09-Nov-2021. Accessed 17-Nov-2021. 
European Medicine Agency (EMA). Guideline on the evaluation of medicinal products 
indicated for treatment of bacterial infections. CPMP/EWP/558/95 rev 2. 15-Dec-2011. 

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Gibson EG, Bax B, Chan PF, et al. Mechanistic and structural basis for the actions of 
antibacterial gepotidacin against staphylococcus aureus gyrase. ACS Infect Dis. 
2019;5(4):570-81. 
Mushtaq S, Vickers A, Sadouki Z, et al. In vitro activities of gepotidacin, a novel 
triazaacenaphthylene and topoisomerase IV DNA gyrase inhibitor, against 
Gram-negative bacteria and Staphylococcus saprophyticus, poster P1849. 2019. Abstr 
29th ECCMID, Amsterdam, The Netherlands. 
Miettinen, O.S., and M.M. Nurminen. 1985. “Comparative Analysis of Two Rates. 
Statistics in Medicine, 213-226.  
Oviatt A, Huang J, Mattern K, et al. Biochemical and genetic evidence that gepotidacin 
demonstrates well-balanced dual targeting against DNA gyrase and topoisomerase IV in 
Escherichia coli, poster L0178. 2022. Abstr 32nd ECCMID, Lisbon, Portugal. 
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Guidance for industry. 
Uncomplicated gonorrhea: developing drugs for treatment. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM401620.pdf. Last updated August 2015. Accessed 05-Apr-2016. 
US National Institute for Allergy and Infectious Disease Division of Microbiology and 
Infectious Disease. Division of Microbiology and Infectious Disease (DMID) Adult 
Toxicity Table. Draft. https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf. 
Last updated November 2007a. Accessed 10-Mar-2017. 
US National Institute for Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases. Division of Microbiology and Infectious Diseases (DMID) Pediatric 
Toxicity Table. Draft. https://www.niaid.nih.gov/sites/default/files/dmidpedtox.pdf. Last 
updated November 2007b. Accessed 10-Mar-2017. 
Workowski KA, Berman SM, Douglas JM Jr. Emerging antimicrobial resistance in 
Neisseria gonorrhoeae: urgent need to strengthen prevention strategies. Ann Intern Med. 
2008;148(8):606-13. 
World Health Organization (WHO). Global priority list of antibiotic-resistant bacteria to 
guide research, discovery, and development of new antibiotics. 2017. 
http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-
ET_NM_WHO.pdf?ua=1. Accessed 12-Apr-2017. 
World Health Organization (WHO). WHO guidelines for the treatment of Neisseria 
gonorrhoeae. 2016. http://apps.who.int/iris/bitstream/10665/246114/1/9789241549691-
eng.pdf?ua=1. Accessed 14-Mar-2017. 

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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
AE 
adverse event 
ALT 
alanine aminotransferase 
CDC 
Centers for Disease Control and Prevention  
CI 
confidence interval  
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
coronavirus disease 
CRF 
case report form 
CT 
Chlamydia trachomatis 
CV 
cardiovascular  
CYP3A4 
cytochrome P450 enzyme 3A4 
DMID 
Division of Microbiology and Infectious Diseases 
EAGLE 
Efficacy of Antibacterial Gepotidacin Evaluated 
ECG 
Electrocardiogram 
eCRF 
electronic case report form  
EMA 
European Medicines Agency  
EU 
European Union 
fAUC 
free drug area under the concentration-time curve 
FDA 
Food and Drug Administration  
fT>MIC 
free mean time above the minimum inhibitory 
concentration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 

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IB 
investigator’s brochure  
ICF 
informed consent form  
ICH 
International Council on Harmonisation 
IEC 
independent ethics committee 
IM 
intramuscular  
IRB 
institutional review board 
IRT 
interactive response technology  
ITT 
Intent-to-Treat  
IV 
intravenous  
Kg 
Kilogram 
M 
Meter 
ME 
Microbiologically Evaluable 
MedDRA 
Medical Dictionary for Regulatory Activities  
Mg 
Milligram 
Mgen 
Mycoplasma genitalium 
MIC 
minimum inhibitory concentration  
MIC50 
50th percentile minimum inhibitory concentration 
MIC90 
90th percentile minimum inhibitory concentration 
micro-ITT 
Microbiological Intent-to-Treat  
Min 
Minute 
mL 
Milliliter 
Mm 
Millimeter 
Msec 
Millisecond 
MSM 
men who have sex with men 
MSW 
men who have sex with women 

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NAAT  
nucleic acid amplification test  
NG 
Neisseria gonorrhoeae 
PD 
Pharmacodynamic 
PK 
pharmacokinetic  
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett 
QTcF 
QT interval corrected for heart rate according to 
Fridericia  
RAP 
reporting and analysis plan  
SAE 
serious adverse event 
SRM 
Study Reference Manual  
SRT 
Safety Review Team 
TdP 
torsades de pointes  
TOC 
Test-of-Cure  
µg 
Microgram 
ULN 
upper limit of normal 
WHO 
World Health Organization  
WOCBP 
woman of childbearing potential  
Trademark Information 
Trademarks of the GSK 
 group of companies 
 
Trademarks not owned by the GSK 
group of companies 
NONE 
 
FIRST RESPONSE 
 
 
MedDRA 

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12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 9 will be performed by the central laboratory.  
− Local laboratory results are only required in the event that the central laboratory 
results are not available in time for response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the 
same time. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 

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Table 9 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC Indices: 
MCV 
MCH 
WBC Count With 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya 
Blood urea 
nitrogen 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT/SGPT 
Total protein 
Glucose, 
nonfasting 
Calcium 
Alkaline 
phosphatase 
Albumin 
Chloride 
Magnesium 
 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, and ketones by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• 
Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and 
benzodiazepines) 
• 
Urine hCG pregnancy test (as needed for women of childbearing 
potential)b 
• 
Serology (HBsAg, hepatitis C virus antibody, and HIV). If serology 
testing was performed within 3 months prior to the first dose of study 
treatment and results were positive, testing at Baseline is not required. 
If testing was performed within 3 months and any result was negative, 
testing at Baseline is required. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report form; 
HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency 
virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; 
SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=while 
blood cell. 
a. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 8. All events of ALT ≥3 × upper limit of normal 
(ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as 
a serious adverse event. 
b. 
See Appendix 6 for urine test requirement details. Local urine testing will be standard for the protocol unless 
serum testing is required by local regulation or the Institutional Review Board/Independent Ethics Committee. 

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

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Informed Consent/Assent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. Participants should advise their sexual partner of their infection; 
this will be discussed with participants as part of the informed consent process and 
will be documented in the medical chart by the study site staff. 
• 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent and/or eConsent (if applicable) that meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study site.  
• 
The medical record must include a statement that written informed consent and/or 
eConsent (if applicable) was obtained before the participant was enrolled in the study 
and the date informed consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s)/eConsent 
during their participation in the study.  
• 
A copy of the ICF(s)/eConsent must be provided to the participant or the 
participant’s legally authorized representative.  
− Adolescent participants should be asked for their written assent or eConsent (if 
appliable) 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). 
Study Conduct Materials and Support 
The following vendors will be used to support study conduct, translations, participant 
recruitment, stipends, and transportation: 
Vendor Name 
Vendor Service 
Medable 
Telemedicine and teleconsent provider 
Proforma ProClinix 
Central advertising/printing/patient recruitment materials 
Signant Health 
Patient Texting Service 
Transperfect 
Translations (including labels & patient cards) 
TAKSEE 
Patient Transportation in Spain 
SERMES 
Patient Reimbursement in Spain  
Jumo Health 
Study Website 

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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. 
• 
GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law and as described in 
the ICF. The level of disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Committees Structure 
To protect the safety interests of participants, an internal GSK Safety Review Team will 
review blinded safety data instream on a regular basis throughout study conduct. Data 
reviewers will include but are not limited to the following participants: medical monitor, 
safety team lead, statistician, clinical team lead, and data quality lead. 
An internal Microbiology Review Team will monitor blinded pathogen identification and 
susceptibility data instream. 
No external data monitoring review committees are planned for the study. 
Provision will be made for a limited degree of unblinding of a minority of participant 
sample data should this be viewed as appropriate for planning closure of trial enrollment. 
Procedures will be described in a separate microbiology sample monitoring plan. 
Written documentation regarding key decisions made by the review teams/committee will 
be promptly distributed to participating investigators and IRB/IECs. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
study site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 

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• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocol summaries 
prior to study start and target results summaries submission within 12 months of the 
primary/study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines. 
• 
Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
− 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report, and will be 
provided reasonable access to statistical tables, figures, and relevant reports. 
GSK will also provide the investigator with the full summary of the study 
results, including a summary of study results understandable to laypersons. The 
investigator is encouraged to share the plain language summary with the study 
participants, as appropriate. The full study report will be made available upon 
request, after decision on marketing authorization by regulatory authorities. 
• 
GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• 
GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by study participants are used to maximum effect in the creation of 
knowledge and understanding. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed case report 
forms (CRFs) or electronic CRFs (eCRFs) unless transmitted to the sponsor or 
designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF.  
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
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. 

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• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process can be found in the Data Validation Manual. 
• 
Document review of financial disclosures, site staff changes, and a list of 
investigators was also supported by Tata Consulting Services. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized study site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
− Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
clinical study report/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the 
sponsor. 
− The Electronic Data Capture system was provided by Medidata Rave. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• 
Definition of what constitutes source data can be found in the Study Reference 
Manual. 
− The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 
− The sponsor or designee will perform monitoring to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

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− Copies of documents are shared with external third parties contracted by 
GSK/PPD for review by a central reader mechanism (e.g. endpoint adjudication 
committee; expert reader). The non-exhaustive list of documents shared to 
inform the central reader may include, discharge summaries, imaging reports, 
ECG reports etc. Participant names or any information which would make the 
participant identifiable or is not essential for the central reader mechanism will 
be redacted by the investigator sites prior to transfer. Details of the list of 
documents and the redaction procedure are provided in the site manual or 
equivalent. These documents will be used by the third party solely for the 
purpose indicated within this protocol. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 

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12.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered related 
to the study treatment. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
• 
A treatment-emergent AE is an event that emerges during treatment having been absent 
pretreatment or worsens relative to the pretreatment state. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., electrocardiograms, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/serious AE (SAE) unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 

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

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

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Recording AEs and SAEs 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related 
to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK/PPD in lieu of completion of the GSK/PPD AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested 
by GSK. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
• 
The severity of AEs and SAEs will be determined by the investigator according to the US 
National Institute of Allergy and Infectious Diseases Division of Microbiology and 
Infectious Diseases criteria for adult toxicity assessment [DMID, 2007a], with the 
exception of serum creatinine adolescent laboratory data, which will be assessed using 
pediatric toxicity criteria [DMID, 2007b] (Appendix 5). 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration, 
will be considered and investigated. 
• 
The investigator will also consult the investigator’s brochure and/or product information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK/PPD. However, it is very important that 

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

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12.5. 
Appendix 5: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment 
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity: 
GRADE 1 
Mild 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate 
Mild to moderate limitation in activity – some assistance 
may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-
threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable 
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a Grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to: 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
• 
Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DAIDS) 
and modified to better meet the needs of participants in Division of Microbiology 
and Infectious Diseases (DMID) trials. 
• For parameters not included in the following Toxicity Tables, study sites should refer 
to the “Guide for Estimating Severity Grade” located above. 
• Criteria are generally grouped by body system. 
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria. 
Note: Adult DMID toxicity criteria will be applied for all laboratory parameters, with the 
exception of serum creatinine adolescent laboratory data, which will be assessed using 
pediatric DMID toxicity criteria. The DMID pediatric toxicity table may be accessed at 
https://www.niaid.nih.gov/sites/default/files/dmidpedtox.pdf. 
 

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HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 to 10.5 gm/dL 
8.0 to 9.4 gm/dL 
6.5 to 7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil Count 
1000 to 1500 /mm3 
750 to 999 /mm3` 
500 to 749 /mm3 
<500 /mm3 
Platelets 
75,000 to 99,999 /mm3 
50,000 to 74,999 /mm3 
20,000 to 49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
11,000 to 13,000 /mm3 
13,000 to 15,000 /mm3 
15,000 to 30,000 /mm3 
>30,000 or <1000 /mm3 
% Polymorphonuclear Leukocytes + 
Band Cells 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
Low: 100 to 200 mg/dL 
High: 400 to 600 mg/dL 
Low: <100 mg/dL 
High: >600 mg/dL 
Low: <50 mg/dL 
High: N/A 
Fibrinogen associated with gross bleeding 
or with disseminated coagulation 
Fibrin Split Product 
20 to 40 mcg/mL 
41 to 50 mcg/mL 
51 to 60 mcg/dL 
>60 mcg/dL 
Prothrombin Time (PT) 
1.01 to 1.25 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.  

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

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ENZYMES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Aspartate aminotransferase (AST) 
1.1 to <2.0 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 to 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 gm loss/day 
2 to 3+ or 
1 to 2 gm loss/day 
4+ or 
2 to 3.5 gm loss/day 
Nephrotic syndrome or 
>3.5 gm loss/day 
Hematuria 
Microscopic only 
<10 RBC/HPF 
Gross, no clots 
>10 RBC/HPF 
Gross, with or without clots, 
or red blood cells casts 
Obstructive or  
required transfusion 
HPF=high powered field; RBC=red blood cells. 

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

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

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change in taste, smell, vision, 
and/or hearing 
mild impairment that is not 
symmetrical 
MUSCULOSKELETAL 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
(joint pain) 
Mild pain not interfering with function 
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL 
Severe paid; pain and/or analgesics 
interfering with ADL 
Disabling pain 
Arthritis 
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function 
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL 
Severe pain with inflammation, 
erythema or joint swelling, and 
interfering with ADL 
Permanent and/or 
disabling joint 
destruction 
Myalgia 
Myalgia with no limitation of activity 
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity 
Severe muscle tenderness with marked 
impairment of activity 
Frank myonecrosis 
ADL=activities of daily living. 
 
SKIN 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
Erythema; pruritus 
Diffuse, maculo papular rash, dry 
desquamation   
Vesiculation or moist 
desquamation or ulceration 
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery 
Induration 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Erythema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Edema 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Rash at injection site 
<15 mm 
15 to 30 mm 
>30 mm 
N/A 
Pruritus 
Slight itching at injection site 
Moderate itching at injection 
extremity 
Itching over entire body 
N/A 
N/A=not applicable. 

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SYSTEMIC 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic reaction 
Pruritus without rash 
Localized urticarial 
Generalized urticarial; angioedema 
Anaphylaxis 
Headache 
Mild, no treatment required 
Transient, moderate; treatment 
required 
Severe; responds to initial narcotic 
therapy 
Intractable; requires 
repeated narcotic therapy 
Fever: oral 
37.7 to 38.5°C or 100.0 to 101.5°F 
38.6 to 39.5°C or 101.6 to 102.9°F 
39.6 to 40.5°C or 103 to 105°F 
>40°C or >105°F 
Fatigue 
Normal activity reduced <48 hours 
Normal activity decreased 25 to 50%; 
>48 hours 
Normal activity decreased >50%; 
cannot work 
Unable to care for self 
 

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12.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note:  Documentation can come from the study site personnel’s review of 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
− 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
− 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
urine pregnancy test.  
• 
Pregnancy testing will be performed at Baseline (Day 1) before study treatment 
administration. The urine pregnancy test at Baseline will determine study 
contraception and abstinence requirements as follows: 
− Pregnancy testing at Baseline (Day 1) should be performed using the urine test 
kit provided to the study site (FIRST RESPONSE Early Result Pregnancy Test 
with a high sensitivity of ≤6.3 mIU/mL). Participants with a negative urine 
pregnancy test result from this test kit may be included in the study with no 
pretreatment contraception or abstinence requirements. 
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 

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the standard test may be included in the study only if the participant has used a 
highly effective contraception method as described in Table 10 or has practiced 
abstinence from penile/vaginal intercourse for at least 14 days before receiving study 
treatment.  
• 
A pregnancy test will also be performed at the Test-of-Cure (Day 4 to 8) Visit.  
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• 
Urine pregnancy test kits were provided by PPD except for sites in Australia where 
urine pregnancy test kits were provided by Flinders and Zuellig Pharma. 
Contraception Guidance – Male and Female Participants 
See the section directly above regarding pregnancy testing for female participants at 
Baseline (Day 1) and associated pretreatment contraception and abstinence requirements. 
Female participants of childbearing potential who enter the study using contraception 
must continue to do so throughout the study.  
For male and female participants, the only contraception requirement from the Baseline 
Visit through the TOC Visit is abstinence or the use of a male condom during intercourse. 
As described in Section 6.3, all participants will be instructed to abstain from sexual 
activity from the Baseline Visit through the TOC Visit to prevent possible re-infection 
with NG. If a participant refuses to abstain and is sexually active, male participants as 
well as male partners of female participants, of both childbearing and nonchildbearing 
potential, must use a male condom during intercourse from the Baseline Visit through 
completion of the TOC Visit. 
Table 10 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
• 
oral 
• 
intravaginal  
• 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 

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Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Note: Male 
partners of female participants, of both childbearing and nonchildbearing potential, must use a 
male condom during intercourse from the Baseline Visit through completion of the TOC Visit.)  
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 treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
WOCBP=woman of childbearing potential. 
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.  
b. 
Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. 
Collection of Pregnancy Information 
Female participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK/PPD 
within 24 hours of learning of a participant’s pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an adverse event (AE) or serious AE 
(SAE), any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a poststudy pregnancy that is considered 
reasonably related to the study treatment by the investigator will be reported to GSK 
as described in Appendix 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 will discontinue study 
treatment. 

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12.7. 
Appendix 7: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
institutional review board/independent ethics committee allow, a blood sample will 
be collected for DNA analysis. 
• 
DNA samples will be used for research related to gepotidacin or urogenital 
gonorrhea and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to gepotidacin and urogenital gonorrhea. Genetic 
research may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome (or analysis of the entire genome) (as 
appropriate). 
• 
DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data.  
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to gepotidacin or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on gepotidacin (or study treatments of 
this class) or urogenital gonorrhea continues but no longer than 15 years after the last 
participant’s last visit or other period as per local requirements. 

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12.8. 
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase III liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
The stopping criteria for discontinuing dosing of study treatment due to liver chemistry 
parameters have limited application in this study, as study treatment is only administered 
as 2 doses of gepotidacin over a 24-hour period starting on Day 1 or as a single 
intramuscular dose of ceftriaxone plus an oral dose of azithromycin on Day 1. However, 
if participants are found to have values consistent with the usual stopping parameters, it is 
appropriate to institute evaluation and monitoring criteria according to standard GSK 
criteria. Therefore, if defined parameters are reached, liver function tests should be 
evaluated as shown in the table below, which is in keeping with the liver stopping 
criteria, and laboratory evaluation should be instituted. 
Phase III liver chemistry evaluation criteria and required follow-up assessments  
Liver Chemistry Evaluation Criteria – Liver Event 
ALT Absolute 
ALT ≥8 x ULN 
ALT Increase 
ALT ≥5 x ULN but <8 x ULN persists for ≥2 weeks 
ALT ≥3 x ULN but <5 x ULN persists for ≥4 weeks 
Bilirubina,b 
ALT ≥3 x ULN and bilirubin ≥2 x ULN (>35% direct bilirubin)  
INRb 
ALT ≥3 x ULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT ≥5 x ULN but <8 x ULN and cannot be monitored weekly for ≥2 weeks 
ALT ≥3 x ULN but <5 x ULN and cannot be monitored weekly for ≥4 weeks 
Symptomaticc 
ALT ≥3 x ULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event eCRF and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb 
• 
Perform liver event follow-up assessments  
• 
Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• 
Viral hepatitis serologyd 
• 
Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
• 
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen), 

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Liver Chemistry Evaluation Criteria – Liver Event 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours 
• 
Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours  
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
quantitative hepatitis B DNA, and 
hepatitis delta antibodye 
• 
Obtain blood sample for PK analysis, 
within 24 hours after last dosef 
• 
Serum creatine phosphokinase and 
lactate dehydrogenase 
• 
Fractionate bilirubin, if total bilirubin 
≥2 x ULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• 
Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over-the-counter medications 
• 
Record alcohol use on the liver event 
alcohol intake eCRF page 
For bilirubin or INR criteria: 
• 
Antinuclear antibody, antismooth 
muscle antibody, type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009]). 
NOTE: not required in China.  
• 
Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or liver biopsy eCRFs. 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report 
form; HPLC=high-performance liquid chromatography; IgM=immunoglobulin M; INR=international normalized 
ratio; PK=pharmacokinetic; SAE=serious adverse event; ULN=upper limit of normal. 

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a. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
b. 
All events of ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (>35% direct bilirubin) or ALT ≥ 3 x ULN and INR >1.5, if INR 
measured which may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants. 
c. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia). 
d. 
Includes: hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen, and hepatitis B core antibody 
(IgM); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing); hepatitis E IgM antibody  
e. 
If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction of 
hepatitis D RNA virus (where needed) [Le Gal, 2005]. 
f. 
The PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Study Reference Manual. 
Phase III liver chemistry increased monitoring criteria  
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT ≥5 x ULN and <8 x ULN and 
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT ≥3 x ULN and <5 x ULN and 
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
• 
Notify the GSK medical monitor within 24 
hours of learning of the abnormality to discuss 
participant safety.  
• 
Participant can continue study treatment. 
• 
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to 
within baseline. 
• 
If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above. 
• 
If ALT decreases from ALT ≥5 x ULN and 
<8 x ULN to ≥3 x ULN but <5 x ULN, continue to 
monitor liver chemistries weekly.  
• 
If, after 4 weeks of monitoring, ALT <3 x ULN 
and bilirubin <2 x ULN, monitor participants 
twice monthly until liver chemistries normalize or 
return to within baseline. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. 

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

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12.9. 
Appendix 9: Additional Guidance on Permitted and 
Prohibited Medications and Crediblemeds.org 
For quick reference, a list of some common concomitant medications that are permitted 
for participants to take during the study for nausea, vomiting, pain, diarrhea, etc. per 
investigator discretion is provided below. A list of some of the commonly used 
medications that are prohibited is also provided in this appendix. Lastly, a topline 
overview of how to use crediblemeds.org is also provided. 
A further detailed list of medications will be provided in the Study Reference Manual. 
List of Concomitant Medications Permitted During the Study: 
Generic Namea 
Common Therapeutic Use(s) 
Dolasetron 
Nausea, vomiting 
Granisetron 
Nausea, vomiting 
Metoclopramide 
Nausea, vomiting 
Palonosetron 
Nausea, vomiting 
Promethazine 
Nausea, vomiting 
Tropisetron (Only on Non-US markets) 
Nausea, vomiting 
Acetaminophen or paracetamol 
Pain  
Tramadol 
Pain 
Hydrocodone ER 
Pain, severe 
Lidocaine (solution for intramuscular injection only) 
Anesthetic 
Loperamide 
Diarrhea 
Cetirizine 
Antihistamine (H1) 
Ebastine 
Antihistamine (H1) 
Fexofenadine 
Antihistamine (H1) 
Loratadine 
Antihistamine (H1) 
Clotrimazole 
Antifungal – topical, nonsystemic 
only 
Tolnaftate 
Antifungal – topical, nonsystemic 
only 
Ketoconazole 
Antifungal – topical, nonsystemic 
only 
Tenofovir and emtricitabine 
Pre-exposure prophylaxis for HIV 
ER=extended release; HIV=human immunodeficiency virus; US=United States. 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 7.7.1 for other permitted medications. 

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List of Concomitant Medications Prohibited During the Study: 
Generic Namea 
Common Therapeutic Use(s) 
Ondansetron 
Nausea, vomiting 
Other investigational products 
Various 
Systemic antibiotics (e.g., ciprofloxacin, 
amoxicillin/clavulanate, cephalexin, doxycycline) 
Antibiotic – all systemic 
Topical and intravaginal antibiotics (e.g., clindamycin, 
Neomycin, polymyxin, clotrimazole, tolnaftate, ketoconazole, 
metronidazole) 
Antibiotic – all topical and 
intravaginal 
Systemic antifungals (e.g., itraconazole, fluconazole) 
Antifungal – all systemic 
Prednisolone or equivalent (refer to Section 7.7.2 for details) 
Immunosuppressive therapy 
Strong CYP3A4 inhibitors 
See Study Reference Manual 
St John’s wort 
Herbal, various 
Succinylcholine and other nondepolarizing paralytic agents 
Muscle relaxation, muscle paralysis 
CYP3A4=cytochrome P450 enzyme 3A4. 
a. 
Check within each local country to assess if other generic names apply. 
Note: See also Section 7.7.2 for other prohibited medications. 
Crediblemeds.org Instructions 
Instructions for accessing www.crediblemeds.org and searching for an exclusionary drug 
due to its “Known Risk of Torsades de Pointes (TdP)” category are summarized below.  
To access www.crediblemeds.org, copy and paste this link into the internet search bar: 
https://www.crediblemeds.org/ 
On the main home page, there are 3 search options available. Choose the first option to 
search for 1 drug at a time. Free registration is required by the website.  
 

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Choosing that option brings you to a screen that allows for you to enter a generic or brand 
drug name and choose Search. If it has a Known risk of TdP (i.e., is a prohibited 
exclusionary medication), it will show a red triangle with an exclamation point as shown 
here: 
 
Always check the www.crediblemeds.org website for the most up-to-date information on 
drugs with a Known Risk of TdP for participant safety. 

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12.10. 
Appendix 10: Clostridium Difficile Testing Procedure and 
Algorithm 
 
CRA = clinical research associate (PPD site monitor); SRM = Study Reference Manual 
Note:  This algorithm is subject to investigator discretion when the clinical 
presentation and time course of diarrhea (e.g., during or within 12 hours immediately 
after dosing) do not fit the Clostridium difficile associated diarrhea definition; 
consideration should be given to diarrhea occurring in this early time frame to be 
suggestive of a cholinergic effect. 

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12.11. 
Appendix 11: COVID-19 Protocol Information 
12.11.1. 
Overall Rationale for this Appendix 
The COVID-19 pandemic may impact the conduct of clinical studies. Challenges may 
arise from quarantines, site closures, travel limitations, interruptions to the supply chain 
for the investigational product or other considerations if site personnel or study 
participants become infected with COVID-19. These challenges may lead to difficulties 
in meeting protocol-specified procedures.  
This appendix outlines measures that may be applicable for any study site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. These measures are expected to be temporary and study sites will be notified of 
any change to these allowances as the COVID-19 pandemic evolves. 
12.11.2. 
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: 
• 
For all study visits, to minimize the amount of time that participants spend at the 
clinic, eConsent may be utilized and remote collection of study-related data may be 
obtained as described in the Study Reference Manual. Thus, some visit data may be 
collected through a combination of telemedicine and on-site visits. Collection of 
information via telemedicine will be performed only where local regulations permit. 
• 
Clinical investigators should document in site/participant/source files how 
restrictions related to COVID-19 led to changes in study conduct, the duration of 
those changes, and indicate which trial participants were impacted and how those 
trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance).  
• 
Missing protocol-required data/visits due to COVID-19 should be noted in 
site/participant/source files and recorded as a COVID-19 protocol deviation.  

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

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12.12. 
Appendix 12: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. 
Amendment 2 16 December 2022 
This global amendment is considered to be non-substantial. 
Overall rationale for the current Amendment:  
This global amendment increased the total enrollment sample size; revised and added key 
populations for analyses to support the planned efficacy analyses per the current reporting 
and analysis plan; and removed the covariate age at Baseline from the primary efficacy 
analyses. The amendment includes minor updates to gepotidacin introductory and risk 
text for consistency with the current investigator’s brochure, and revised 
crediblemeds.org instructions for consistency with the current website. The amendment 
also includes minor administrative and wording edits and editorial text additions per the 
current protocol template. 
List of main changes in the protocol and their rationale: 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
5.2 Number of 
Participants 
10.2.1 Justification of 
Sample Size 
Increased the total number of 
enrolled participants from 
approximately 600 to 
approximately 620. 
Based on the microbiological 
evaluability rate, the total sample 
size was increased to ensure the 
number of participants in the 
micro-ITT Population was 
reached.  
10.3 Populations for 
Analyses 
The key populations for analyses 
have been updated and added. 
Revisions were made to support 
the planned efficacy analyses 
per the current reporting and 
analysis plan. 
10.4.2 Efficacy 
Analyses 
Excluded the covariate “Age at 
Baseline” from the primary 
efficacy analyses. Of note, there is 
no change to the randomization 
stratification. 
Based on current enrollment 
projections, there will be an 
insufficient number of 
participants in the <18 and 
>65 years age categories in 
each treatment group at the end 
of the study; thus, the sample 
size in those categories will not 
be sufficient to support the 
primary analysis. 
Section 3 Introduction 
 
Updated gepotidacin text based 
on the investigator’s brochure. 
Revised for consistency with the 
investigator’s brochure. 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 3.3.1 Risk 
Assessment 
Minor text updates were made to 
the QTcF, 
acetylcholinesterase-inhibition, 
and reproduction sections for 
gepotidacin. 
Revised for clarification and 
consistency with current 
investigator’s brochure. 
Section 9 Study 
Assessments and 
Procedures 
The demographic data that is 
collected at the Baseline Visit was 
clarified and rationale text was 
added. 
Information was added per the 
current GSK protocol template. 
12.3 Appendix 3: 
Study Governance 
Considerations 
Clarified that redaction of source 
documents will be performed by 
study sites before documents are 
shared with outside vendors. 
Study Conduct Materials and 
Support subsection was added. 
Information was added per the 
current GSK protocol template. 
12.4 Appendix 4: 
Adverse Events 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow-up, 
and Reporting 
Definition of a treatment-emergent 
adverse event was added. 
Information was added per the 
current GSK protocol template. 
12.9 Appendix 9: 
Additional Guidance 
on Permitted and 
Prohibited 
Medications and 
Crediblemeds.org 
Updated the text and picture to 
indicate free registration is now 
required. 
Revised for consistency with the 
current website. 
Throughout 
Vendor information was added.  
Information was added per the 
current GSK protocol template. 
Throughout 
Minor editorial and document 
formatting revisions, including the 
addition of text per the current 
protocol template. 
Minor, therefore, have not been 
summarized. Updated text added 
per the current GSK protocol 
template provided further 
clarification of the original text. 
Amendment 1 14 December 2021 
This global amendment was considered to be non-substantial. 
Overall Rationale for the Amendment:  
This global amendment revised the primary analysis to be performed using the Miettinen 
and Nurminen method instead of the Cochran-Mantel-Haenszel method; added estimand 

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text; indicated study operational allowances with regard to COVID-19; incorporated past 
administrative and site notification letters; provided minor clarifications to the 
microbiology and NAAT defining criteria in the response and outcomes tables; indicated 
the total enrollment population will be approximately 600 participants; added micro-ITT 
subpopulations for participants with NG isolated in their rectal/pharyngeal specimen; and 
incorporated updates per the most recent safety and PK data known for gepotidacin, 
which included removal of P-glycoprotein inducers from the prohibited medications. 
Minor clarifications were also made throughout the protocol including, but not limited to, 
the Schedule of Activities table, inclusion and exclusion criteria, primary and secondary 
objectives, randomization stratification text, and adverse events of special interest. The 
amendment also includes additional minor administrative and wording edits. 
Summary of changes table of previous amendments: 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
4 Objectives and 
Estimands/Endpoints 
Table 3 Estimands 
Added estimands for the primary 
and secondary objectives and 
endpoints 
To meet current ICH guidelines 
on estimands 
Synopsis 
5.1 Overall Design 
Figure 1 Study Design 
Schematic 
5.4 Scientific 
Rationale for Study 
Design 
7.3 Method of 
Treatment 
Assignment 
10.4.2 Efficacy 
Analyses 
Updated text to clarify that 
participants will be stratified by 
“sex and sexual orientation 
combination” and age 
Text clarification as the 
stratification factor of “gender” 
(i.e., male/female) was 
inadvertently being used 
interchangeably for sex 
characteristics that are 
biologically defined. To avoid 
confusion, the term “sex” will be 
used from this point forward. 
Synopsis 
4 Objectives and 
Estimands/Endpoints 
Removed the analysis population 
(i.e., micro-ITT) from the primary 
and secondary objectives  
Not a requirement in the 
objectives text and the analysis 
populations are further described 
in Section 10 of the protocol 
Synopsis 
5.2 Number of 
Participants 
10.2.1 Justification of 
Sample Size 
Revised the target number of 
randomized participants to 
approximately 600 
To reflect currently known safety 
database requirements for 
regulatory authorities 

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Section # and Name 
Description of Change 
Brief Rationale 
2 Schedule of 
Activities (Table 1) 
Divided the “Interactive response 
technology” row into 2 separate 
rows specific for the screening 
and randomization modules; 
removed the “Randomization” row 
accordingly 
To align with how the interactive 
response is being used at study 
sites and to more closely follow 
the expected order of procedures 
2 Schedule of 
Activities (Table 1) 
5.1 Overall Study 
Design 
9 Study Assessments 
and Procedures 
Appendix 3 Study 
Governance 
Considerations 
Appendix 11 
COVID-19 Protocol 
Information 
Added text and table footnotes to 
allow for eConsent, telemedicine 
study-related data collection, 
collection of visit data as a 
combination of telemedicine and 
on-site visits, remote source data 
verification, and eCRF sign-off 
flexibility for investigators 
To support ongoing study 
conduct from safety and 
operational perspectives during 
the COVID-19 pandemic 
Synopsis 
3.3.3 Overall 
Benefit:Risk 
Conclusion 
5.4 Scientific 
Rationale for Study 
Design 
10.6 Data Monitoring 
Committee or Other 
Review Board 
Appendix 3 Study 
Governance 
Considerations 
Clarified only internal review 
teams will monitor study data 
during the study and that no 
external data monitoring 
committee is planned 
Text clarification 

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Section # and Name 
Description of Change 
Brief Rationale 
2 Schedule of 
Activities (Table 2) 
9.1.2 NAAT Assay 
Clarified that any specimens 
collected for NG NAAT assay at 
the central laboratory for NG 
would also be assayed for CT per 
standard laboratory procedures 
Incorporation of Protocol 
Administration Letter 4 dated 
06-MAY-2020, which addressed 
that CT can cause infection at all 
3 body sites (urogenital, rectal, 
pharyngeal) that are being 
evaluated in this study. Thus, 
when NAAT samples are 
submitted for NG testing, they 
are also routinely tested for CT 
and results are reported for both 
pathogens. 
2 Schedule of 
Activities (Table 2) 
9.1.2 NAAT Assay 
Clarified text and table footnotes 
for the NAAT assay at the 
Follow-up Visit to specify 
pathogens be tested and to refer 
to presence of nucleic acid 
instead of a positive result 
Text clarifications 
3.2 Background 
5.4 Scientific 
Rationale for Study 
Design 
5.5 Dose Justification 
Included text regarding the US 
CDC current standard of care 
treatment recommendations for 
gonococcal infection. Per FDA 
communications, no changes to 
the comparator arm are 
warranted. 
Incorporation of the Site 
Notification Letter dated 
26-JAN-2021 (sent to US-only 
sites), which described the most 
recent US CDC 
recommendations for treatment 
of gonococcal infection 
3.3.1 Risk 
Assessment 
Minor text clarifications for 
gepotidacin (clinical QTc effects, 
added relevant exposures for 
nonclinical embryofetal effects, 
etc.). Note, the risk benefit 
assessment for the study did not 
change. 
Consistency with currently 
known safety and PK data for 
gepotidacin 

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Section # and Name 
Description of Change 
Brief Rationale 
3.3.1 Risk 
Assessment 
6.2 Exclusion Criteria 
#15 
7.7.2 Prohibited 
Medications and 
Nondrug Therapies 
Appendix 9 Additional 
Guidance on 
Permitted and 
Prohibited 
Medications and 
Crediblemeds.org 
Removed exclusion for strong 
P-glycoprotein inhibitors 
Consistency with currently 
known PK data for gepotidacin 
6.1 Inclusion Criteria 
#2 
Figure 1 Study Design 
Schematic 
Revised the criterion to further 
describe what would be 
considered clinical suspicion of a 
urogenital gonococcal infection 
based on investigator feedback  
Incorporation of Protocol 
Administration Letter 2 dated 
30-SEP-2019, which provided 
additional details for expected 
clinical presentation of urogenital 
gonococcal infection 
6.1 Inclusion Criteria 
#4b 
Revised the criterion to state there 
was no requirement for 
contraception use or abstinence 
within 14 days of study entry in 
WOCBP who have a negative 
high sensitivity urine pregnancy 
test result 
Incorporation of Protocol 
Administration Letter 2 dated 
30-SEP-2019, which streamlined 
the criterion text for clarification 
and consistency with Appendix 6  
6.2 Exclusion Criteria 
#3 and #5 
Edited to include “uncontrolled” 
before high blood pressure and 
diabetes 
Text clarification 
6.2 Exclusion Criteria 
#17  
Added details to the exclusion 
criterion note for ECG exclusion 
To support consistency in ECG 
measurements 
7.7 Concomitant 
Therapy 
Clarified that any antibiotic use 
within 6 months of the Baseline 
Visit should be recorded 
To support the study analysis 
9 Study Assessments 
and Procedures 
Removed the requirement for 
participants to remain at the site 
for approximately 30 minutes after 
dosing at the Baseline Visit; 
however, retained text indicating 
that posttreatment assessments 
still need to be completed 
To support site flexibility for 
study conduct  

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Section # and Name 
Description of Change 
Brief Rationale 
9.1.1 Bacteriology 
6Samples for Culture 
Minor text clarifications were 
added to the defining criteria in 
the outcome and response 
Table 5  
Clarification to support the 
planned statistical analyses and 
programming details 
9.1.2 NAAT Assay 
Minor text clarifications were 
added to the defining criteria in 
the outcome and response Table 
6 and Table 7  
Clarification to support the 
planned statistical analyses and 
programming details 
10.2.1 Justification of 
Sample Size 
Clarified the significance level is a 
0.025 one-sided significance level 
rather than a 0.05 two-sided 
significance level, noted the 
estimated power was approximate 
in Table 8, and clarified that no 
treatment difference is assumed 
Text clarifications 
10.2.2 Sample Size 
Sensitivity 
Revised the percentage of power 
in Table 8 for the 92% and 88% 
success rate rows by a single 
digit; removed unnecessary text; 
and clarified that no treatment 
difference is assumed  
Minor text update for consistency 
in rounding the numbers and text 
clarifications 
10.1 Statistical 
Hypothesis 
10.4.2 Efficacy 
Analysis 
Revised the primary analysis to be 
performed using the Miettinen and 
Nurminen method instead of the 
Cochran-Mantel-Haenszel method 
and expanded text to state there 
would be 9 total subgroups based 
on the randomization stratification 
variables  
Consistency with the reporting 
and analysis plan 
10.3 Populations for 
Analyses 
10.4.2 Efficacy 
Analysis 
Added micro-ITT subpopulations 
for participants who have NG 
isolated from the 
rectal/pharyngeal specimen 
To support the planned analysis 
10.5 Interim Analysis 
Clarification that no interim 
analysis is planned 
Text clarification 
Appendix 2 Clinical 
Laboratory Tests 
Added magnesium to the 
laboratory assessments 
Consistency with the chemistry 
laboratory panel that will be 
conducted in the study 

TMF-16433266 
CONFIDENTIAL 
 
 
BTZ116577 
 
116 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 3 Study 
Governance 
Considerations 
Clarified that study participants 
should advise their sexual 
partners of their infection status 
and that it should be documented 
in the medical chart per study site 
staff 
Incorporation of Protocol 
Administration Letter 1 dated 
22-JUL-2019, which supports 
notification of NG infection status 
to sexual partners of study 
participants 
Appendix 3 Study 
Governance 
Considerations 
Clarified that, in countries where 
certain responsibilities reside with 
the sponsor instead of the 
investigator, GSK or its designee 
will be responsible for those 
activities  
To support site feasibility 
Throughout 
Updated the second dose window 
for gepotidacin to 10 to 12 hours 
after the first dose; the original 
second dose window was 6 to 
12 hours 
Incorporation of Protocol 
Administration Letter 3 dated 
12-FEB-2020, which narrowed 
the second dose window for 
gepotidacin for safety reasons 
and to support uniformity in study 
conduct and subsequent data 
analysis. Note: There is no 
evidence this impacts efficacy. 
Throughout 
Updated text to state Clostridium 
difficile and acetylcholinesterase 
inhibition events are considered 
adverse events of special interest 
To support the planned safety 
analysis 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore, have not been 
summarized