A Pharmacokinetic, Multi-cohort Study in Healthy Adult Subjects to Assess Gepotidacin as Victim and as Perpetrator of Drug-Drug Interactions Via CYP450, Renal and Intestinal Transporters, and to Assess Gepotidacin Pharmacokinetics in Japanese Healthy Adults
Phase: PHASE1
Conditions: Infections, Bacterial
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A Pharmacokinetic, multi-cohort study in Healthy Adult Subjects to 
Assess Gepotidacin as Victim and as Perpetrator of Drug-Drug Interactions via CYP450, 
Renal and Intestinal Transporters, and to Assess Gepotidacin Pharmacokinetics in 
Japanese Healthy Adults
Protocol Number: 213678
Compound Number
or Name:
GSK2140944
Brief Title: Drug Interactions between Gepotidacin and Select CYP450, Renal, and 
Intestinal Transporters, and Gepotidacin Pharmacokinetics in Japanese Healthy Adults
Study Phase: Phase I
Sponsor Name and Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Regulatory Agency Identifying Number(s): IND: 111885
Approval Date: 13-JUL-2020
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited.

PPD
PPD
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ......................................................................................................16
1.3.
Schedule of Activities (SoA)........................................................................19
2.
INTRODUCTION....................................................................................................35
2.1.
Study Rationale ..........................................................................................35
2.2.
Background ................................................................................................37
2.3.
Benefit/Risk Assessment ............................................................................37
2.3.1.
Risk Assessment .........................................................................38
2.3.2.
Benefit Assessment.....................................................................47
2.3.3.
Overall Benefit: Risk Conclusion..................................................47
3.
OBJECTIVES AND ENDPOINTS...........................................................................47
4.
STUDY DESIGN ....................................................................................................52
4.1.
Overall Design ............................................................................................52
4.2.
Scientific Rationale for Study Design ..........................................................55
4.3.
Justification for Dose ..................................................................................58
4.4.
End of Study Definition ...............................................................................59
5.
STUDY POPULATION...........................................................................................59
5.1.
Inclusion Criteria.........................................................................................59
5.2.
Exclusion Criteria........................................................................................61
5.3.
Lifestyle Considerations..............................................................................63
5.3.1.
Meals and Dietary Restrictions ....................................................63
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................64
5.3.3.
Activity .........................................................................................64
5.4.
Screen Failures...........................................................................................64
5.5.
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
Administration.............................................................................................64
6.
STUDY INTERVENTIONS AND CONCOMITANT THERAPY................................64
6.1.
Study Interventions Administered ...............................................................65
6.2.
Preparation/Handling/Storage/Accountability..............................................66
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................66
6.4.
Study Intervention Compliance ...................................................................66
6.5.
Dose Modification .......................................................................................67
6.6.
Continued Access to Study Intervention after the End of the Study ............67
6.7.
Treatment of Overdose...............................................................................67
6.8.
Concomitant Therapy..................................................................................68
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................68
7.1.
Discontinuation of Study Intervention..........................................................68
7.1.1.
Liver Chemistry Stopping Criteria ................................................69
7.1.2.
QTc Stopping Criteria ..................................................................69
7.1.3.
Gastrointestinal Evaluation Criteria..............................................70

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7.1.4.
Rash/Hypersensitivity Evaluation Criteria.....................................70
7.1.5.
Temporary Discontinuation ..........................................................70
7.1.6.
Rechallenge.................................................................................70
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................71
7.3.
Lost to Follow-Up........................................................................................71
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................71
8.1.
Efficacy and/or Immunogenicity Assessments ............................................72
8.2.
Safety Assessments ...................................................................................72
8.2.1.
Physical Examinations.................................................................72
8.2.2.
Vital Signs....................................................................................72
8.2.3.
Electrocardiograms......................................................................72
8.2.4.
Clinical Safety Laboratory Assessments ......................................73
8.2.5.
Pregnancy Testing.......................................................................73
8.3.
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting....................................................................................................74
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................74
8.3.2.
Method of Detecting AEs and SAEs.............................................74
8.3.3.
Follow-up of AEs and SAEs.........................................................75
8.3.4.
Regulatory Reporting Requirements for SAEs .............................75
8.3.5.
Pregnancy ...................................................................................75
8.3.6.
Adverse Events of Special Interest ..............................................76
8.4.
Pharmacokinetics .......................................................................................76
8.5.
Genetics and/or Pharmacogenomics ..........................................................76
8.6.
Biomarkers .................................................................................................76
8.7.
Immunogenicity Assessments.....................................................................76
8.8.
Medical Resource Utilization and Health Economics ..................................77
9.
STATISTICAL CONSIDERATIONS........................................................................77
9.1.
Statistical Hypotheses.................................................................................77
9.2.
Sample Size Determination ........................................................................77
9.3.
Analysis Sets..............................................................................................78
9.4.
Statistical Analyses.....................................................................................79
9.4.1.
Pharmacokinetic and Biomarker Analyses...................................79
9.4.2.
Safety Analyses...........................................................................81
9.4.3.
Other Analysis .............................................................................81
9.5.
Interim Analysis ..........................................................................................81
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................82
10.1.
Appendix 1: Abbreviations and Trademarks................................................82
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................85
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................87
10.3.1.
Regulatory and Ethical Considerations ........................................87
10.3.2.
Financial Disclosure.....................................................................87
10.3.3.
Informed Consent Process ..........................................................87
10.3.4.
Data Protection............................................................................88
10.3.5.
Committees Structure ..................................................................89
10.3.6.
Dissemination of Clinical Study Data ...........................................89
10.3.7.
Data Quality Assurance ...............................................................89

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10.3.8.
Source Documents ......................................................................90
10.3.9.
Study and Site Start and Closure.................................................90
10.3.10. Publication Policy.........................................................................91
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................92
10.4.1.
Definition of AE............................................................................92
10.4.2.
Definition of SAE..........................................................................93
10.4.3.
Cardiovascular and Gastrointestinal Events of Special 
Interest ........................................................................................94
10.4.4.
Recording and Follow-Up of AE and SAE....................................94
10.4.5.
Reporting of SAE to GSK.............................................................96
10.5.
Appendix 5: Contraceptive and Barrier Guidance .......................................98
10.5.1.
Definitions:...................................................................................98
10.5.2.
Contraception Guidance: .............................................................99
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................101
10.7.
Appendix 7: Covid-19 ...............................................................................103
10.7.1.
Overall Rationale for this Appendix............................................103
10.7.2.
Study Procedures During COVID-19 Pandemic.........................103
10.7.3.
Protocol Defined Procedures/Visits:...........................................103
10.7.4.
Data Management/Monitoring:...................................................104
10.8.
Appendix 8: Clostridium difficile Testing Procedure and Algorithm............105
10.9.
Appendix 9: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment.........................................106
11. REFERENCES.....................................................................................................113

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Pharmacokinetic, multi-cohort Study in Healthy Adult Subjects to 
Assess Gepotidacin as Victim and as Perpetrator of Drug-Drug Interactions via CYP450, 
Renal and Intestinal Transporters, and to Assess Gepotidacin Pharmacokinetics in 
Japanese Healthy Adults.
Brief Title: Drug Interactions between Gepotidacin and Select CYP450, Renal, and 
Intestinal Transporters, and Gepotidacin Pharmacokinetics in Japanese Healthy Adults
Rationale: The rationale for this study is 2-fold: 1) to determine the magnitude and 
clinical relevance of potential drug-drug interactions (DDIs) and 2) to generate 
pharmacokinetic (PK), safety, and tolerability data in a separate Japanese cohort. Clinical 
PK and safety data generated in Japanese participants will be used to support clinical 
development (uncomplicated urinary tract infections [uUTI] and gonorrhea) in Japan  
and provide additional safety data prior to evaluation of gepotidacin in Japanese patients.
.
Comparisons will be made between Japanese and non-Japanese subjects to characterise 
potential differences in pharmacokinetics across the two groups. 
GlaxoSmithKline (GSK) has conducted in vitro studies and used physiologically-based 
PK (PBPK) modeling to evaluate the DDI potential with gepotidacin. Based on these 
analyses, GSK conducted a risk assessment for gepotidacin as a DDI victim and 
perpetrator: 
1) Gepotidacin is a substrate of MATE and potentially of OCT transporter: Gepotidacin 
renal clearance exceeds glomerular filtration rate by greater than 2-fold, which predicts a 
significant role of tubular secretion in renal elimination. In vitro data suggests that 
gepotidacin is a substrate of MATE and although it does not suggest that gepotidacin is a 
substrate of the currently known OCTs, MATE transporters are usually coupled with 
OCTs. For the uUTI and gonorrhea indications, the DDI risk included the potential 
increased plasma gepotidacin exposure (may lead to safety implications). For the uUTI 
indication, there is an added potential risk for reduced gepotidacin urine levels (may 
translate to a loss of uUTI efficacy); 
2) Gepotidacin is a CYP3A4 substrate: Potential cytochrome P450 (CYP)3A4 induction 
could result in enhanced gepotidacin metabolism, reducing its exposure, which could also 
lead to lack of efficacy in both gonorrhea and uUTI; 
3) Gepotidacin is a P-gp inhibitor: At the high dose (3000 mg, 2 doses given 12 hours 
apart) for the gonorrhea indication, gepotidacin might inhibit P-glycoprotein (P-gp) at the 
gut level, potentially increasing the exposure of P-gp substrates that could impact
substrate-driven safety. 

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4) Gepotidacin is a CYP3A4 inhibitor: Potential inhibition of CYP3A4 enzyme by 
gepotidacin (perpetrator) at both doses for gonorrhea and uUTI may enhance substrate 
exposure, possibly impacting safety for both indications. 
The DDI observations generated from this study will inform the gepotidacin drug label.
Objectives and Endpoints:
A summary of study cohorts 1-4 can be found in Table 14.
Objectives
Endpoints
Primary
Cohort 1: Gepotidacin is a substrate of MATE and 
potentially of OCT transporter

To characterize the drug-drug interaction 
(DDI) effect of repeat oral dosing of cimetidine 
on the pharmacokinetics (PK) of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Cmax, Tmax, t1/2, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Cohort 2: Gepotidacin is a CYP3A4 substrate

To characterize the DDI effect of repeat oral 
dosing of rifampicin on the PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Cohort 3: Gepotidacin is a P-gp and CYP3A4 
inhibitor

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart 
given with food on the PK for co-administered 
drugs digoxin and midazolam in an adult 
healthy population

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of digoxin and midazolam in plasma, as data 
permit
Cohort 4: Japanese PK

To assess the PK, safety, and tolerability of a 
single 1500 mg dose of gepotidacin under fed 
and fasted states, and two 3000 mg doses of 
gepotidacin given 12 hours apart under fed 
state in Japanese adult participants 

Cmax, Tmax, AUC(0-24), AUC(0-48),
AUC(0-t), and AUC(0-) of gepotidacin in 
plasma following a single 1500 mg dose, as 
data permit

Cmax, Tmax, and AUC(0-) of gepotidacin 
after the first dose; AUC(0-), Cmax, Tmax,
RoCmax, and RoAUC of gepotidacin after the 
second dose; AUC(0-24), AUC(0-48), and 
AUC(0-t) of gepotidacin using the full profile 

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Objectives
Endpoints

To evaluate the effect of a Japanese meal on 
the bioavailability of the gepotidacin tablet 
formulation
(both doses) following two 3000 mg doses, as 
data permit

Adverse events (AEs), clinical laboratory tests, 
vital signs (systolic and diastolic blood 
pressure and heart rate), and 12-lead 
electrocardiogram (ECG) readings

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Secondary
Cohort 1

To characterize the plasma PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

AUC(0-24), AUC(0-48), Tlag, Vz/F, and CL/F 
of gepotidacin in plasma after a single 
1500 mg dose of gepotidacin, as data permit

To characterize the DDI effect of repeat oral 
dosing of cimetidine on the urine PK of a 
single 1500 mg oral dose of gepotidacin given 
with food in an adult healthy population

To characterize the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Ae total, AUC(0-24), AUC(0-48), and CLr of 
gepotidacin in urine following a single 1500 
mg dose, as data permit

Ae(t1-t2) and fe% of gepotidacin in urine 
following a single 1500 mg dose, as data 
permit

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings

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Objectives
Endpoints
Cohort 2

To characterize the plasma PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To characterize the DDI effect of repeat oral 
dosing of rifampicin on the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To characterize the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

AUC(0-24), AUC(0-48), t1/2, Vz/F, and CL/F 
of gepotidacin in plasma after a single 
1500 mg dose of gepotidacin, as data permit

Ae total, AUC(0-24), AUC(0-48), and CLr of 
gepotidacin in urine following a single 1500 
mg dose, as data permit

Ae(t1-t2) and fe% of gepotidacin in urine 
following a single 1500 mg dose, as data 
permit

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings
Cohort 3

To characterize the plasma PK of gepotidacin 
two 3000 mg doses given 12 hours apart with 
food in an adult healthy population

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart with 
food on the PK of co-administered drugs 
digoxin and midazolam in an adult healthy 
population

To characterize the urine PK of gepotidacin 
(two 3000 mg doses given 12 hours apart) 
given with food in an adult healthy population

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

Cmax, Tmax, Tlag, AUC(0-) of gepotidacin 
after the first dose; Cmax, Tmax, AUC(0-), 
RoCmax, and RoAUC of gepotidacin after the 
second dose; AUC(0-24), AUC(0-48), 
AUC(0-t), Vz/F, CL/F, and t1/2 of gepotidacin 
using the full profile (both doses), as data 
permit

Cmin, t1/2, Vz/F, and CL/F of digoxin and 
midazolam in plasma, as data permit

Ae total, Ae(t1-t2), AUC(0-), AUC(0-24), 
AUC(0-48), fe%, and CLr of gepotidacin in 
urine following two 3000 mg doses, as data 
permit

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings

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Objectives
Endpoints
Cohort 4

To characterize the PK of a single 1500 mg 
oral dose of gepotidacin given with and 
without food in Japanese adult healthy 
participants

To assess the plasma PK of two 3000 mg 
doses of gepotidacin given 12 hours apart with 
food in Japanese adult healthy participants

To assess the urine PK of a single 1500 mg 
dose or two 3000 mg doses of gepotidacin 
given 12 hours apart with food in Japanese 
adult healthy participants

t1/2, Vz/F, and CL/F of gepotidacin in plasma 
after a single 1500 mg dose of gepotidacin, as 
data permit

Tlag of gepotidacin after the first dose; Vz/F,
CL/F, and t1/2 of gepotidacin using the full 
profile (both doses) following two 3000 mg 
doses, as data permit

Ae total, Ae(t1-t2), AUC(0-), AUC(0-24), 
AUC(0-48), fe%, and CLr of gepotidacin in 
urine following a single 1500 mg dose and two 
3000 mg doses, as data permit
Exploratory
Cohort 1

To characterize the DDI effect of repeat oral 
dosing of cimetidine on the PK of plasma and 
urine for N1-methylnicotinamide (1-NMN) 
biomarker in adult healthy participants

To evaluate concentrations of serum and urine 
creatinine after administration of gepotidacin 
with and without cimetidine in adult healthy 
participants

To evaluate cimetidine PK to assess 
transporter inhibition in adult healthy 
participants

C average, Cmax, Ctrough, AUC(0-24), 
AUC(0-48), and AUC(0-t) of 1-NMN in plasma, 
as data permit 

Ae total and CLr of 1-NMN in urine, as data 
permit

1-NMN plasma and urine PK parameters 
normalized to creatinine, as data permit

Serum and urine creatinine concentrations, as 
data permit

1-NMN plasma and urine PK parameters 
normalized to creatinine, as data permit

Cimetidine plasma PK concentrations, as data 
permit

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Objectives
Endpoints
Cohort 3

To evaluate the plasma PK for the metabolite 
1’-hydroxymidazolam

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart 
given with food on the urine PK of co-
administered digoxin in an adult healthy 
population

Cmin, Cmax, Tmax, t1/2, AUC(0-t), and 
AUC(0-) of 1’-hydroxymidazolam in plasma, 
as data permit

Molecular weight normalized 
parent-to-metabolite AUC(0-) ratio, as data 
permit

Ae total, fe%, and CLr of digoxin in urine
following a single 1500 mg dose, as data 
permit
Cohort 4

To compare the plasma and urine PK of 
gepotidacin 1500 mg single dose (SD) data 
from the Cohort 4 Japanese versus the 
gepotidacin-only 1500 mg SD data the DDI 
Cohorts in adult (non-Japanese) healthy 
participants

To compare the plasma and urine PK of 
gepotidacin 3000 mg twice daily data from the 
Cohort 4 Japanese versus the Cohort 3 
gepotidacin 3000 mg twice daily data in adult 
(non-Japanese) healthy participants

Plasma and urine concentrations and 
parameters for gepotidacin, as data permit

Plasma and urine concentrations and 
parameters for gepotidacin, as data permit
Cohorts 1, 2, 3, and 4

To determine the effect of gepotidacin 
concentrations on the QT interval corrected 
with Fridericia’s method (QTcF) in adult 
healthy participants

Change from Baseline in QTcF versus 
gepotidacin concentration

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Overall Design: This study is a Phase I, DDI, PK, safety, and tolerability study in 
healthy adult participants, including a Japanese cohort, to be conducted at 1 center in the 
United States. This study is designed to assess co-administration of probe substrates with 
gepotidacin in study Cohorts 1 to 3 and establishing PK and safety in a Japanese cohort in 
Cohort 4. 
In all Cohorts, participants will be screened within 28 days before the first dose of study 
intervention.
Cohort 1: Cohort 1 is an open-label, fixed sequence DDI study to investigate the effect
of cimetidine (OCT/MATE inhibitor) on the PK of gepotidacin under fed conditions. 
Participants will receive the treatments in a fixed sequence: gepotidacin 1500 mg on Day 
1 (Treatment A) of Period 1, followed by cimetidine 400 mg 4 times daily on Days 1
through 4 (Treatment B) of Period 2. Gepotidacin 1500 mg will be administered 1 hour 
after the first dose of cimetidine on Day 2 of Period 2. On Day 4 of Period 2, cimetidine 
dosing will be discontinued after the last PK sample is collected. There will be a washout 
of at least 3 days after dosing with gepotidacin in Period 1. A follow-up visit will occur 
5 to 7 days after the last dose of cimetidine.
Participants will receive a standard meal 30 minutes prior to dosing. Participants will eat 
this meal in 30 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption. Participants will not receive any further food until at 
least 2 hours after gepotidacin dosing.
Pharmacokinetic blood and urine samples for analysis of gepotidacin, creatinine, and the 
endogenous biomarker N1-methylnicotinamide (1-NMN) will be obtained at 
pre-specified time points, and sparse blood samples will be collected for cimetidine after 
dosing at pre-specified time points. Safety and tolerability will be assessed by monitoring 
and recording of adverse events (AEs), clinical laboratory test results, vital sign 
measurements, 12-lead electrocardiogram (ECG) results, and physical examination 
findings.
Cohort 2: Cohort 2 is an open-label, fixed sequence DDI to investigate the effect of 
rifampicin (CYP3A4 inducer) on the PK of gepotidacin under fed conditions. Participants 
will receive the following treatments in a fixed sequence: gepotidacin 1500 mg single 
dose (SD) on Day 1 of Period 1 (Treatment C); rifampicin 600 mg (administered in the 
evenings) once daily for 7 days (to elicit maximal enzyme induction) on Days 1 through 
7 of Period 2 (Treatment D); and gepotidacin 1500 mg SD administered in the morning 
on Day 8 of Period 2 with rifampicin 600 mg administered in the evening on Days 8 and 
9 of Period 2 (Treatment E). There will be a washout of at least 3 days after gepotidacin
dosing in Period 1. A follow-up visit will occur 7 to 10 days after the last dose of 
rifampicin in Period 2.
The participants will receive a standard meal 30 minutes prior to dosing. Participants will 
eat this meal in 30 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption. Participants will not receive any further food until at 
least 2 hours after gepotidacin dosing. Rifampicin will be administered 1 hour before the 
evening meal.

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Pharmacokinetic blood and urine samples of gepotidacin will be obtained at pre-specified 
time points before and after dosing. Safety and tolerability will be assessed by monitoring 
and recording of AEs, clinical laboratory test results, vital sign measurements, 12-lead 
ECG results, and physical examination findings.
Cohort 3: Cohort 3 is an open-label, 2-sequence, 2-period crossover randomized DDI 
study to investigate the effect of gepotidacin on the PK of the 2 probe substrates digoxin
(P-gp substrate) and midazolam (CYP3A4 substrate) under fed conditions. Participants 
will be randomized to 1 of 2 treatment sequences in a 1:1 ratio. In Sequence 1, 
participants will receive digoxin 0.5 mg and midazolam 2 mg (Treatment F) in Period 1 
then two doses of gepotidacin up to 3000 mg  (given 12 hours apart) co-administered 
with digoxin 0.5 mg and midazolam 2 mg in Period 2, with the 2 probe drugs
administered with the second daily dose of gepotidacin only (Treatment G). In Sequence 
2, these regimens are reversed. There will be a washout of at least 10 days between 
Period 1 and 2. A follow-up visit will occur 7 to 10 days after the last dose of study 
intervention (to ensure clearance of digoxin) in Period 2. 
The participants will receive a standard meal 30 minutes prior to dosing (similar in 
calorie content and similar ratios of protein, carbohydrates, and fat as the previous meal).
Participants will eat this meal in 30 minutes or less. All dose administration will occur 
within 5 minutes of completion of meal consumption. Participants will not receive any 
further food until at least 2 hours after dosing.
Pharmacokinetic blood samples for analysis of gepotidacin, midazolam, 
1’-hydroxymidazolam, and digoxin, and urine samples for gepotidacin and digoxin PK
will be obtained at pre-specified time points before and after dosing. Safety and 
tolerability will be assessed by monitoring and recording of AEs, clinical laboratory test 
results, vital sign measurements, pulse oximetry, 12-lead ECG results, Holter monitoring, 
and physical examination findings.
Cohort 4: Cohort 4 is a double-blind, placebo-controlled, randomized sequence 
(Periods 1 and 2 only) study to investigate the safety and PK of gepotidacin under fed and 
fasted conditions in Japanese participants. Participants will be randomly assigned 
(10 active:2 placebo) to receive gepotidacin or placebo. Within each treatment group, 
participants will be randomized to each of the 2 sequences in 1:1 ratio: HIJ versus IHJ (to 
elucidate the food effect). In Sequence 1, participants will receive a SD of gepotidacin 
1500 mg or placebo under fed conditions in Period 1 (Treatment H), then a SD of 
gepotidacin 1500 mg or placebo under fasted conditions in Period 2 (Treatment I), 
followed by two doses of gepotidacin up to 3000 mg or placebo (given 12 hours apart) 
under fed conditions in Period 3 (Treatment J). In Sequence 2, the first 2 treatments are
reversed (Sequence IHJ). There will be a washout of at least 3 days between each 
treatment. A follow-up visit will occur 5 to 7 days after the last dose of gepotidacin or 
placebo.
Participants receiving Treatments H and J will receive a standard meal 30 minutes prior
to dosing. Participants will eat this meal in 30 minutes or less. Dose administration will 
occur within 5 minutes of completion of meal consumption. Participants receiving 

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Treatment I will fast overnight for at least 8 hours prior to dosing. Participants will not 
receive any food until at least 2 hours after dosing.
Pharmacokinetic blood and urine samples for analysis of gepotidacin will be obtained at 
pre-specified time points before and after dosing. Safety and tolerability will be assessed 
by monitoring and recording of AEs, clinical laboratory test results, vital sign 
measurements, 12-lead ECG results, Holter monitoring (Period 3 only), and physical 
examination findings.
Brief Summary: The purpose of this study to determine potential gepotidacin DDIs and 
to generate PK, safety, and tolerability data in a Japanese cohort. Study details include:
Study duration: The duration (including screening) for Cohort 1 is up to 42 days, for 
Cohort 2 up to 50 days, for Cohort 3 up to 50 days, and for Cohort 4 up to 44 days.
Treatment duration: For Cohort 1, two study treatments will be given over 7 days 
(including a 3-day washout); for Cohort 2, two study treatments will be given over the 
course of 12 days (including a 3-day washout); for Cohort 3, two study treatments will be 
given over the course of 11 days (including a 10-day washout), and for Cohort 4, 
three study treatments will be given over the course of a minimum of  9 days (including a 
3-day washout between each treatment).
Visit frequency: Continuous confinement during treatment.
Number of Participants: Approximately 14 participants will be recruited for Cohort 1, 
2, and 4 to ensure that each Cohort has at least 12 completers, allowing for up to 20% 
withdrawal rate. Participants in the Japanese Cohort will be randomly assigned 
(10 active:2 placebo) to receive gepotidacin or placebo, ensuring at least 10 participants 
in the gepotidacin Cohort. For Cohort 3, 22 participants will be enrolled to achieve at 
least 18 completers to accommodate the narrower therapeutic window of digoxin. If 
participants prematurely discontinue the study, additional participants may be enrolled 
after consultation with the Sponsor to ensure that the required number of evaluable 
participants complete each Cohort of the study.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
Intervention Groups and Duration:
Cohort 1: Participants in Cohort 1 will receive the following study treatments in a fixed 
sequence (Sequence AB):

Treatment A: Gepotidacin 1500 mg SD on Day 1 of Period 1.

Treatment B: Cimetidine 400 mg 4 times daily Days 1 through 4 of Period 2 and 
gepotidacin 1500 mg SD. Gepotidacin will be administered 1 hour after the first 
dose of cimetidine on Day 2 of Period 2 (gepotidacin administration is delayed 

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for 1 hour due to the changes in gastric pH by cimetidine that could impact 
gepotidacin dissolution and absorption). On Day 4 of Period 2, cimetidine 
dosing will be discontinued after the last PK sample is collected.
Including screening, a washout of at least 3 days between Treatment A and Treatment B,
and a follow-up visit 5 to 7 days after the last dose of cimetidine, the total duration of 
Cohort 1 is up to 42 days.
Cohort 2: Participants in Cohort 2 will receive the following study treatments in a fixed 
sequence (Sequence CDE):

Treatment C: Gepotidacin 1500 mg SD on Day 1 of Period 1.

Treatment D: Rifampicin 600 mg (administered in the evenings) once daily for 
7 days (Days 1 through 7) in Period 2.

Treatment E: Gepotidacin 1500 mg SD administered in the morning on Day 8
and rifampicin 600 mg administered in the evening on Days 8 and 9 in Period 2.
Including screening, a washout of at least 3 days between Treatment C and Treatment D, 
and a follow-up visit 7 to 10 days after the last dose of rifampicin, the total duration of 
Cohort 2 is up to 50 days.
Cohort 3: Participants in Cohort 3 will receive the following study treatments in a 
randomized sequence (Sequence FG or Sequence GF):

Treatment F: Digoxin 0.5 mg and midazolam 2 mg on Day 1.

Treatment G: Gepotidacin two 3000 mg doses (given 12 hours apart) on Day 1 
with digoxin 0.5 mg and midazolam 2 mg given with the second gepotidacin 
dose on Day 1.
Including screening, a washout of at least 10 days between treatments, and a follow-up 
visit 7 to 10 days after the last dose of study treatment, the total duration of Cohort 3 is up 
to 50 days.
Cohort 4: Participants in Cohort 4 will receive the following study treatments in a 
randomized sequence (Sequence HIJ or Sequence IHJ):

Treatment H: Gepotidacin 1500 mg or placebo SD under fed conditions on Day 
1.

Treatment I: Gepotidacin 1500 mg or placebo SD under fasted conditions on 
Day 1.

Treatment J: Two doses of gepotidacin up to 3000 mg (given 12 hours apart) 
under fed conditions on Day 1.
Including screening, a washout of at least 3 days between each treatment, and a follow-up 
visit 5 to 7 days after the last dose of gepotidacin, the total duration of Cohort 4 is up to 
44 days.
Data Monitoring/ Other Committee: No

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1.2.
Schema
The overall study designs for DDI Cohorts 1, 2, and 3, and for PK and safety in Japanese 
participants Cohort 4 are summarized in Figure 1, Figure 2, Figure 3, and Figure 4, 
respectively.
Figure 1
Cohort 1 (Gepotidacin and Cimetidine) Study Design Schematic
PK = pharmacokinetic; QID = 4 times daily; SD = single dose.
There will be a washout of at least 3 days after dosing of gepotidacin in Period 1.
Figure 2
Cohort 2 (Gepotidacin and Rifampicin) Study Design Schematic
PK = pharmacokinetic; QD = once daily; SD = single dose.
There will be a washout of at least 3 days after dosing of gepotidacin in Period 1.
1
2
3
1
Gepodacin 1500 mg SD
2
3
4
Follow-up 
7-10 days 
a er last 
dose of 
rifampicin 
Period 1
Period 2
Gepodacin 1500 mg SD 
dosed in the morning
Rifampicin 600 mg QD
dosed in evening
PK Sampling
6
5
7
8
9
10
PK Sampling
1
2
3
1
Gepodacin 1500 mg SD
2
3
4
Follow-up 
5 to 7 days 
a er last dose 
of cimedine
Period 1
Period 2
Gepodacin 1500 mg SD (1 hour a er 
ﬁrst dose of Cimedine on Day 2 of Period 2)
Cimedine 400 mg QID
(Disconnued a er ﬁnal PK 
sample on Day 4 of Period 2
PK Sampling
PK Sampling

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Figure 3
Cohort 3 (Gepotidacin, Digoxin, and Midazolam) Study Design 
Schematic
h = hour; PK = pharmacokinetic; SD = single dose; W = washout.
1
There will be a washout of at least 10 days between treatments.
1
2
3
1
2
3
4
Follow-up 
7 to 10 days 
a er last 
dose
Period 1
Period 2
Gepodacin 3000 mg 2 doses 12h apart
Midazolam 2 mg SD
Digoxin 0.5 mg SD
4
With second daily dose of Gepodacin:
Midazolam 2 mg SD
Digoxin 0.5 mg SD
Randomizaon
1
2
3
4
Gepodacin 3000 mg 2 doses 12h apart
With second daily dose of Gepodacin:
Midazolam 2 mg SD
Digoxin 0.5 mg SD
1
2
3
Midazolam 2 mg SD
Digoxin 0.5 mg SD
4
5
PK Sampling
5
PK Sampling
5
5
PK Sampling
PK Sampling
W1
W1

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Figure 4
Cohort 4 (Japanese Cohort) Study Design Schematic
h = hour; PK = pharmacokinetic; SD = single dose; W = washout.
1.There will be a washout of at least 3 days between each treatment.
1
2
3
Gepodacin 1500 mg 
or placebo SD under 
fed condions
1
2
3
Follow-up 
5 to 7 days  
a er last 
dose
Period 1
Period 2
PK Sampling
1
2
3
Period 3
PK Sampling
Gepodacin 1500 mg 
or placebo SD under 
fasted condions
1
2
3
Gepodacin 1500 mg 
or placebo SD under 
fasted condions
1
2
3
Gepodacin 1500 mg 
or placebo SD under 
fed condions
PK Sampling
Randomizaon
PK Sampling
Gepodacin up to 3000 mg or placebo 
2 doses 12h apart under fed condions
PK Sampling
W1
W1
W1
W1

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1.3.
Schedule of Activities (SoA)

The timing of planned study assessments may change during the course of the 
study based on emerging data/in-stream data review (e.g., to obtain data closer to 
the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing of time points for any planned study assessments as the 
result of emerging pharmacokinetic PK/pharmacodynamic (PD) data from this 
study must be documented and approved by the relevant study team member and 
then archived in the Sponsor and site study files but will not constitute a protocol 
amendment.

The Competent Authority (CA) and ethics committee (EC) will be informed of 
any safety issues that constitute a substantial amendment and require alteration of 
the safety monitoring scheme or amendment of the informed consent form (ICF). 
The changes will be approved by the CA and the EC before implementation.
Table 1
Screening Visit - All Cohorts
Procedure
Screening (up to 28 
days before Day -1)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Complete physical examination including height and weight1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
Screening for COVID-192
X
12-lead electrocardiogram4
X
Vital sign measurements3
X
Medication/drug/alcohol history
X
Past and current medical conditions
X
Serum pregnancy test
X
Follicle-stimulating hormone (as needed, to confirm postmenopausal status)
X
Drug, alcohol, and cotinine screen
X
HIV, Hepatitis B and C screening
X
Serious adverse event review
X
HIV = human immunodeficiency virus.
1
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal (GI), and neurological systems.
2
COVID 19 Testing will be done according to site procedures.
3
Respiratory rate and temperature collected at Screening only.
4
Single ECG

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Table 2
Schedule of Activities - Cohort 1 (Gepotidacin and Cimetidine)
Procedure1
Check-
in
Period 1 (Days)
Period 2 (Days)
Early 
Termination
Follow-up
Notes
–1
1
2
3
1
2
3
4
–
5-7 Days After 
Last Cimetidine 
Dose
In-house stay
X
X
X
X
X
X
X
X
Discharge after last scheduled 
assessment on Day 4.
Inclusion and exclusion criteria
X
Brief physical examination2
X
X
X
X
Urine pregnancy test
X
X
Refer to Section 8.2.5 –
pregnancy testing for instruction 
on time points.
Drug, alcohol, and cotinine 
screen
X
See Table 16.
Laboratory assessments
X
X
X
X
X
See Table 16. 
12-lead ECG3
X
X
X
X
X
X
X
X
X
X
See Table 3 and Table 4 for 
timing of assessments.
Vital signs
X
X
X
X
X
X
X
X
X
X
See Table 3 and Table 4 for 
timing of assessments.
Gepotidacin administration
(victim)
X
X
1500 mg SD. Period 2 Day 2 
dose given 1 hour after first 
cimetidine dose of the day.

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Procedure1
Check-
in
Period 1 (Days)
Period 2 (Days)
Early 
Termination
Follow-up
Notes
–1
1
2
3
1
2
3
4
–
5-7 Days After 
Last Cimetidine 
Dose
Cimetidine administration 
(perpetrator)
X
X
X
X
400 mg 4 times daily. Cimetidine 
dosing on Day 4 will be 
discontinued after the last PK 
sample is collected.
Blood collection for PK
X
X
X
X
X
X
See Table 3 and Table 4 for 
timing of assessments.
Urine collection for PK
X
X
X
X
X
X
See Table 3 and Table 4 for 
timing of assessments.
AE review
================================
X
X
SAE review
X
================================
X
X
Concomitant medication 
review
X
================================
X
X
AE = adverse event; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; SD = Single dose. 
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
3
Triplicate 12-lead ECGs will be measured on Pre-dose and Single ECGs on Day -1 and at all other timepoints 

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Table 3
Safety and Pharmacokinetic Assessments - Cohort 1 (Relative to Gepotidacin) Period 1
Procedure1
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
24
36
48
Gepotidacin 1500 mg administration
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Gepotidacin PK blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gepotidacin PK urine sample3
X
X
X
X
X
X
X
X
X
Serum creatinine
X4
X
X
X
Urine creatinine3
X4
X
X
X
X
X
X
X
X
N1-methylnicotinamide blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
N1-methylnicotinamide urine sample3
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after 
gepotidacin administration.
4
This pre-dose serum and urine creatinine to be drawn with Day -1 labs

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Table 4
Safety and Pharmacokinetic Assessments - Cohort 1 (Relative to Gepotidacin) Period 2
Procedure1
Time point (hours)
-1 Gepotidacin 
Pre-dose
0
0.5
1
1.5
2
2.5
3
4
5
6
8
11 12 17 23 24
29
35
36
41
47 48
Relative to gepotidacin
(Period 2/Day 2)
Gepotidacin 1500 mg administration
X
Cimetidine 400 mg QID administration
X
X
X
X
X
X
X
X
X
12-lead ECG
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Gepotidacin PK blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gepotidacin PK urine sample2
X
X
X
X
X
X
X
X
X
Cimetidine blood PK sample
X
X3
X4
Serum creatinine
X
X
X
X3
X4
Urine creatinine2
X
X
X
X
X
X
X
X
X
N1-methylnicotinamide blood sample 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
N1-methylnicotinamide urine sample2
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic; QID = 4 times daily.
1
When coinciding with safety and/or PK assessments, Electrocardiograms, vital signs, and PK blood collections should be performed in said order.
2
Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after 
gepotidacin administration.
3
This PK sample is equivalent to 25 hours after the first dose of cimetidine on Day 2 of Period 2.
4
This PK sample is equivalent to 49 hours after the first dose of cimetidine on Day 2 of Period 2.
5
Triplicate ECGs at pre-dose Period 2

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Table 5
Schedule of Activities - Cohort 2 (Gepotidacin and Rifampicin)
Procedure1
Check
-in
Period 1 (Days)
Period 2 (Days)
Follow-up
Notes
–1
1
2
3
1
2
3
4
5
6
7
8
9
10
Early 
Termination
7-10 Days 
After Last 
Dose of 
Rifampicin
In-house stay
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion and 
exclusion criteria
X
Brief physical 
examination2
X
X
X
X
Urine pregnancy 
test
X
X
Refer to Section 8.2.5 –
pregnancy testing for 
instruction on time 
points.
Drug, alcohol, and 
cotinine screen
X
See Table 16. 
Laboratory 
assessments
X
X
X
X
X
X
See Table 16.
12-lead ECG3
X
X
X
X
X
X
X
X
X
See Table 6 for timing of 
assessments.
Vital signs
X
X
X
X
X
X
X
X
X
See Table 6 for timing of 
assessments.
Gepotidacin 
administration 
(victim)
X
X
1500 mg SD in the 
morning.

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Procedure1
Check
-in
Period 1 (Days)
Period 2 (Days)
Follow-up
Notes
–1
1
2
3
1
2
3
4
5
6
7
8
9
10
Early 
Termination
7-10 Days 
After Last 
Dose of 
Rifampicin
Rifampicin 
administration 
(perpetrator)
X
X
X
X
X
X
X
X
X
600 mg once daily in the 
evening.
Blood collection for 
gepotidacin PK
X
X
X
X
X
X
See Table 6 for timing of 
assessments.
Urine collection for 
gepotidacin PK
X
X
X
X
X
X
See Table 6 for timing of 
assessments.
AE review
============================================================
X
SAE review
X
============================================================
X
Concomitant 
medication review
X
============================================================
X
AE = adverse event; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; SD = single dose.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
3
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.

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Table 6
Safety and Pharmacokinetic Assessments - Cohort 2 (Gepotidacin and Rifampicin) Period 1 and Period 2
Procedure1
Time Point (Hours)
Pre-dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
24
36
48
Gepotidacin 1500 mg administration
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Gepotidacin PK blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gepotidacin PK urine sample3
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after 
gepotidacin administration.

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Table 7
Schedule of Activities - Cohort 3 (Gepotidacin, Digoxin, and Midazolam)
Procedure1
Check
-in
Period 1 or Period 22
(Days)
W
Period 1 or Period 22
(Days)
Early 
Termination
Follow-up
Notes
–13
1
2
3
4
5
6-10
1
2
3
4
5
–
7-10 Days 
After Last 
Dose
In-house stay
X
X
X
X
X
X
X
X
X
X
X
X
Participants should remain confined
during the washout after Period 1. If
there is an urgent need to leave the 
clinic, allowable furlough will be 
determined on a case-by-case 
basis with approval from the 
investigator.
Inclusion and 
exclusion criteria
X
Recheck clinical status before study 
intervention if participant is 
furloughed between periods.
Brief physical 
examination4
X
D10
X
X
X
Urine pregnancy 
test
X
X
Refer to Section 8.2.5 – pregnancy 
testing for instruction on time points.
Drug, alcohol, 
and cotinine 
screen
X
See Table 16.
Laboratory 
assessments
X
D10
X
X
X
See Table 16.
12-lead ECG5
X
X
X
X
D10
X
X
X
X
X
See Table 8 and Table 9 for timing 
of assessments.
Holter ECG 
monitoring
X
X
D10
X
See Table 8 and Table 9 for timing 
of assessments.
Vital signs
X
X
X
X
D10
X
X
X
X
See Table 8 and Table 9 for timing 
of assessments.

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Procedure1
Check
-in
Period 1 or Period 22
(Days)
W
Period 1 or Period 22
(Days)
Early 
Termination
Follow-up
Notes
–13
1
2
3
4
5
6-10
1
2
3
4
5
–
7-10 Days 
After Last 
Dose
Randomization6
X
On Day -1 of Period 1 only; day 
prior to first dose of study 
intervention.
Pulse oximetry
X
X
See Table 8 for timing of 
assessments.
Gepotidacin 
administration 
(perpetrator)
X
3000 mg twice daily, approximately 
12 hours apart.
Probe drug 
administration -
digoxin and 
midazolam
(victims)
X
X
Digoxin 0.5 mg and midazolam 
2 mg. Probe drugs are dosed with 
second daily dose of gepotidacin 
during the coadministration period.
Blood collection 
for PK
X
X
X
X
X
X
X
X
X
X
See Table 8 and Table 9 for timing 
of assessments.
Urine collection 
for PK
X
X
X
X
X
X
X
X
X
X
AE review
===========================================
X
X
SAE review
X
===========================================
X
X
Concomitant 
medication 
review
X
===========================================
X
X
AE = adverse event; D10 = Day 10; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event; W = washout. 
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Actual period depends on which sequence participant is randomized to.
3
Check-in procedures necessary for Period 2 only if participant is furloughed from the clinic between treatment periods.
4
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
5
Triplicate 12-lead ECGs will be measured on Pre-dose and Single ECGs on Day -1 and at all other timepoints 
6
Participants will be randomized to a sequence on Day -1 of Period 1 only.

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Table 8
Safety and Pharmacokinetics Assessments - Cohort 3 (Relative to Digoxin and Midazolam) Period 1 and Period 2
Procedure1
Time point (hours)
Pre-dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
14
16
18
20
24
36
48 60 72 96
Digoxin 0.5 mg and midazolam 2 mg 
administration
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Holter ECG monitoring3
=======================================================
Vital signs
X
X
X
X
X
X
X
X
X
X
Pulse oximetry
X
X
X
X
X
X
X
X
X
Digoxin PK blood sample4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Digoxin PK urine sample4, 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Midazolam and 1’-hydroxymidazolam PK 
blood sample 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
When the probe drugs are given alone, Holter ECG monitoring will start 12 hours prior to probe dosing and continue until 10 hours after dosing.
4
Pre-dose blood and urine PK sample for digoxin should be taken no more than 2 hours before the dose. 
5
Digoxin urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 
20 hours, 20 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 to 60 hours, 60 to 72 hours, and 72 to 96 hours after digoxin administration.

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Table 9
Safety and Pharmacokinetic Assessments - Cohort 3 (Relative to Gepotidacin) Period 1 or Period 2
Procedure1
Time point (hours)
Pre-
dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
12.5
13
13.5
14
14.5
15
16
18
20
24
36
48
60
Gepotidacin 3000 mg 
administration
X
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Holter ECG monitoring3
=================================================================================================
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood PK sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sample4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
Holter ECG monitoring will start 12 hours prior to the first dose of gepotidacin and continue until 24 hours after the first dose of gepotidacin.
4
Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 
20 to 24 hours, 24 to 36 hours, 36 to 48 hours, and 48 to 60 hours after gepotidacin administration.

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Table 10
Schedule of Activities - Cohort 4 (Japanese Cohort)
Procedure1
Check-
in
Period 1 or Period 22
Period 3
Early 
Termination
Follow-up Visit
Notes
–1
1
2
3
1
2
3
–
5-7 Days After 
Last Dose
In-house stay
X
X
X
X
X
X
X
Washout of at least 3 days 
between dosing in each period.
Inclusion and exclusion criteria
X
Brief physical examination3
X
X
X
X
Urine pregnancy test
X
X
Refer to Section 8.2.5 – pregnancy 
testing for instruction on time 
points.
Drug, alcohol, and cotinine 
screen
X
See Table 16.
Laboratory assessments
X
X
X
X
X
See Table 16.
12-lead ECG4
X
X
X
X
X
X
X
X
X
See Table 11 and Table 12 for 
timing of assessments.
Vital signs
X
X
X
X
X
X
X
X
X
See Table 11 and Table 12 for 
timing of assessments.
Gepotidacin or placebo
administration5
X
X
Single dose gepotidacin 1500 mg 
or placebo in on Day 1 in Periods 1 
and 2. 
Gepotidacin upto 3000 mg or 
placebo twice daily (approximately 
12 hours apart) on Day 1 in 
Period 3.

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Procedure1
Check-
in
Period 1 or Period 22
Period 3
Early 
Termination
Follow-up Visit
Notes
–1
1
2
3
1
2
3
–
5-7 Days After 
Last Dose
Randomization6
X
On Day 1 of Period 1 only; prior to 
first dose of study intervention.
Holter ECG monitoring
X
X
X
See Table 12 for timing of 
assessments.
Blood collection for PK
X
X
X
X
X
X
See Table 11 and Table 12 for 
timing of assessments.
Urine collection for PK7
X
X
X
X
X
X
AE review
============================
X
X
SAE review
X
============================
X
X
Concomitant medication review
X
============================
X
X
AE = adverse event; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Actual period depends on which sequence participant is randomized to.
3
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
4
Triplicate 12-lead ECGs will be measured on Day 1 pre-dose only of each period.
5
Gepotidacin will be administered under fasted or fed conditions in Period 1 and Period 2 per randomization sequence, and under fed conditions only in Period 3.
6
Participants will be randomized to gepotidacin or placebo and to a treatment sequence on Day 1 of Period 1 only.
7
Urine PK obtained only when gepotidacin is given under fed conditions.

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Table 11
Safety and Pharmacokinetic Assessments - Cohort 4 (Japanese Cohort) Period 1 and Period 2
Procedure1
Time point (hours)
Pre-dose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
24
36
48
Gepotidacin 1500 mg or placebo administration
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Gepotidacin blood sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gepotidacin urine sample3
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = phamacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
Collected only when gepotidacin is administered under fed conditions. Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 
12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after gepotidacin administration.

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Table 12
Safety and Pharmacokinetic Assessments - Cohort 4 (Japanese Cohort) Period 3
Procedure1
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
12.5
13
13.5
14
14.5
15
16
18
20
24
36
48
60
Gepotidacin upto 3000 
mg or placebo 
administration
X
X
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Holter ECG monitoring3
==================================================================================================
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood PK sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sample4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at pre-dose. Single 12-lead ECGs will be measured at all other time points.
3
Holter ECG monitoring will start 12 hours prior to the first daily dose of gepotidacin and continue until 24 hours after the first daily dose of gepotidacin.
4
Urine is collected when gepotidacin is given under fed conditions. Urine collection intervals include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 
hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 20 to 24 hours, 24 to 36 hours, 36 to 48 hours, and 48 to 60 hours after the first dose of gepotidacin.

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2.
INTRODUCTION
Gepotidacin (GSK2140944) is a first in class, novel triazaacenaphthylene antibacterial 
that inhibits bacterial type II topoisomerases. It has activity versus key pathogens, 
including drug-resistant strains associated with a range of conventional and biothreat 
infections and is being developed with intravenous (IV) and oral formulations [IB; 
GlaxoSmithKline Document Number CM2010/00033/06, 2019] for further details on 
Gepotidacin].
Gepotidacin has demonstrated in vitro activity and in vivo efficacy against conventional 
and biothreat pathogens, including isolates resistant to existing classes of antimicrobials. 
Gepotidacin selectively inhibits bacterial deoxyribonucleic acid (DNA) gyrase and 
topoisomerase IV by a unique mechanism, which is not utilized by any currently 
approved human therapeutic agent. Structural data with a type II topoisomerase, DNA 
gyrase, reveals the novel binding mode of the triazaacenaphthylene class and 
distinguishes it from the binding mode of the quinolone antibacterials [Bax, 2010]. As a 
consequence of its novel mode of action, gepotidacin is active in vitro against target 
pathogens carrying resistance determinants to established antibacterials, including 
fluoroquinolones.
2.1.
Study Rationale
The rationale for this study is 2-fold:
1) to determine the magnitude and clinical relevance of potential drug-drug interactions 
(DDIs) and 2) to generate pharmacokinetic (PK), safety, and tolerability data in a 
separate Japanese cohort. Clinical PK and safety data generated in Japanese participants 
will be used to support clinical development (uncomplicated urinary tract infections 
[uUTIs] and gonorrhea) in Japan and provide additional safety data prior to evaluation of 
gepotidacin in Japanese patients. Comparisons will be made between Japanese and non-
Japanese subjects to characterise potential differences in pharmacokinetics across the two 
groups.
The rationale for conducting each of the study Cohorts is summarized in Table 13.
Table 13
Rational for Study 213678
Finding
Importance
Study Treatment
Rationale
Gepotidacin is a 
MATE substrate and 
potentially an 
organic cationic
transporter (OCT)
substrate (Cohort 1)
Gepotidacin plasma 
concentrations may 
increase leading to 
potential safety 
implications. May also 
impact gepotidacin 
efficacy for uUTI due 
to lower concentration 
in urine
Cimetidine (perpetrator-
inhibitor of MATE and 
nonspecific OCT inhibitor)
Gepotidacin (victim)
Gepotidacin renal clearance exceeds 
glomerular filtration rate by greater than
2-fold, which predicts a significant role of 
tubular secretion in renal elimination. 
Based on in vitro data, MATE likely 
contributes to the transportation of 
gepotidacin from the renal cell into the 
urine, while a non-identified OCT might 
transport gepotidacin from blood into the 
renal tubular cell (OCTs are usually 
coupled with MATEs). Not conducting the 
study could lead to cautionary language 
(reduced efficacy and/or safety) when co-

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Finding
Importance
Study Treatment
Rationale
administering with a MATE inhibitor 
(cimetidine)
Gepotidacin is a 
CYP3A4 substrate 
(Cohort 2)
Gepotidacin exposures 
could decrease when 
co-administered with a 
CYP3A4 inducer 
(lower gepotidacin 
efficacy)
Rifampicin (perpetrator)
Gepotidacin (victim)
There may be some effect from a strong 
inducer; data could limit risk when used 
with a moderate or weak inducer and/or 
inform dose modification 
recommendations.
Gepotidacin inhibits 
CYP3A4 and P-gp
(Cohort 3)
Victim drug levels 
increase with potential 
safety implications
Digoxin and midazolam 
(victims)
Gepotidacin (perpetrator)
Digoxin (P-gp substrate) is a narrow 
therapeutic index drug commonly used. 
CYP3A4 substrates (midazolam) are 
common; data is important for 
gepotidacin prescribing to improve 
patient safety. A negative result will 
decrease risk of interactions at any 
gepotidacin dose. In vitro data flagged 
potential interaction via P-gp at the high 
dose only (gonorrhea) in the gut.
Japanese PK cohort
(Cohort 4)
PK, safety, and 
tolerability to include 
food effect as advised 
by GSK Japan based 
on PMDA guidance
Gepotidacin
Characterisation of the safety and 
pharmacokinetic profile will support the 
dose rationale in future studies in 
Japanese subjects/patients
CYP = cytochrome P450; MATE = multidrug and toxin extrusion; OCT = organic cationic transporter; 
P-gp = P-glycoprotein, PMDA = Pharmaceuticals and Medical Devices Agency; PK = pharmacokinetic; 
uUTI = uncomplicated urinary tract infection.
GlaxoSmithKline (GSK) has conducted in vitro studies and used physiologically-based 
PK (PBPK) modeling to evaluate the DDI potential with gepotidacin. Based on these 
analyses, GSK conducted a risk assessment for gepotidacin as a DDI victim and 
perpetrator:
1) Gepotidacin is a substrate of MATE and potentially of OCT transporter: gepotidacin 
renal clearance exceeds glomerular filtration rate by greater than 2-fold, which predicts a 
significant role of tubular secretion in renal elimination. In vitro data suggests that 
gepotidacin is a substrate of MATE and although it does not suggest that gepotidacin is a 
substrate of the currently known OCTs, MATE transporters are usually coupled with 
OCTs. For the uUTI and gonorrhea indications, the DDI risk includes the potential 
increased plasma gepotidacin exposure (may lead to safety implications). For the uUTI 
indication, there is an added potential risk for reduced gepotidacin urine levels (may 
translate to a loss of uUTI efficacy);
2) Gepotidacin is a CYP3A4 substrate: Potential cytochrome P450 (CYP)3A4 induction 
could result in enhanced gepotidacin metabolism, reducing its exposure, which could also 
lead to lack of efficacy in both gonorrhea and uUTI; 
3) Gepotidacin is a P-gp inhibitor: At the high dose (up to 3000 mg, 2 doses given 12 
hours apart) for the gonorrhea indication, gepotidacin might inhibit P-glycoprotein (P-gp) 
at the gut level, potentially increasing the exposure of P-gp substrates that could impact 
substrate-driven safety; 

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4) Gepotidacin is a CYP3A4 inhibitor: Potential inhibition of CYP3A4 enzyme by 
gepotidacin (perpetrator) at both doses for gonorrhea and uUTI may enhance substrate 
exposure, possibly impacting safety for both indications. 
The DDI observations generated from this study will inform the gepotidacin drug label.
2.2.
Background
Gepotidacin has demonstrated clinical efficacy in a Phase II study for acute bacterial skin 
and skin structure infections (ABSSSI), in a Phase II study for uUTI, and in a Phase II 
study for gonorrhea. A detailed description of the chemistry, pharmacology, efficacy, and 
safety of gepotidacin is provided in the Investigator’s Brochure [IB; GSK Document 
Number CM2010/00033/06, 2019].
Gepotidacin may act as a perpetrator (may increase levels of the victim drug) when 
co-administered with midazolam or digoxin and as a victim when co-administered with 
rifampicin (potential reduction on efficacy) and cimetidine (potential reduction safety 
and/or on efficacy). A detailed description of the chemistry, pharmacology, efficacy, and 
safety of the probe drugs can be found in the prescribing information [Cimetidine, 2019; 
Rifampin, 2019; Midazolam, 2012; Digoxin, 2011].
2.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
gepotidacin can be found in the IB. The following section outlines the risk assessment 
and mitigation strategy for this protocol.

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2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Gepotidacin
Gastrointestinal (GI) Effects
Based on nonclinical data, GI 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 GI effects (soft stools, 
flatulence, and diarrhea) are among 
the most common AEs reported in 
gepotidacin clinical studies.
Gastrointestinal effects observed in gepotidacin clinical studies, both 
Phase I studies and the Phase II ABSSSI study, included diarrhea 
(very common, ≥10%) and flatulence (common; ≥1% and <10%); all 
nonserious and mild in severity (see Section 6 of the IB).
In the Phase II urogenital gonorrhea study, the most frequently 
reported GI AEs overall were diarrhea, flatulence, abdominal pain, 
and nausea. Comparing the treatment groups, the incidence of 
diarrhea and nausea was higher in the 3000 mg treatment group and 
incidence of flatulence was higher in the 1500 mg treatment group. 
Few occurrences of Clostridium difficile (C. difficile) have been 
reported in clinical studies (see Section 6 of the IB). Of the 
282 healthy participants in Phase I studies who have received 
gepotidacin, C. difficile was reported in 8 participants, including 
2 elderly participants in association with soft stools or diarrhea. In the 
Phase I renal impairment and hepatic impairment studies and in the 
Phase II ABSSSI, urogenital gonorrhea, and uUTI studies, no cases 
of C. difficile-associated diarrhea were reported.
Exclusion criterion (Section 5.2) and close 
monitoring of clinical parameters and AEs will be 
conducted to mitigate and assess GI effects.
Suspected C. difficile infection will be managed 
according to a prespecified algorithm provided in 
Appendix 8.
Participant evaluation criteria: Participants 
experiencing Grade 3 or Grade 4 AEs will be 
followed as appropriate until resolution of the AE 
(see Section 7.1.3).
Cardiovascular Effects
Reversible increase in QT 
prolongation and a mild increase in 
heart rate in human participants.
In Study BTZ115775 [GSK Document Number 2015N227098_00],
the infusion of gepotidacin at a dose of 1000 mg and 1800 mg over 2 
hours (given an oral bioavailability of 50%, these doses would equate 
to oral doses of 2000 mg and 3600 mg, respectively) caused a mild 
heart rate effect of approximately 6 bpm to 10 bpm and a QT 
prolongation, measured as ΔΔQTcF, of 12 msec to 22 msec in 
healthy volunteers. The QT prolongation evolved during the infusion 
and was quickly reversed over 2 hours after the end of the infusion. 
Blood pressure observations were within normal ranges. 
Exclusion criteria, close monitoring of clinical 
parameters, and AEs will be conducted and 
stopping criteria will be utilized to mitigate and 
assess cardiovascular effects.
Note: Participants with baseline QTcF interval 
>450 msec will be excluded.
Participant monitoring criteria: Participants 
experiencing a QTcB and/or QTcF >500 msec 
and/or a change from baseline in QTc >60 msec 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
No changes in QRS or corrected QT interval (QTc) of clinical concern 
have been seen in the clinic (Phase I studies, including renal 
impairment and hepatic impairment studies, and Phase II ABSSSI 
and uUTI [acute cystitis] studies) (see Section 6 in the IB). There 
were electrocardiographic changes noted in a Phase I hepatic 
impairment study evaluating a single 1500mg oral dose of 
gepotidacin. The majority of participants with severe hepatic 
impairment had both predose and maximum postdose ECG 
parameter corrected QT interval using the Bazett formula (QTcB) and 
corrected QT interval using the Fridericia formula (QTcF) values of 
<450 to ≤479 msec throughout the study. Cardiovascular events 
reported in the Phase II urogenital gonorrhea study were ECG ST 
segment elevation and palpitations (1 participant each) in the 
1500 mg (oral) treatment group and tachycardia (1 participant) in the 
3000 mg (oral) treatment group. In the 1500 mg treatment group, 
cardiovascular AEs consisted of moderate, unrelated ECG ST 
segment elevation and mild, unrelated palpitations. In the 3000 mg 
treatment group, cardiovascular AEs consisted of mild, related 
tachycardia. All cardiovascular AEs resolved. No AEs led to study 
withdrawal.
(see Section 7.1.2).
For cohort 3, subjects will be monitored by holter 
monitoring during the probe administration with or 
without gepotidacin
Acetylcholinesterase (AChE) 
Inhibition
In a mass spectrometry model 
performed with gepotidacin, AChE 
was inhibited with a concentration of 
inhibitor where the response (or 
binding) was reduced by half 
(inhibitory concentration) of 
approximately 5 µg/mL (7.5 µg/mL of 
At higher doses, some participants have experienced effects 
consistent with increased cholinergic tone, including central nervous 
system and GI effects (increased salivation, slurred speech, blurred 
vision, dizziness, light-headedness, and GI upset). These effects 
appear to be related to maximum observed concentration (Cmax)
and are significantly attenuated when Cmax is below 14 g/mL.
Coadministration of anticholinergics and 
administration in participants with certain 
concomitant conditions will be excluded.
Close monitoring of clinical parameters and AEs 
will be conducted to assess effects potentially 
related to AChE inhibition. 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
total drug concentration).
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was seen in 3 of 
6 participants following 10 days of dosing 1500 mg 3 times daily 
[GSK Document Number 2014N198291_00 , Study ID BTZ115198].
Rash was reported as an AE for 4 of 122 participants (3%) and 
consisted of mild, related urticaria; moderate, related rash 
maculopapular; mild, related rash; mild, related urticaria; and mild, 
not related arthropod bite [GSK Document Number 
2015N243789_00 Study ID BTZ116704].
There has been no other evidence of hypersensitivity in human 
participants to date.
Exclusion criterion: History of sensitivity to any of 
the study drugs, components thereof, or a history 
of drug or other allergy that, in the opinion of the 
Investigator or GSK Medical Monitor, 
contraindicates their participation.
Participant monitoring: Participants will be 
monitored closely for cutaneous effects 
throughout the study, and specialist advice will be 
sought as needed to evaluate any clinically 
significant finding.
Participant evaluation criteria: Grade 3 or higher 
rash or Grade 2 rash with evidence of systemic 
involvement (see Section 7.1.4).
Hepatic Effects
In preclinical studies, increases in 
ALT, GLDH, alkaline phosphatase, 
and total bilirubin were observed in 
some rat studies of varying exposure. 
A few healthy volunteer participants 
experienced isolated ALT/AST 
increases following repeat oral (up to 
14 days) and IV (up to 10 days) 
dosing. Effects were reversible, 
asymptomatic, and no changes in 
bilirubin were observed.
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.
In a Phase I hepatic impairment study, a substantial increase in 
Cmax and AUC and decrease in clearance was observed in severe 
hepatic impairment.
Participants with severe hepatic impairment are 
excluded from this trial. See Section 5.2 for 
excluded medical conditions.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Renal Effects
In preclinical trials, mild to moderate 
tubular degeneration was noted in the 
rat and proteinuria in the dog. 
Proteinuria was also observed in 
humans.
No clinical evidence of renal toxicity has been seen in clinical trials to 
date. 
In a Phase I renal impairment study, a substantial increase in Cmax 
and AUC and decrease in clearance was observed in severe renal 
impairment/ESRD participants not on hemodialysis and 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 this trial. See Section 5.2 for 
excluded medical conditions.
Reproductive System Effects
Preclinical studies demonstrated that 
gepotidacin was not genotoxic and no 
drug-related malformations were 
observed. 
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.
There are no data on the use of gepotidacin in pregnant women. 
Gepotidacin is contraindicated in pregnant or 
nursing mothers and women of childbearing 
potential (WOCBP) who are not employing 
adequate contraceptive measures. See 
Appendix 5 for contraceptive measures.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cimetidine
Cardiovascular and GI Effects; 
Serum Chemistry/Hematology 
Abnormalities
Cimetidine can cause the following AEs: diarrhoea, headache, 
gynecomastia, rare cases of leukocytopenia and agranulocytosis, 
dose-related increases in transaminases, rare cases of bradycardia, 
tachycardia, and atrioventricular block.
Inclusion or exclusion criteria: Only healthy 
participants will be allowed to participate in the 
proposed study. Any condition or symptom 
contraindicated for administration of cimetidine as 
per the patient information leaflet will be excluded 
from this study.
Participant monitoring: Liver function tests, 
hematology parameters, and 12-lead ECGs will 
be assessed periodically.
Rifampicin
Various Systemic Effects
The following considerations before use of rifampicin are 
documented in the patient information leaflet: Individuals with the 
following conditions should not take rifampicin: Individuals who are 
allergic (hypersensitive) to rifampicin or any of the other ingredients,
or who are jaundiced. Special care with rifampicin should be taken 
for individuals in the following situations: Individuals with porphyria, 
individuals using contact lenses (taking rifampicin may permanently 
stain soft contact lenses), and individuals taking other medicines 
because rifampicin can affect the way some other medicines work 
and some medicines can affect the way rifampicin works. During 
treatment with rifampicin and for a period of 2 weeks after the last 
dose of rifampicin, drugs administered that are victim to induction 
may be impacted; resulting in reduced victim drug levels when co-
administered with rifampicin followed by an increase in victim drug 
when induction has stopped.
The following side effects are documented in the patient information 
leaflet:
Inclusion or exclusion criteria: Only healthy 
participants will be allowed to participate in the 
proposed study. Any condition or symptom 
contraindicated for administration of rifampicin as 
per the patient information leaflet or any history of 
porphyria, elevated liver function tests, or 
concomitant administration of protease inhibitors 
will exclude a participant from this study.
Participant monitoring: Close monitoring of clinical 
parameters and AEs will be conducted. Stopping 
criteria will be utilized to mitigate and assess 
cardiovascular and liver effects. Participants who 
normally wear contact lenses should wear 
glasses for the duration of the study and for 
5 half-lives thereafter.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Allergic reaction including a rash, swallowing or breathing 
problems, wheezing, and swelling of the lips, face, throat, or 
tongue

Liver effects including fever, jaundice, feeling tired, weak or 
generally unwell, anorexia, nausea, and vomiting

Skin effects including blistering, peeling, bleeding, scaling, or 
fluid filled patches on any part of the skin

Bruising more easily than usual or purpura

Chills, tiredness, unusually pale skin color, shortness of breath, 
fast heartbeat, or dark colored urine

Kidney effects including hematuria or an increase or decrease in 
amount of urine produced

Sudden severe headache

Shock

Leukopenia

Bleeding from the nose, ear, gums, throat, skin, or stomach

Pseudomembranous colitis, symptoms include severe watery 
diarrhea that will not stop, feeling of weakness, and fever

Water retention (edema), which may cause swollen face, 
stomach, Cohorts or legs

Muscle weakness or pain or loss of muscle reflexes

Dizziness, feel lightheaded and faint especially on standing or 
sitting up quickly

Hair loss

Being unable to concentrate, feeling nervous

Irritability or depression; short-term memory loss, anxiety, being 
less alert or responsive

Insomnia

Wasting of muscles or other body tissues

Eosinophilia

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Midazolam
Cardiac, Respiratory, Neurologic, 
and GI Effects
Midazolam is contraindicated in patients with a known 
hypersensitivity to the drug or allergies to formulation excipients. 
Potential AEs may include transient drowsiness, nausea and emesis, 
dizziness and confusion, respiratory depression, decreased systolic 
and diastolic blood pressure, and increased heart rate.
Inclusion or exclusion criteria: Only healthy 
participants will be allowed to participate in the 
proposed study. Any condition or symptom 
contraindicated for administration of midazolam 
as per the patient information leaflet or any 
participant with narrow angle glaucoma will be 
excluded from this study.
Participant monitoring: Continuous cardiac 
monitoring and pulse oximetry will be performed 
following dosing with midazolam to monitor 
participant safety. In addition, flumazenil, which 
selectively blocks the binding of benzodiazepines 
to the central nervous system and acts to reverse 
the clinical effects of toxicity, will be available at 
the bedside in case of emergency in this study.
Digoxin
Cardiovascular and Electrolyte 
Effects
Digoxin should not be used in participants with Wolff-Parkinson-
White Syndrome. It has been shown that after IV digoxin therapy, 
some patients with paroxysmal atrial fibrillation or flutter and a 
coexisting accessory atrioventricular pathway (Wolff-Parkinson-White 
Syndrome) have developed increased antegrade conduction across 
the accessory pathway bypassing the atrioventricular node, leading 
to a very rapid ventricular response or ventricular fibrillation.
Patients with certain disorders involving heart failure associated with 
preserved left ventricular ejection fraction may be particularly 
susceptible to toxicity of the drug. Such disorders include restrictive 
cardiomyopathy, constrictive pericarditis, amyloid heart disease, and 
acute cor pulmonale. Patients with idiopathic hypertrophic subaortic 
Inclusion or exclusion criteria: Only healthy 
participants will be allowed to participate in the 
proposed study. Any condition or symptom 
contraindicated for administration of digoxin as 
per the patient information leaflet, any participant 
with a history of ventricular fibrillation, or a known 
hypersensitivity to other digitalis compounds will 
be excluded from the study.
Participant monitoring: Serum electrolytes, renal 
function (serum creatinine concentrations), and 
12-lead ECGs will be assessed periodically.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
stenosis may have worsening of the outflow obstruction due to the 
inotropic effects of digoxin.
Digoxin is primarily excreted by the kidneys; therefore, patients with 
impaired renal function require smaller than usual maintenance 
doses of digoxin.
In patients with hypokalemia or hypomagnesemia, toxicity may occur 
despite serum digoxin concentrations below 2 ng/mL, because 
potassium or magnesium depletion sensitizes the myocardium to 
digoxin. Therefore, it is desirable to maintain normal serum 
potassium and magnesium concentrations in patients being treated 
with digoxin. 
Calcium, particularly when administered rapidly by the IV route, may 
produce serious arrhythmias in digitalized patients.
Patients receiving digoxin should have their serum electrolytes and 
renal function (serum creatinine concentrations) assessed 
periodically.
Because digoxin slows sinoatrial and atrioventricular conduction, the 
drug commonly prolongs the PR interval. The drug may cause 
severe sinus bradycardia or sinoatrial block in patients with 
pre-existing sinus node disease and may cause advanced or 
complete heart block in patients with pre-existing incomplete 
atrioventricular block. Potential side effects from digoxin are not 
common, and include, but are not limited to the following: 

Loss of appetite, nausea and vomiting, drowsiness, dizziness, 
headache, confusion, depression, apathy, anxiety, fatigue and 
muscle weakness 

Visual disturbances, such as flashes or flickering of light, 
sensitivity to light, seeing things larger or smaller than they are, 
blurring, color changes (yellow or green), and seeing halos or 
borders on objects 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Symptoms caused by rhythm disturbances, such as palpitation, 
light-headedness, presyncope and syncope
ABSSSI = acute bacterial skin and skin structure infection; AChE = Acetylcholinesterase; AE = adverse event; bpm = beats per minute; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; AUC = area under the concentration-time curve; Cmax = maximum observed concentration; ECG =
electrocardiogram; ESRD = end-stage renal disease; GI = gastrointestinal; GLDH = glutamate dehydrogenase; IB = Investigator’s Brochure; IV = intravenous; msec
= millisecond; 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 formula; QTcF = interval corrected for heart rate according to Fridericia formula; uUTI = uncomplicated urinary
tract infection.

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2.3.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy adult participants, there is no direct 
clinical benefit to study participants. Participation in this study will contribute to the 
process of developing new antibiotic therapies in areas of growing unmet need.
2.3.3.
Overall Benefit: Risk Conclusion
The risk of adverse events (AEs) is minimized for the population being investigated in 
the proposed study by careful selection of dose and participants for the study, the 
relatively short duration of study drug exposure, and the extent of safety monitoring 
incorporated into the study.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Cohort 1: Gepotidacin is a substrate of MATE and 
potentially of OCT transporter

To characterize the drug-drug interaction 
(DDI) effect of repeat oral dosing of cimetidine 
on the pharmacokinetics (PK) of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Cmax, Tmax, t1/2, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Cohort 2: Gepotidacin is a CYP3A4 substrate

To characterize the DDI effect of repeat oral 
dosing of rifampicin on the PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Cohort 3: Gepotidacin is a P-gp and CYP3A4 
inhibitor

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart 
given with food on the PK for co-administered 
drugs digoxin and midazolam in an adult 
healthy population

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of digoxin and midazolam in plasma, as data 
permit
Cohort 4: Japanese PK

To assess the PK, safety, and tolerability of a 
single 1500 mg dose of gepotidacin under fed 
and fasted states, and two 3000 mg doses of 
gepotidacin given 12 hours apart under fed 
state in Japanese adult participants 

Cmax, Tmax, AUC(0-24), AUC(0-48),
AUC(0-t), and AUC(0-) of gepotidacin in 
plasma following a single 1500 mg dose, as 
data permit

Cmax, Tmax, and AUC(0-) of gepotidacin 
after the first dose; AUC(0-), Cmax, Tmax,
RoCmax, and RoAUC of gepotidacin after the 

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Objectives
Endpoints

To evaluate the effect of a Japanese meal on 
the bioavailability of the gepotidacin tablet 
formulation
second dose; AUC(0-24), AUC(0-48), and 
AUC(0-t) of gepotidacin using the full profile 
(both doses) following two 3000 mg doses, as 
data permit

Adverse events (AEs), clinical laboratory tests, 
vital signs (systolic and diastolic blood 
pressure and heart rate), and 12-lead 
electrocardiogram (ECG) readings

Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-) 
of gepotidacin in plasma, as data permit
Secondary
Cohort 1

To characterize the plasma PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

AUC(0-24), AUC(0-48), Tlag, Vz/F, and CL/F 
of gepotidacin in plasma after a single 
1500 mg dose of gepotidacin, as data permit

To characterize the DDI effect of repeat oral 
dosing of cimetidine on the urine PK of a 
single 1500 mg oral dose of gepotidacin given 
with food in an adult healthy population

To characterize the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

Ae total, AUC(0-24), AUC(0-48), and CLr of 
gepotidacin in urine following a single 1500 
mg dose, as data permit

Ae(t1-t2) and fe% of gepotidacin in urine 
following a single 1500 mg dose, as data 
permit

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings

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Objectives
Endpoints
Cohort 2

To characterize the plasma PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To characterize the DDI effect of repeat oral 
dosing of rifampicin on the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To characterize the urine PK of a single 
1500 mg oral dose of gepotidacin given with 
food in an adult healthy population

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

AUC(0-24), AUC(0-48), t1/2, Vz/F, and CL/F 
of gepotidacin in plasma after a single 
1500 mg dose of gepotidacin, as data permit

Ae total, AUC(0-24), AUC(0-48), and CLr of 
gepotidacin in urine following a single 1500 
mg dose, as data permit

Ae(t1-t2) and fe% of gepotidacin in urine 
following a single 1500 mg dose, as data 
permit

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings
Cohort 3

To characterize the plasma PK of gepotidacin 
two 3000 mg doses given 12 hours apart with 
food in an adult healthy population

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart with 
food on the PK of co-administered drugs 
digoxin and midazolam in an adult healthy 
population

To characterize the urine PK of gepotidacin 
(two 3000 mg doses given 12 hours apart) 
given with food in an adult healthy population

To evaluate the safety and tolerability of 
gepotidacin in adult healthy participants

Cmax, Tmax, Tlag, AUC(0-) of gepotidacin 
after the first dose; Cmax, Tmax, AUC(0-), 
RoCmax, and RoAUC of gepotidacin after the 
second dose; AUC(0-24), AUC(0-48), 
AUC(0-t), Vz/F, CL/F, and t1/2 of gepotidacin 
using the full profile (both doses), as data 
permit

Cmin, t1/2, Vz/F, and CL/F of digoxin and 
midazolam in plasma, as data permit

Ae total, Ae(t1-t2), AUC(0-), AUC(0-24), 
AUC(0-48), fe%, and CLr of gepotidacin in 
urine following two 3000 mg doses, as data 
permit

Adverse events, clinical laboratory tests, vital 
signs (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG readings

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Objectives
Endpoints
Cohort 4

To characterize the PK of a single 1500 mg 
oral dose of gepotidacin given with and 
without food in Japanese adult healthy 
participants

To assess the plasma PK of two 3000 mg 
doses of gepotidacin given 12 hours apart with 
food in Japanese adult healthy participants

To assess the urine PK of a single 1500 mg 
dose or two 3000 mg doses of gepotidacin 
given 12 hours apart with food in Japanese 
adult healthy participants

t1/2, Vz/F, and CL/F of gepotidacin in plasma 
after a single 1500 mg dose of gepotidacin, as 
data permit

Tlag of gepotidacin after the first dose; Vz/F,
CL/F, and t1/2 of gepotidacin using the full 
profile (both doses) following two 3000 mg 
doses, as data permit

Ae total, Ae(t1-t2), AUC(0-), AUC(0-24), 
AUC(0-48), fe%, and CLr of gepotidacin in 
urine following a single 1500 mg dose and two 
3000 mg doses, as data permit
Exploratory
Cohort 1

To characterize the DDI effect of repeat oral 
dosing of cimetidine on the PK of plasma and 
urine for N1-methylnicotinamide (1-NMN) 
biomarker in adult healthy participants

To evaluate concentrations of serum and urine 
creatinine after administration of gepotidacin 
with and without cimetidine in adult healthy 
participants

To evaluate cimetidine PK to assess 
transporter inhibition in adult healthy 
participants

C average, Cmax, Ctrough, AUC(0-24), 
AUC(0-48), and AUC(0-t) of 1-NMN in plasma, 
as data permit 

Ae total and CLr of 1-NMN in urine, as data 
permit

1-NMN plasma and urine PK parameters 
normalized to creatinine, as data permit

Serum and urine creatinine concentrations, as 
data permit

1-NMN plasma and urine PK parameters 
normalized to creatinine, as data permit

Cimetidine plasma PK concentrations, as data 
permit

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Objectives
Endpoints
Cohort 3

To evaluate the plasma PK for the metabolite 
1’-hydroxymidazolam

To characterize the DDI effect of two 3000 mg 
doses of gepotidacin given 12 hours apart 
given with food on the urine PK of co-
administered digoxin in an adult healthy 
population

Cmin, Cmax, Tmax, t1/2, AUC(0-t), and 
AUC(0-) of 1’-hydroxymidazolam in plasma, 
as data permit

Molecular weight normalized 
parent-to-metabolite AUC(0-) ratio, as data 
permit

Ae total, fe%, and CLr of digoxin in urine
following a single 1500 mg dose, as data 
permit
Cohort 4

To compare the plasma and urine PK of 
gepotidacin 1500 mg single dose (SD) data 
from the Cohort 4 Japanese versus the 
gepotidacin-only 1500 mg SD data the DDI 
Cohorts in adult (non-Japanese) healthy 
participants

To compare the plasma and urine PK of 
gepotidacin 3000 mg twice daily data from the 
Cohort 4 Japanese versus the Cohort 3 
gepotidacin 3000 mg twice daily data in adult 
(non-Japanese) healthy participants

Plasma and urine concentrations and 
parameters for gepotidacin, as data permit

Plasma and urine concentrations and 
parameters for gepotidacin, as data permit
Cohorts 1, 2, 3, and 4

To determine the effect of gepotidacin 
concentrations on the QT interval corrected 
with Fridericia’s method (QTcF) in adult 
healthy participants

Change from Baseline in QTcF versus 
gepotidacin concentration

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4.
STUDY DESIGN
4.1.
Overall Design
This study is a Phase I, DDI, PK, safety, and tolerability study in adult healthy 
participants, including a Japanese cohort, to be conducted at 1 center in the United States.
Further phase 1 units may be used to perform this study should the need arise, due to 
interruptions around recruitment of participants during the Covid-19 pandemic.  This 
study is designed to assess co-administration of probe substrates with gepotidacin in 
study Cohorts 1 to 3 and establishing PK and safety in a Japanese cohort in Cohort 4.
The study Cohorts are summarized in Table 14.
Table 14
Summary of Study Cohorts
Study 
Cohort
Co-administered Drug Probe
Gepotidacin
Design
Cohort 1
Cimetidine 400 mg 4 times daily for 
4 days (perpetrator)
Gepotidacin 1500 mg × 1
(victim)
Fixed sequence
Cohort 2
Rifampicin 600 mg once daily for 
9 days (perpetrator)
Gepotidacin 1500 mg × 1
(victim)
Fixed sequence
Cohort 3
Midazolam 2 mg SD
Digoxin 0.5 mg SD
(victims)
Gepotidacin 3000 mg × 2
12 hours apart
(perpetrator)
Randomized 
sequence
Cohort 4
(Japanese 
cohort)
N/A
Gepotidacin 1500 mg × 1
Gepotidacin upto 3000 mg 
× 2
Randomized 
sequence for 
Periods 1 and 2; 
fixed sequence for 
Period 3
SD = single dose; N/A= not applicable
In all Cohorts, participants will be screened within 28 days before the first dose of study 
treatment.
Cohort 1: Cohort 1 is an open-label, fixed sequence DDI study to investigate the effect 
of cimetidine on the PK of gepotidacin under fed conditions. Participants will receive the 
following treatments in a fixed sequence (Sequence AB). A follow-up visit will occur 
5 to 7 days after the last dose of cimetidine.

Treatment A: Gepotidacin 1500 mg single dose (SD) on Day 1 of Period 1.

Treatment B: Cimetidine 400 mg 4 times daily on Days 1 through 4 of Period 2
and gepotidacin 1500 mg SD. Gepotidacin will be administered 1 hour after the 
first dose of cimetidine on Day 2 of Period 2 (gepotidacin administration is 
delayed for 1 hour due to the changes in gastric pH by cimetidine that could 
impact gepotidacin dissolution and absorption). On Day 4 of Period 2, 
cimetidine dosing will be discontinued after the last PK sample is collected.
There will be a washout of at least 3 days after dosing with gepotidacin in Period 1. 
Cimetidine will be administered in the fasted condition. Prior to dosing with gepotidacin, 
participants will receive a standard meal 30 minutes prior to dosing. Participants will eat 

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this meal in 30 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption. Participants will not receive any further food until at 
least 2 hours after gepotidacin dosing.
Pharmacokinetic blood and urine samples for analysis of gepotidacin, creatinine, and the 
endogenous biomarker N1-methylnicotinamide (1-NMN) will be obtained at 
pre-specified time points, and sparse blood samples will be collected for cimetidine after 
dosing as indicated in the schedule of activities (SoA) (Table 2, Table 3, and Table 4).
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results, vital sign measurements, 12-lead electrocardiogram (ECG) results, 
and physical examination findings.
Including screening, a washout of at least 3 days between Treatment A and Treatment B, 
and a follow-up visit 5 to 7 days after the last dose of cimetidine, the total duration of 
Cohort 1 is up to 42 days.
Cohort 2: Cohort 2 is an open-label, fixed sequence DDI to investigate the effect of 
rifampicin on the PK of gepotidacin under fed conditions. Participants will receive the 
following treatments in a fixed sequence (Sequence CDE). A follow-up visit will occur 
7 to 10 days after the last dose of rifampicin.

Treatment C: Gepotidacin 1500 mg SD on Day 1 of Period 1.

Treatment D: Rifampicin 600 mg (administered in the evenings) once daily for 
7 days (Days 1 through 7 of Period 2, to elicit maximal enzyme induction).

Treatment E: Gepotidacin 1500 mg SD administered in the morning on Day 8
and rifampicin 600 mg administered in the evening on Days 8 and 9 of Period 2. 
There will be a washout of at least 3 days after dosing of gepotidacin in Period 1. The 
participants will receive a standard meal 30 minutes prior to dosing. Participants will eat 
this meal in 30 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption. Participants will not receive any further food until at 
least 2 hours after gepotidacin dosing. Rifampicin will be administered 1 hour before the 
evening meal.
Pharmacokinetic blood and urine samples of gepotidacin will be obtained at pre-specified 
time points before and after dosing as indicated in the SoA (Table 5 and Table 6). Safety 
and tolerability will be assessed by monitoring and recording of AEs, clinical laboratory 
test results, vital sign measurements, 12-lead ECG results, and physical examination 
findings.
Including screening, a washout of at least 3 days between Treatment C and Treatment D, 
and a follow-up visit 7 to 10 days after the last dose of rifampicin, the total duration of 
Cohort 2 is up to 50 days.
Cohort 3: Cohort 3 is an open-label, 2-sequence, 2-period crossover randomized DDI 
study to investigate the effect of gepotidacin on the PK of 2 probe drugs (digoxin and 
midazolam) under fed conditions. Participants will be randomized to 1 of 2 treatment 
sequences in a 1:1 ratio. In Sequence 1, participants will receive digoxin 0.5 mg and 

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midazolam 2 mg (Treatment F) in Period 1 on Day 1 then gepotidacin two 3000 mg doses 
(given 12 hours apart) co-administered with digoxin 0.5 mg and midazolam 2 mg in 
Period 2 on Day 1, with the 2 probe drugs administered with the second daily dose of 
gepotidacin only (Treatment G). In Sequence 2, these regimens are reversed. A follow-up 
visit will occur 7 to 10 days after the last dose of study intervention in Period 2 (to ensure 
clearance of digoxin). The 2 treatments are as follows:

Treatment F: Digoxin 0.5 mg and midazolam 2 mg on Day 1.

Treatment G: Gepotidacin two 3000 mg doses (given 12 hours apart) on Day 1 
with digoxin 0.5 mg and midazolam 2 mg given with the second gepotidacin 
dose on Day 1.
There will be a washout of at least 10 days between treatments. The participants will 
receive a standard meal 30 minutes prior to dosing. Participants will eat this meal in 
30 minutes or less. All dose administrations will occur within 5 minutes of completion of 
meal consumption. Another standard meal (similar in calorie content and similar ratios of 
protein, carbohydrates, and fat as the previous meal) will be provided prior to the second 
gepotidacin dose (Treatment G). Participants will eat this meal in 30 minutes or less. 
Dose administration will occur within 5 minutes of completion of meal consumption.
Participants will not receive any further food until at least 2 hours after dosing.
Blood samples for analysis of gepotidacin, midazolam, 1’-hydroxymidazolam, and 
digoxin PK; and urine samples for gepotidacin and digoxin PK will be obtained at 
pre-specified time points before and after dosing as indicated in the SoA (Table 7, 
Table 8, and Table 9). Safety and tolerability will be assessed by monitoring and 
recording of AEs, clinical laboratory test results, vital sign measurements, pulse 
oximetry, 12-lead ECG results, Holter monitoring, and physical examination findings.
Including screening, a washout of at least 10 days between treatments, and a follow-up 
visit 7 to 10 days after the last dose of study treatment, the total duration of Cohort 3 is up 
to 50 days.
Cohort 4: Cohort 4 is a double-blind, placebo-controlled, randomized sequence 
(Periods 1 and 2 only) study to investigate the safety and PK of gepotidacin under fed and 
fasted conditions in Japanese participants. Participants will be randomly assigned
(10 active:2 placebo) to receive gepotidacin or placebo. Within each treatment group, 
participants will be randomized to each of the 2 sequences in 1:1 ratio: HIJ versus IHJ (to 
elucidate the food effect). In Sequence 1, participants will receive a SD of gepotidacin 
1500 mg or placebo under fed conditions in Period 1 (Treatment H), then a SD of 
gepotidacin 1500 mg or placebo under fasted conditions in Period 2 (Treatment I), 
followed by two doses of gepotidacin up to 3000 mg or placebo (given 12 hours apart) 
under fed conditions in Period 3 (Treatment J). In Sequence 2, the first 2 treatments are 
reversed (Sequence IHJ). A follow-up visit will occur 5 to 7 days after the last dose of 
gepotidacin or placebo.

Treatment H: Gepotidacin 1500 mg or placebo SD under fed conditions on Day 
1.

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
Treatment I: Gepotidacin 1500 mg or placebo SD under fasted conditions on 
Day 1.

Treatment J: Two doses of gepotidacin up to 3000 mg or placebo (given 12 
hours apart) under fed conditions on Day 1.
There will be a washout of at least 3 days between each treatment. Participants receiving 
Treatments H and J will receive a standard meal 30 minutes prior to dosing. Participants 
will eat this meal in 30 minutes or less. Dose administration will occur within 5 minutes 
of completion of meal consumption. Participants receiving Treatment I will fast overnight 
for at least 8 hours prior to dosing. Participants will not receive any further food until at 
least 2 hours after dosing.
Pharmacokinetic blood and urine samples for analysis of gepotidacin will be obtained at 
pre-specified time points before and after dosing, as indicated in the SoA (Table 10, 
Table 11, and Table 12). Safety and tolerability will be assessed by monitoring and 
recording of AEs, clinical laboratory test results, vital sign measurements, 12-lead ECG 
results, Holter monitoring (Period 3 only), and physical examination findings.
Including screening, a washout of at least 3 days between each treatment, and a follow-up 
visit 5 to 7 days after the last dose of gepotidacin, the total duration of Cohort 4 is up to 
44 days.
4.2.
Scientific Rationale for Study Design
Following a single oral administration of [14C]-gepotidacin to humans (study 
BTZ115774), approximately 50% of the dose was absorbed, consistent with the oral 
bioavailability of 44%. After oral administration, gepotidacin was eliminated mainly as 
parent in urine, accounting for approximately 20% of the administered dose. Elimination
via metabolism (urine plus feces) accounted for a total of 13% to 19% of the dose. The 
oxidative metabolism of gepotidacin in vitro is mediated primarily by CYP3A4. In 
addition, gepotidacin is a substrate of the human P-gp and breast cancer resistance protein 
(BCRP) transporters in vitro. Gepotidacin exposure may, therefore, be affected by any 
co-medications that are CYP3A4 and/or P-gp and BCRP inhibitors. Gepotidacin renal 
clearance exceeds glomerular filtration rate by greater than 2-fold, suggesting that renal 
transporters are involved in gepotidacin renal elimination. Based on in vitro data, MATE 
likely contributes to gepotidacin urine levels. Therefore, concomitant administration with 
a MATE inhibitor may lead to increased plasma levels and decreased gepotidacin levels 
in the urine, and thus, potentially less safety for both indications and/or efficacy for 
uUTIs.
Gepotidacin may act as an inhibitor for CYP3A4 and P-gp. Concomitant use of 
gepotidacin with sensitive CYP3A4 or P-gp substrates (e.g., midazolam, digoxin) may 
increase the area under the concentration-time curve (AUC) and maximum observed 
concentration (Cmax) of the substrate drug. This may increase the risk of toxicities when 
these drugs are taken together. 
Cohort 1: Cimetidine is an H2 antagonist used to reduce the acid in the stomach with a 
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administration and peak levels occur in 45 to 90 minutes. After oral administration, the 
drug is extensively metabolized in which the sulfoxide is the major metabolite. Following 
a single oral dose, 48% of the drug is recovered from the urine after 24 hours as the 
parent compound.
Cimetidine as a nonspecific inhibitor of organic cationic transporter (OCT) and an 
inhibitor of MATE: Cimetidine will be employed to assess the impact on gepotidacin 
(victim) plasma and urine levels via inhibition of MATE and potentially via inhibition of 
OCTs in the basolateral membrane of the renal tubular cells. While none of the in vitro 
testing pointed to currently known OCTs as responsible for the transportation of 
gepotidacin, MATE transporters are usually coupled with OCTs. MATE is responsible 
for transporting gepotidacin at the apical membrane from the tubular renal cell into the 
urine. These data will inform on gepotidacin safety regarding potential enhanced plasma 
exposure and efficacy specific to the uUTI indication (inhibition of MATE and possibly 
unknown OCTs might reduce gepotidacin urine exposure, potentially also reducing its 
efficacy in uUTI). Therefore, cimetidine will be administered 400 mg 4 times daily
aligned to the prescribing information [Cimetidine, 2019] before and during gepotidacin 
administration together with PK sampling to ensure adequate systemic exposure.
Cimetidine PK samples will be collected at 1, 25, and 49 hours after the first dose of 
cimetidine to assess if the MATE transporter is fully inhibited based on clinical exposure 
and in vitro data (compared to half maximal inhibitory concentration).
The endogenous biomarker 1-NMN is taken up by OCT2 and secreted by MATEs. 
Levels of 1-NMN will help assess OCT2 inhibition, and a reduction in clearance to 
MATE inhibition. Given the unknown mechanism for transportation of gepotidacin from 
blood to the renal tubular cell, the endogenous biomarker 1-NMN will be assessed to 
provide direct confirmation if renal organic cationic transport systems are inhibited, and 
therefore involved in the transportation of gepotidacin on the basolateral membrane (not 
demonstrated in vitro). Serum and urine creatinine will also provide data on renal 
inhibition.
Cohort 2: Rifampicin is a semisynthetic antibiotic derivative of rifamycin indicated for 
the treatment of tuberculosis and meningococcal carrier state. Rifampicin is usually 
administered on a daily basis at doses not exceeding 600 mg/day. Protein binding is 
approximately 80% and the terminal half-life is approximately 3 hours. Although some 
enzyme induction is noted with the first dose of rifampicin, repeat dose administration 
(daily for approximately 9 days) is required to achieve maximal induction [Nassr, 2009].
Rifampicin as a CYP3A4 inducer: Rifampicin is a potent inducer of CYP3A4, CYP2C9, 
CYP2C19, and a potent inducer of P-gp transporter. It strongly induces the expression of 
CYP3A4 in both the liver and intestine; thereby reducing the plasma concentrations and 
effects of several CYP3A4 substrates. In most cases, rifampicin reduces the plasma 
concentrations of a drug which itself is active and has no important active metabolites, 
the result being a reduction in its pharmacodynamic (PD) effects [Niemi, 2003]. As 
gepotidacin is a CYP3A4 substrate, this Cohort will identify potential for reduced 
gepotidacin exposure that may impact efficacy. These findings will be appropriate for 
both uUTI and gonorrhea indications.

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Cohort 3: A 2-probe (digoxin and midazolam) approach will be used to assess
gepotidacin as the perpetrator of CYP3A4 and P-gp inhibition. These observations will 
be appropriate for both the uUTI (CYP3A4 inhibition only) and gonorrhea (both 
CYP3A4 and P-gp inhibition) indications.
Digoxin: Digoxin is indicated for the treatment of mild to moderate heart failure and for 
rate control in chronic atrial fibrillation. Following oral administration, Cmax of digoxin 
occurs between 1 and 3 hours. Oral absorption of digoxin tablets is between 60% and 
80%. In healthy participants with normal renal function, t1/2 is 1.5 to 2 days; therefore,
steady-state concentrations are not achieved until approximately 10 days. When given 
after a meal, the rate of absorption is slowed, but the total amount of digoxin absorbed is 
usually unchanged. Digitalis glycosides are contraindicated in patients with ventricular 
fibrillation or in patients with a known hypersensitivity to digoxin. A hypersensitivity 
reaction to other digitalis preparations usually constitutes a contraindication to digoxin; 
thus participants with a known hypersensitivity to digoxin or other digitalis preparations 
will be excluded from this study. 
Digoxin as P-gp substrate: In vitro experiments suggest that gepotidacin is a P-gp 
inhibitor at the gut level at the gonorrhea dose (2 × 3000 mg). Since digoxin is a substrate 
for P-gp, co-administration of gepotidacin gonorrhea dose with digoxin may change the 
PK profile of digoxin. In addition, digoxin has a narrow therapeutic range, a low safety 
margin, and has been shown to interact with many other drugs that are substrates, 
inhibitors (e.g., fostamatinib), or inducers (e.g., rifampicin) of P-gp in several clinical 
studies [Fuhr, 2007]. Thus, digoxin has been used as a probe for potential drug 
interactions with other drugs that affect P-gp. A low dose of digoxin 0.5 mg has been 
selected to minimize the risk of AEs.
Midazolam: Midazolam, a short-acting benzodiazepine used for pre-operative sedation, is 
a well characterized probe drug for CYP3A4/5 [Huang, 2007; Fuhr, 2007]. Midazolam is 
well absorbed after oral dosing, has a terminal half-life of approximately 2 hours and is 
almost exclusively metabolized by CYP3A enzymes to its primary metabolite, 
1’-hydroxymidazolam, as well as to the minor metabolites 4-hydroxymidazolam and 
1’, 4-hydroxymidazolam [Heizmann, 1983]. 
Midazolam as CYP3A probe: IV midazolam is used to probe the metabolic activity of 
hepatic CYP3A enzymes, while oral administration allows simultaneous assessment of 
both intestinal and hepatic CYP3A activity [Thummel, 1996]. More than 200 drug 
interaction studies involving midazolam have been reported. The US Food and Drug 
Administration has developed a CYP3A inhibitor classification system based on the 
magnitude of inhibitory effect on midazolam plasma AUC that serves to benchmark the 
risk of clinically significant CYP3A-mediated DDIs.
Oral midazolam doses in drug interaction studies have ranged from 1.75 to 15 mg, with 
the majority of studies using a dose ≥5 mg [University of Washington School of 
Pharmacy, 2020]. The midazolam dose (as one of the probe drugs) will be 2 mg orally. A 
lower dose was chosen to reduce the chance of excessive sedation in the presence of an 
interaction causing increasing levels of midazolam. As an added precaution, flumazenil, a 

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benzodiazepine antagonist, will be readily available if any participant experiences 
excessive sedation.
Cohort 4: A Japanese (healthy participant) cohort will be recruited to evaluate a single 
1500 mg gepotidacin oral dose (fed and fasted) to cover uUTI indication. The data for the 
1500 mg dose will be compared to gepotidacin PK profiles generated in the DDI Cohorts 
1 and 2 (periods without co-administration of DDI drugs). This cohort may also be used 
to evaluate a 2-dose regimen to cover the gonorrhea indication. Dose selection for 
gonorrhea is subject to ongoing PK modeling but will be a maximum 3000 mg dose 
given twice daily 12 hours apart. A 3000mg dose given twice daily has previously been 
studied (209611 in IB) in adult and adolescent healthy participants and was generally 
well tolerated. Completed PK modelling will inform on the final 2-dose regimen to cover 
the gonorrhea indication in healthy Japanese participants. The final 2-dose regimen will 
be communicated to the site before dosing cohort 4 in period 3.  The gepotidacin PK data 
in Japanese for the gonorrhea indication will be compared to 2 × 3000 mg doses in the 
population from the 2-probe Cohort (Cohort 3).
This study (Cohorts 1 to 4) will collect gepotidacin PK data in plasma and urine (where 
applicable) following dosing of gepotidacin. For the 2-probe (Cohort 3) administration, 
plasma PK for midazolam, and digoxin will be collected, including intensive gepotidacin 
PK sampling at specific timepoints, to serve as a control (ensure adequate gepotidacin 
exposure and for comparison with the Japanese PK data).
4.3.
Justification for Dose
The 1500 mg dose was tested in the recently completed Phase I study in healthy adult and 
adolescent participants [GSK Document Number 2019N422403_00, 209611], and no 
new safety issues were identified. The majority of AEs were mild in intensity and 
involved gastrointestinal (GI) events, a known risk with gepotidacin as indicated in 
Section 2.3.1. The 1500 mg dose is also being studied in 2 ongoing Phase 3 studies in 
uUTIs [GSK Document Number 2017N318043_01 and GSK Document Number
2019N407320_01, study number 204989 and 212390].
Based on PK modeling, gepotidacin will be administered for gonorrhea as 2 single oral 
3000 mg doses, given either 10 or 12 hours apart with a minimum body weight of 40 kg.
This will provide higher daily systemic exposures that allow coverage of Neisseria 
gonorrhoeae isolates with higher gepotidacin minimum inhibitory concentration values, 
which are likely to be observed in the global Phase III study and reduce the risk of 
resistance emergence. The 2 single oral 3000 mg doses given 12 hours apart was one of 
the dosing regimens tested in the recently completed Phase I study in healthy adult and 
adolescent participants [GSK Document Number 2019N422403_00], and, as indicated 
above, no new safety issues were identified. The 2 single oral 3000 mg doses, given 
either 10 or 12 hours apart, is also being studied in an ongoing Phase III study in 
gonorrhea [GSK Document Number 2017N317989_01, BTZ116577]. An oral dose of up 
to 6g has been administered to healthy volunteers in completed studies [IB; GSK
Document Number CM2010/00033/06, 2019] for further details on Gepotidacin].

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In the current study, gepotidacin will be administered as either a single 1500 mg oral dose 
or as two 3000 mg oral doses. The single 1500 mg dose is expected to provide additional 
PK and safety data for the uUTI indication. The two 3000 mg doses, given 12 hours 
apart, are expected to provide valuable PK and safety data to guide Phase III studies and 
the prescribing information for the gepotidacin tablet for the N. gonorrhoeae indication.
The doses of the substrate drugs are typical doses for this type of study as indicated in 
Section 4.2.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled visit shown in the SoA (Section 1.3) for the last participant in the 
study.
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit shown in the SoA (Section 1.3).
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Healthy participants will be recruited to this study meeting the inclusion and exclusion 
criteria. The Japanese cohort aims to enroll at least 30% females with a target of 50% 
(depending on feasibility). The inclusion of females in the Japanese cohort is especially 
associated with the uUTI indication being pursued.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be ≥18 to ≤50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are healthy as determined by the investigator or medically qualified 
designee based on medical evaluation including medical history, physical 
examination, clinical laboratory tests, vital sign measurements, and 12-lead ECG 
results. A participant with clinical abnormality or laboratory parameters outside the 
reference range for the population being studied may be included only if the 
investigator feels and documents that the finding is unlikely to introduce additional 
risk factors and will not interfere with the study procedures.
3.
Additional inclusion criteria for Japanese participants (Cohort 4):

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
The participant is a non-naturalized Japanese citizen and holds a Japanese 
passport (current or expired).

The participant has/had 2 Japanese parents and 4 Japanese grandparents who 
are/were all non-naturalized Japanese citizens, as confirmed by interview.

The participant has been living outside of Japan for up to 10 years as confirmed 
by interview.
Weight
4.
Participants have a body weight ≥40 kg and body mass index within the range 18.5 
to 32.0 kg/m2 (inclusive).
Sex
Sex and Contraceptive/Barrier Requirements
5.
Male and/or female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
a.
Female participants:

A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and 1 of the following conditions applies:
o
Is a woman of non-childbearing potential as defined in Appendix 5
OR
o
Is a woman of childbearing potential (WOCBP) and using a contraceptive 
method that is highly effective, with a failure rate of <1%, as described in 
Appendix 5 for at least 30 days prior to dosing until completion of the 
follow-up Visit. The investigator should evaluate the potential for 
contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) before the first dose of study intervention and 
for women not on effective contraception at least 14 days prior to baseline visit.
See Section 8.2.5 Pregnancy Testing.

Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.2.5.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

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Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 3, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Clinically significant abnormality in the past medical history or at the screening 
physical examination that in the investigator’s opinion may place the participant at 
risk or interfere with the outcome variables of the study. This includes, but is not 
limited to, history or current cardiac, hepatic, renal, neurologic, GI, respiratory, 
hematologic, or immunologic disease. 
2.
Any surgical or medical condition (active or chronic) that may interfere with drug 
absorption, distribution, metabolism, or excretion of the study intervention, or any 
other condition that may place the participant at risk, in the opinion of the 
investigator.
3.
Female participant has a positive pregnancy test result or is lactating at Screening or 
upon admission to the clinic.
4.
Positive test for SARS-CoV-2. Note: Testing will be performed according to site 
procedures.
5.
Within 2 months before Screening, either a confirmed history of Clostridium difficile
(C. difficile) diarrhea infection or a past positive of C. difficile toxin test.
6.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
7.
History of drug and/or alcohol abuse within 6 months before Screening, as 
determined by the investigator, or has a positive drug screen at Screening or upon 
admission to the clinic.
8.
History of sensitivity/hypersensitivity to any of the study drugs, components thereof, 
or a history of drug or other allergy that, in the opinion of the Investigator or GSK 
Medical Monitor contraindicates their participation.
9.
Cohort 2 Only: Participant is a contact lens wearer who is unable or unwilling to 
wear glasses for the duration of the study and for 5 half-lives after the last dose of 
rifampicin.
Prior/Concomitant Therapy
10. Use of any systemic antibiotic within 30 days of screening.
11. Participants must abstain from taking prescription or non-prescription drugs (except 
for hormonal contraceptives and/or acetaminophen at doses of 2 grams/day), 
vitamins, and dietary or herbal supplements, unless specified in Section 6.8, within 
7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 

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(whichever is longer) prior to study intervention until completion of the follow-up 
Visit, unless, in the opinion of the investigator and Sponsor, the medication will not 
interfere with the study. Any exceptions will be discussed with the Sponsor or 
Medical Monitor on a case-by-case basis and the reasons will be documented.
Prior/Concurrent Clinical Study Experience
12. Previous exposure to gepotidacin.
13. Participant has participated in a clinical trial and has received an investigational 
product (IP) prior to gepotidacin administration within 30 days, 5 half-lives, or twice 
the duration of the biological effect of IP (whichever is longer).
14. Past participation in this clinical study.
Diagnostic assessments
15. Baseline corrected QT interval using the Fridericia formula (QTcF) of 
>450 milliseconds (msec) at Screening or Check-in.
16. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result at 
Screening or within 3 months prior to starting study intervention.
17. Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) at Screening or 
Check-in.
18. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) at Screening or Check-in.
19. History of any kidney disease or current or chronic history of mild impaired renal 
function as indicated by an estimated creatinine clearance ≤90 mL/min.
20. A positive test for human immunodeficiency virus (HIV) antibody.
21. History of regular alcohol consumption within 6 months of Screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males 
or an average weekly intake of >14 units (or an average daily intake >2 units) for 
females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 
30 mL of spirits, or 100 mL of wine.
22. Cohort 3 Only: Digoxin-related exclusions include the following at Screening:

Serum potassium >5.5 mEq/L or < 3.6 mEq/L

Serum magnesium <1.6 mg/dL

Serum calcium (total) <8.5 mg/dL

History of hypersensitivity to digoxin or other digitalis glycosides

Any clinically relevant abnormality on 12-lead ECG at Screening or Check-in.

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Other Exclusions
23. Participant has donated blood in excess of 500 mL within 12 weeks prior to dosing 
or participation in the study would result in donation of blood or blood products in 
excess of 500 mL within a 56-day period.
24. Participant is unable to comply with all study procedures, in the opinion of the 
investigator.
25. Participant should not participate in the study, in the opinion of the investigator or 
Sponsor.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Participants receiving study intervention under fed conditions will receive a 
standard meal 30 minutes prior to dosing. Participants will eat this meal in 30
minutes or less. Dose administration will occur within 5 minutes of completion 
of meal consumption. Approximately 240 mL of water will be provided for 
swallowing the dose. Up to 480 mL of water is allowed if needed to swallow the 
entire dose. Participants will not receive any further food until at least 2 hours 
after dosing.

Participants receiving study intervention under fasted conditions will fast 
overnight for at least 8 hours prior to dosing. Approximately 240 mL of water 
will be provided for swallowing the dose. Up to 480 mL of water is allowed if 
needed to swallow the entire dose. Participants will not receive any food until at 
least 2 hours after dosing.

For doses scheduled to occur 12 hours after the initial dose, participants will 
have the standard meal in the morning and will receive another standard meal 
(similar in calorie content and similar ratios of protein, carbohydrates, and fat as 
the previous meal) prior to the second dose. Participants should consume this 
meal in 30 minutes or less. Dose administration will occur within 5 minutes of 
completion of meal consumption. Participants will not receive any further food 
until 2 hours after dosing.

Standard meals will be provided during the study intervention period at times 
that do not interfere with study procedures.

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the start of dosing until after collection of the final PK sample.

No water is allowed until 2 hours after dosing, unless administered under the 
investigator’s direct order for treatment of an AE. Water is allowed ad libitum at 
all other times.

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5.3.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before the 
start of dosing until after collection of the final PK sample.

Participants will abstain from alcohol for 24 hours before the start of dosing 
until after collection of the final PK sample.

Use of tobacco products will not be allowed from 3 months before Screening 
until after the final follow-up visit.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).

After dosing gepotidacin, the participants will remain in semi-supine position 
where possible up to 4 hours post dose.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
serious AEs (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened (for the same Cohort or another Cohort of the study, subject to 
meeting eligibility criteria). Rescreened participants should be assigned a new participant 
number for every screening/rescreening event.
5.5.
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention Administration
Not applicable for this study.
6.
STUDY INTERVENTIONS AND CONCOMITANT 
THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.

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6.1.
Study Interventions Administered
Cohort Name
All Cohorts
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Intervention Name
Gepotidacin
Cimetidine
Rifampicin
Midazolam
Digoxin
Placebo (matched to 
gepotidacin)
Type
Drug
Drug
Drug
Drug
Drug
Drug
Dose Formulation
Tablet containing gepotidacin 
mesylate (GSK2140944E)
Tablet
Capsule
Oral syrup
Tablet
Tablet
Unit Dose Strengths
750 mg
400 mg
300 mg
2 mg/mL
0.25 mg
Not applicable
Dosage Levels
1500 mg (2 × 750 mg) SD
(Cohorts 1, 2, and 4) or 
3000 mg (4 × 750 mg) 2 doses 
12 hours apart (Cohorts 3 and 4).
400 mg 4 times per 
day
600 mg once per 
day 
2 mg (1.0 mL) SD
0.5 mg SD
Not applicable
Route of Administration
Oral
Oral
Oral
Oral
Oral
Oral
Use
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
IMP and NIMP
IMP
IMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided locally by 
the trial site
Provided locally by 
the trial site
Provided locally by 
the trial site
Provided locally by 
the trial site
Provided centrally by 
the Sponsor
Packaging and Labeling
Study Intervention will be provided 
in HDPE bottles. Each bottle will be 
labeled as required per country 
requirement.
Study Intervention 
will be provided in 
HDPE bottles. 
Each bottle will be 
labeled as required 
per country 
requirement.
Study Intervention 
will be provided in 
HDPE bottles. 
Each bottle will be 
labeled as required 
per country 
requirement.
Study Intervention 
will be provided in 
amber glass 
bottles of 118 mL 
of syrup. Each 
bottle will be 
labeled as per 
country 
requirement.
Study Intervention 
will be provided in 
HDPE bottles. 
Each bottle will be 
labeled as required 
per country 
requirement.
Study Intervention 
will be provided in 
HDPE bottles. Each 
bottle will be labeled 
as required per 
country requirement.
HDPE = high-density polyethylene; IMP = investigational medicinal product; NIMP = non-investigational medicinal product; SD = single dose.

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6.2.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study intervention is 
not expected to pose significant safety risks to site staff.

A Material Safety Data Sheet/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request 
from GSK.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Participants will act as their own controls in all Cohorts of the study (with the exception 
of Cohort 4, Period 3). Treatment sequences in Cohorts 3 and 4 are randomized. Cohort 4 
contains blinded treatment of gepotidacin and placebo. An unblinded pharmacist will 
dispense study intervention in Cohort 4; neither the participant nor immediate study 
personnel (i.e., investigators, PPD staff) will know which study intervention the 
participant is receiving. Participants who are randomly assigned to receive placebo will 
receive a matching placebo form of the active treatment. The matching placebo will look 
identical to the active form.
6.4.
Study Intervention 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. 

When participants are dosed at the site, they will receive study intervention
directly from the investigator or designee, under medical supervision. The date 
and time of each dose administered in the clinic will be recorded in the source 
documents. The dose of study intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. Study site staff will 
examine each participant’s mouth to ensure that the study intervention was 
ingested.

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6.5.
Dose Modification
Dose modification is not applicable in this study.
6.6.
Continued Access to Study Intervention after the End of the 
Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for study participation.
6.7.
Treatment of Overdose
For this study, any dose of gepotidacin or the substrate drugs greater than the planned 
dose within a 24-hour time period (± 2 hours) will be considered an overdose. All study 
interventions will be administered at the clinic, thus limiting the risk of overdose. In the 
unlikely event that an overdose should occur, the investigator must notify the Sponsor
promptly. There is no specific antidote for overdose with a bacterial topoisomerase 
inhibitor such as gepotidacin. 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 clinic status.
GlaxoSmithKline does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
gepotidacin or any of the probe drugs can no longer be detected systemically (at least 
3 days).
3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the electronic case report form (eCRF).
5.
For midazolam (Cohort 3), flumazenil, a benzodiazepine antagonist, will be readily 
available if any participant experiences excessive sedation.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.

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6.8.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant is receiving at the time of enrollment or receives during the study must be 
recorded along with:

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.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up Visit, unless, in the opinion of the 
investigator and Sponsor, the medication will not interfere with the study.
For Cohort 2, participants should be advised that taking medications within 14 days of 
the last dose of rifampicin that are victim to induction may be impacted; resulting in 
reduced victim drug levels when co-administered with rifampicin followed by an increase 
in victim drug when induction has stopped.
Since gepotidacin is known to have some prolongation of the corrected QTc interval 
(QTc), any drugs known to increase QTc interval should be avoided when treating an AE.
Due to the potential for acetylcholinesterase (AChE) inhibition with gepotidacin, the 
following medications are prohibited:

Succinylcholine or other depolarizing muscle relaxants

AChE inhibitors as required for myasthenia gravis including edrophonium, 
pyridostigmine, neostigmine, etc
Hormonal contraceptives and acetaminophen at doses of 2 grams/day are permitted for 
use any time during the study. Other concomitant medication may be considered on a 
case-by-case basis by the investigator in consultation with the Medical Monitor.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety. See the SoA (Section 1.3) for data to be 

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collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed.
7.1.1.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of 
normal.
Refer to Appendix 6 for required Liver Safety Actions and Follow up Assessments.
7.1.2.
QTc Stopping Criteria

A participant who meets the following bulleted criteria based on triplicate ECG 
readings will be withdrawn from study intervention:

QTc >500 msec 

Change from baseline of QTc >60 msec

For participants with underlying bundle-branch block, follow the 
discontinuation criteria listed below:
Baseline QTc with Bundle-Branch Block
Discontinuation QTc with Bundle-Branch Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec

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
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may 
not be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on corrected QT 
interval using the Fridericia formula (QTcF), then QTcF must be used for 
discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception.

The QTc should be based on single or averaged QTc values of ECG readings
obtained over a brief (e.g., 5 to 10 minute) recording period.

If a clinically significant finding is identified (including, but not limited to 
changes from baseline in QT interval corrected using QTcF) after enrollment, 
the investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. 
This review of the ECG printed at the time of collection must be documented. 
Any new clinically relevant finding should be reported as an AE.
See the SoA (Section 1.3) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed
7.1.3.
Gastrointestinal Evaluation Criteria
If a participant meets the criteria in Appendix 8, C. difficile toxin testing should be 
conducted.
7.1.4.
Rash/Hypersensitivity Evaluation Criteria
A participant presenting with a Grade 3 AE or higher rash (diffuse macular, 
maculopapular, OR morbilliform rash with vesicles or limited number of bullae; OR 
superficial ulcerations of mucous membrane limited to 1 site) or a Grade 2 rash (diffuse 
macular, maculopapular, or morbilliform rash; OR target lesions) with evidence of 
systemic involvement will be followed as appropriate until resolution of the AE(s).
7.1.5.
Temporary Discontinuation
Temporary discontinuation is not allowed during this study.
7.1.6.
Rechallenge
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.

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7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA (Section 1.3). See SoA for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
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 clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 3.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3).

Protocol waivers or exemptions are not allowed 

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
Immediate safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

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 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy and/or Immunogenicity Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, GI, and neurological systems. Height and weight 
will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include systolic and diastolic blood pressure and heart rate. Temperature and 
respiratory rate will be collected at Screening only. Each measurement will be 
recorded in the eCRF. Pulse oximetry will be measured in Cohort 3 only, during 
administration of midazolam.
8.2.3.
Electrocardiograms

Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

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
Twelve-lead ECGs will be performed with the participant in a semi-supine 
position after a rest of at least 10 minutes.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession but no more than 
2 minutes apart. The full set of triplicates should be completed over a brief (e.g., 
5 to 10 minutes) recording period.

ECG Holter (telemetry) monitoring will be obtained as outlined in the SoA 
(Section 1.3). The Holter monitoring data will be sent to GSK and may be 
analyzed at a later date.
8.2.4.
Clinical Safety Laboratory Assessments

See Table 16 (Appendix 2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study and until completion of the follow-up Visit
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the Investigator or Medical Monitor.
o
If clinically significant values do not return to normal/baseline within a period 
of time judged reasonable by the investigator, the etiology should be identified 
and the Sponsor notified.

All protocol-required laboratory tests, as defined in Table 16, must be conducted 
in accordance with the laboratory manual and the SoA (Section 1.3).

If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded.

Additional considerations around Covid-19 can be found in Appendix 7.
8.2.5.
Pregnancy Testing

Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted the time points indicated in the SoA (Section 1.3) during the study 
intervention period.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the
study.

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8.3.
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting
The definitions of AEs or SAEs can be found in Appendix 4.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up on AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the the follow-up 
Visit at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a 
GSK product will be recorded from the time a participant consents to participate 
in the study.

All AEs will be collected from the start of study intervention until the follow-up 
Visit at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions sections of the eCRF, not as AEs.

All SAEs will be recorded and reported to the Sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the Sponsor
within 24 hours of it being available.

Investigators are not obligated to actively seek information on AEs or SAEs after 
the conclusion of the study participation. However, if the investigator learns of 
any SAE, including a death, at any time after a participant has been discharged 
from the study, and he/she considers the event to be reasonably related to the 
study intervention or study participation, the investigator must promptly notify the 
Sponsor.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.

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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 2.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 4.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/Independent EC (IEC), and investigators.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
Sponsor will review and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until
the follow-up Visit.

If a pregnancy is reported, the investigator will record pregnancy information on 
the appropriate form and submit it to GSK within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the 
necessary signed informed consent from the female partner) pregnancy. While 
pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported as such.

The participant/pregnant female partner will be followed to determine the 
outcome of the pregnancy. The investigator will collect follow-up information on 
the participant/pregnant female partner and the neonate and the information will 
be forwarded to the Sponsor.

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
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this 
information in former study participants/pregnant female partner, he or she may
learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study.
8.3.6.
Adverse Events of Special Interest
Adverse events of special interest for this study are cardiovascular and GI events 
(including C. difficile infection), and AchE inhibition.
8.4.
Pharmacokinetics

Plasma and urine samples will be collected for PK assessment. Time points for 
PK collection are indicated in the SoA (Section 1.3). All volumes for PK 
assessment will be provided in the SRM.

There are samples in storage that GSK may retrieve for analysis at a later date if
unexpected results are observed.

Instructions for the collection and handling of biological samples will be provided 
by the Sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded.

Processing, storage, and shipping procedures for blood and urine samples are 
provided in the SRM and/or laboratory manual.

Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.5.
Genetics and/or Pharmacogenomics
Genetics are not evaluated in this study.
8.6.
Biomarkers
Plasma and urine samples will be collected to evaluate 1-NMN and creatinine in Cohort 1 
only. Samples will be collected according to the schedule described in the SoA 
(Section 1.3). Details of sample collection will be provided in the SRM.
GSK may store samples for up to 15 years after the end of the study to achieve study 
objectives. Additionally, with participants consent, samples may be used for further 
research by GSK or others such as universities or other companies to contribute to the 
understanding of infections or other diseases, the development of related or new 
treatments or research methods.
8.7.
Immunogenicity Assessments
Immunogenicity is not evaluated in this study.

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8.8.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There is no formal research hypothesis that will be statistically tested in this study.
9.2.
Sample Size Determination
Approximately 14 participants will be recruited for Cohort 1, 2, and 4 to ensure that each 
Cohort has at least 12 completers, allowing for up to a 20% withdrawal rate. Participants 
in the Japanese Cohort will be randomly assigned (11 active:3 placebo) to receive 
gepotidacin or placebo, ensuring at least 10 completers in the gepotidacin arm. For 
Cohort 3, 22 participants will be enrolled to achieve at least 18 completers to 
accommodate the narrower therapeutic window of digoxin.
The precision, measured by the relative distance of the upper 90% confidence interval 
(CI) to the geometric mean (GM) of the victim drug PK parameters, is determined using 
the reported intrasubject coefficient of variability (CVw%) for each of the PK parameters 
in each Cohort under the current planned sample size. The CVw% values are obtained 
from either previous GSK studies for gepotidacin (Study BTZ117349 [GSK Document 
Number 2014N199850_00]; for digoxin and midazolam (Study AI468063 [Bristol-Myers 
Squibb Document Control Number 930102301]); or from the literature for 
1’-hydroxymidazolam [Paulson, 2017]. Results are presented in Table 15 below. The 
precision ranges from 4.8% to 12.8%. Taking the AUC(0-) for the gepotidacin in 
Cohort 1 under sample size 12 as an example, this means that the upper bound of the 90% 
CI for the GM ratio of gepotidacin + cimetidine: gepotidacin would be within 
approximately 4.8% of the observed GM ratio for AUC(0-). Example CIs based on 
GM=1 are also included in Table 15.
Based on the previous gepotidacin Study 209611 [GSK Document 
Number 2019N422403_00], the GM of Cmax of gepotidacin 2 × 3000 mg dose after the 
second dose was 11.02 µg/mL with a standard deviation on the log scale of 0.2753. For 
the Japanese cohort (Cohort 4), with 10 participants in the active Cohort, the 95% CI for 
Cmax assuming the same GM is (9.05, 13.41). The upper limit of this CI is below 14 
µg/mL which has been associated with mild transient AEs in previous studies. 
Table 15
Sample Size Precision
Cohort
Active Arm
Sample Size
Victims
PK 
Parameter
CVw%
Precision1
90% CI if GM 
Ratio=1
Cohorts 1
and 2
12
Gepotidacin
AUC(0-)
9.01%
4.8%
(0.954, 1.048)
Cmax
20.6%
11.4%
(0.898, 1.114)

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Cohort
Active Arm
Sample Size
Victims
PK 
Parameter
CVw%
Precision1
90% CI if GM 
Ratio=1
Cohort 3
18
Midazolam
AUC(0-)
21.93%
9.29%
(0.915, 1.093)
Cmax
23.23%
9.86%
(0.91, 1.099)
1’-hydroxy-
midazolam
AUC(0-)
14.06%
5.9%
(0.944, 1.059)
Cmax
25.23%
10.7%
(0.903 1.107)
Digoxin
AUC(0-)
13.84%
5.81%
(0.945, 1.058)
Cmax
20.04%
8.48%
(0.922, 1.085)
Cohort 4
10
Gepotidacin
AUC(0-)
9.01%
5.3%
(0.950, 1.053)
Cmax
20.6%
12.8%
(0.886, 1.128)
        AUC(0-) = area under the concentration-time curve from time 0 (predose) extrapolated to infinite time; Cmax = 
maximum observed concentration; CI = confidence interval; CVw% = intrasubject coefficient of variability; GM = 
geometric mean; PK = pharmacokinetic.
1
Precision: (Upper Limit-GM)/GM or (GM-Lower Limit)/Lower Limit.
If participants prematurely discontinue the study, additional participants may be enrolled 
after consultation with the Sponsor to ensure that the required number of evaluable 
participants complete each Cohort of the study.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility 
for the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
9.3.
Analysis Sets
For the purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF.
Randomized
All participants who are randomized.
Safety
All participants who receive at least 1 dose of study intervention. This 
population will be used for all demographic and safety summaries.
PK
Participants who receive at least 1 dose of study intervention and have 
at least 1 non-missing plasma or urine PK concentration. This primary 
analysis population will be used in the assessment and characterization 
of PK concentrations (summary tables and figures).
PK Parameter
All participants in the PK population who received study intervention for 
whom valid and evaluable plasma or urine PK parameters are derived.
This primary analysis population will be used in the assessment and 
characterization of PK parameters (summary and analysis tables and 
figures).

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9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the primary and 
key secondary endpoints.
9.4.1.
Pharmacokinetic and Biomarker Analyses
Plasma and urine gepotidacin, 1-NMN, creatinine, and digoxin; and plasma cimetidine, 
midazolam, and 1’-hydroxymidazolam concentration-time data will be analyzed by PPD, 
under the oversight of the Department of Bioanalysis, Immunogenicity and Biomarkers 
within GSK. Pharmacokinetic and biomarker analysis will be performed by PPD using 
noncompartmental methods with Phoenix WinNonlin Version 8.0 or higher and SAS 
Version 9.4 or higher under the oversight of Clinical Pharmacology Modeling &
Simulation within GSK. Statistical analysis will be performed by PPD, under the 
oversight of Biostatistics, GSK. Calculations will be based on the actual sampling times 
recorded during the study.
The underlying distributional assumptions involved in the statistical analyses will be 
assessed by visual inspection of residual plots. Normality will be examined by normal 
probability plots while homogeneity of variance will be assessed by plotting the residuals 
against the predicted values for the model. If the assumptions are violated, then 
alternative statistical methods will be considered. Within- and between-subject 
coefficient of variation (CV) will also be displayed for all analyses.
Endpoint
Statistical Analysis Methods
Primary
The primary endpoints of this study are PK related. The analysis for the primary PK 
endpoints will be performed for the PK Parameter Population. 
Cohort 1
Analysis will be performed to compare the PK exposure of gepotidacin with and 
without cimetidine. Analysis will be performed on the natural logarithms of plasma 
gepotidacin AUC(0-t), AUC(0-), Cmax and t1/2 using a linear mixed-effect model 
with treatment as a fixed effect and participant as a random effect. Effects will be 
estimated, and 90% CIs will be constructed for the following treatment comparison:

Gepotidacin + cimetidine versus gepotidacin alone
Point estimates and 90% CIs for treatment differences on the log scale derived from 
the model will be exponentiated to obtain estimates for geometric mean (GM) ratios 
and CIs on the original scale. Within and between-subject CV will be calculated as 
well.
Cohort 2
Analysis will be performed to compare the PK exposure of gepotidacin with and 
without rifampicin as described above for the Cohort 1. Analysis will be performed on 
plasma gepotidacin AUCs and Cmax for the following treatment comparison:

Gepotidacin + rifampicin versus gepotidacin alone

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Endpoint
Statistical Analysis Methods
Cohort 3
Analysis will be performed to compare the PK exposure of digoxin, and midazolam 
with and without gepotidacin. Analyses will be performed on the natural logarithms of 
plasma digoxin and midazolam AUC(0-t), AUC(0-), and Cmax using linear 
mixed-effect models with treatment and period, as fixed effects and participant as a 
random effect. Effects will be estimated, and CIs will be constructed for the following 
treatment comparison:

Gepotidacin + digoxin and midazolam versus digoxin and midazolam alone
Point estimates and 90% CIs for treatment differences on the log scale derived from 
the model will be exponentiated to obtain estimates for GM ratios and CIs on the 
original scale. Within and between-subject CV will be calculated as well.
Cohort 4
The effect of food on the PK exposure of gepotidacin in Japanese participants will be 
similarly analyzed as described above for Cohort 3. Analysis will be performed on 
plasma gepotidacin AUC(0-24), AUC(0-48), AUC(0-t), AUC(0-), and Cmax for the 
following treatment comparison:

Gepotidacin under fed conditions versus gepotidacin under fasted 
conditions
All Cohorts
Summary statistics (arithmetic mean, GM, median, 95% CI (arithmetic and 
geometric), standard deviation (arithmetic and geometric), minimum, maximum, and 
geometric CV) for plasma gepotidacin, and plasma digoxin and midazolam PK 
parameters, will be summarized by treatment for each Cohort, as applicable.
Time variables, including Tmax, and Tlag, may be analysed. Nonparametric analysis 
using the Wilcoxon signed-rank test will be used to compute the point estimate. 90% 
CIs for the median difference for each comparison of interest will also be computed.
Secondary
The analysis for the secondary PK endpoints will be performed for the PK Parameter 
Population.
Cohorts 1, 2, 3 and 4
DDI endpoints will be analyzed using the same statistical model as described for 
primary endpoints. Summary statistics (arithmetic mean, GM, median, 95% CI 
(arithmetic and geometric), standard deviation (arithmetic and geometric), minimum, 
maximum, and geometric CV) for plasma and urine gepotidacin PK parameters, will 
be summarized by treatment.
Time variables, including Tmax, Tlag, and t1/2, may be analyzed as described above 
for the primary endpoints.
Exploratory
The analysis for the exploratory biomarker endpoints will be performed for the PK
Parameter Population. The analysis for the exploratory biomarker endpoints will be 
performed for the PK or PK Parameter Population, as appropriate.
Cohort 1
Summary statistics (arithmetic mean, GM, median, 95% CI (arithmetic and 
geometric), standard deviation (arithmetic and geometric), minimum, maximum, and 
geometric CV) for plasma and urine 1-NMN parameters will be summarized by 
treatment.
Summary statistics (arithmetic mean, median, standard deviation, minimum, 
maximum, and CV) for plasma cimetidine concentrations and serum and urine 
creatinine concentrations will be summarized by treatment.

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Endpoint
Statistical Analysis Methods
Cohort 3
Analysis will be performed to compare the PK exposure of 1’-hydroxymidazolam with 
and without gepotidacin as described above for midazolam under the primary 
statistical analysis method for Cohort 3. Analysis will be performed on plasma 
1’-hydroxymidazolam AUC(0-t), AUC(0-), and Cmax for the following treatment 
comparison:

Gepotidacin + digoxin and midazolam versus digoxin and midazolam alone
Summary statistics (arithmetic mean, GM, median, 95% CI (arithmetic and 
geometric), standard deviation (arithmetic and geometric), minimum, maximum, and 
geometric CV) for plasma 1’-hydroxymidazolam PK parameters, will be summarized 
by treatment.
Cohort 4
Summary statistics (arithmetic mean, GM, median, 95% CI (arithmetic and 
geometric), standard deviation (arithmetic and geometric), minimum, maximum, and 
geometric CV) will be used to compare the plasma and urine gepotidacin PK 
parameters for Japanese and non-Japanese subjects for the following:
Single dose:

Japanese subject data (Cohort 4, fed only) versus non-Japanese subject 
data (Cohorts 1 and 2, gepotidacin alone only)
Multi-dose:

Japanese subject data (Cohort 4, fed only) versus non-Japanese subject 
data (Cohort 3)
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards. No formal statistical analysis of the 
safety data will be conducted. 
The details of the statistical analyses of safety and PK data will be provided in the 
reporting and analysis plan.
9.4.3.
Other Analysis
Not applicable.
9.5.
Interim Analysis
No formal interim analysis is planned for this study.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Trademarks
1-NMN
N1-methylnicotinamide
ABSSSI
acute bacterial skin and skin structure infection
AChE
acetylcholinesterase
AE
adverse event
Ae total
total unchanged drug
Ae(t1-t2)
amount of drug excreted in urine in a time interval
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-)
area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
AUC(0-24)
area under the concentration-time curve from time 0 (predose) 
to 24 hours post dose administration following the first dose
AUC(0-48)
area under the concentration-time curve from time 0 (predose) 
to 48 hours post dose administration following the first dose
AUC(0-t)
area under the concentration-time curve from time 0 to the time 
of the last quantifiable concentration
AUC(0-τ)
area under the concentration-time curve from time 0 (predose) 
to time tau
BCRP
breast cancer resistance protein
bpm
beats per minute
CA
Competent Authorities
CIOMS
Council for International Organizations of Medical Sciences
CL/F
apparent oral clearance
CI
confidence interval
CLr
renal clearance of drug
Cmax
maximum observed concentration
Cmin
trough concentration
CV
coefficient of variation
CVw%
intrasubject coefficient of variability
CYP
cytochrome P450
DDI
drug-drug interaction
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
ESRD
end-stage renal disease
fe%
percentage of the given dose of drug excreted in urine
FSH
follicle-stimulating hormone

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GCP
Good Clinical Practice
GI
gastrointestinal
GM
geometric mean
GSK
GlaxoSmithKline
HDPE
high-density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
MATE
multidrug and toxin extrusion
mm Hg
millimeters of mercury
msec
millisecond
NIAID
National Institute of Allergy and Infectious Disease
OCT
organic cationic transporter
P-gp
P-glycoprotein
PBPK
Physiologically-based pharmacokinetics
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QID
four times daily
QTc
corrected QT interval; the measure of time between the start of 
the Q wave and the end of the T wave
QTcB
corrected QT interval using the Bazett formula
QTcF
corrected QT interval using the Fridericia formula
QTL
quality tolerance limit
RoAUC
accumulation ratio for AUC
RoCmax
accumulation ratio for Cmax
SAE
serious adverse event
SoA
schedule of activities
SD
single dose
SRM
Study Reference Manual
t1/2
terminal phase half-life
tlag
lag time before observation of drug concentrations
Tmax
time to reach maximum observed plasma concentration
ULN
upper limit of normal
uUTI
uncomplicated urinary tract infection
Vz/F
apparent volume of distribution
WOCPB
Wome(a)n of childbearing potential

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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
NONE

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 16 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing should be conducted at the time points indicated in the SoA 
(Section 1.3).

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study. 
Table 16
Protocol-Required Safety Laboratory Tests
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell Indices:
White blood cell count 
with differential:
Red Blood Cell 
Count
Mean corpuscular volume
Neutrophils
Hemoglobin
Mean corpuscular hemoglobin Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry1
Blood urea nitrogen
Aspartate aminotransferase
Chloride
Creatinine
Alanine aminotransferase
Carbon dioxide
Glucose (fasting)
Alkaline phosphatase
Total protein
Potassium
Total and direct bilirubin
Albumin
Sodium
Creatine phosphokinase
Magnesium
Calcium
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, nitrite, and leukocyte esterase 
by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is 
abnormal)

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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serology: HIV-1 and -2 antigen/antibody immunoassay, hepatitis B surface 
antigen, hepatitis C antibody)

Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Pregnancy

Follicle-stimulating hormone

Fecal occult blood test and stool cultures as appropriate for gastrointestinal 
(GI) adverse events (8).
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Appendix 6. All events of ALT 3 ULN and bilirubin 2 × 
ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR measured, which may indicate severe liver 
injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations
10.3.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations
10.3.2.
Financial Disclosure
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.3.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or their legally authorized representative and answer all questions 
regarding the study.

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
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 that meets the requirements of 21 Code of Federal Regulations
Part 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or their legally 
authorized representative

Participants who are rescreened are required to sign a new ICF.
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about gepotidacin or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have gepotidacin approved for 
medical use or approved for payment coverage. 
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. There are samples in storage that GSK may retrieve for analysis 
at a later date if unexpected results are observed.
10.3.4.
Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 

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the Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.3.5.
Committees Structure
Not applicable.
10.3.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
participants received. The investigator(s) is/are encouraged to share the summary 
results with the study participants, as appropriate.

Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. 
Requests for access may be made through www.clinicalstudydatarequest.com.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.
10.3.7.
Data Quality Assurance

All participant data relating to the study will be recorded in the eCRF 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. 

Guidance on completion of eCRFs will be provided in the eCRF guidelines.

Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report.

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
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.

The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
clinical study report/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
10.3.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.

Definition of what constitutes source data and its origin can be found in the SRM.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
10.3.9.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.

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The first act of recruitment is the first participant screened and will be the study start 
date.
Study/Site Termination
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include 
but are not limited to:
For study termination:

Discontinuation of further study intervention development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator

If the study is prematurely terminated or suspended, the Sponsor shall promptly 
inform the investigators, the IRBs/IECs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up.
10.3.10.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected DDI interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
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.

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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.4.2.
Definition of SAE
An SAE is defined as any serious adverse event 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 admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) 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:

Possible Hy’s Law case: ALT ≥3 × ULN AND total bilirubin ≥2 × ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as an SAE.

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 

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significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.
o
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse.
10.4.3.
Cardiovascular and Gastrointestinal Events of Special Interest
Investigators will be required to fill out the specific cardiovascular or GI event page of 
the eCRF for the following AEs and SAEs:
Cardiovascular Events:
Gastrointestinal 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

Nausea

Vomiting

Dysphagia

Abdominal pain

Diarrhea

Flatulence

Feces soft

Constipation
10.4.4.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study according to the US National Institute of Allergy and Infectious 
Disease (NIAID) Division of Microbiology and Infectious Diseases (DMID) criteria 
for adult toxicity assessment (Appendix 9).
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
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 intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.4.5.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Medical Monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper Data Collection Tool

Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the Medical Monitor.

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
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the SRM.

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10.5.
Appendix 5: Contraceptive and Barrier Guidance 
10.5.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
Women in the following categories are considered WOCBP (fertile):
1. Following menarche
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below)
Notes:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 
o
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.

Permanent sterilization methods (for the purpose of this study) include:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Müllerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.

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Women of Non-childbearing Potential
Women in the following categories are considered women of non-childbearing potential:
1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study):
a) Documented hysterectomy
b) Documented bilateral salpingectomy
c) Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Müllerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
2. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required.
o
Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
10.5.2.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS) b
Bilateral tubal occlusion
Azoospermic partner (vasectomized or due to a medical cause)

Azoospermia is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential (WOCBP) and the absence of sperm 
has been confirmed. If not, an additional highly effective method of contraception should be 
used. Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s 

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review of the participant’s medical records, medical examination, or medical history interview.)

Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc

oral

intravaginal

transdermal

injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable
Sexual abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.

Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥1% per year when 
used consistently and correctly.
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Male or female condom with or without spermicidee
Cervical cap, diaphragm, or sponge with spermicide
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ 
from those when used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
d.
Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence 
(calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method are not acceptable methods of contraception. 
e.
Male condom and female condom should not be used together (due to risk of failure from friction).

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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Required Follow Up Assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND total bilirubin 2 × ULN (>35% direct bilirubin) or INR >1.5, 
report to GSK as an SAE.1,2
Required Actions, Monitoring and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study intervention

Report the event to GSK within 24 hours

Complete the liver event form and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments as 
described in the Follow Up Assessment 
column.

Do not restart or rechallenge participant with 
study intervention 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING)
MONITORING:
If ALT≥3 × ULN AND total bilirubin 2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, 
aspartate aminotransferase (AST), alkaline 
phosphatase, total bilirubin, and INR) and 
perform liver event follow up assessments 
within 24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferase values show downward 
trend

Obtain blood sample for PK analysis within 
24 hours after the most recent dose4 

Obtain serum creatine phosphokinase, lactate 
dehydrogenase, gamma-glutamyl transferase, 
glutamate dehydrogenase, and serum 
albumin.

Fractionate bilirubin, if total bilirubin 2 × ULN

Obtain complete blood count with differential 
to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the liver event form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, recreational 
drugs, and other over the counter medications.

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Liver Chemistry Stopping Criteria 
If ALT ≥3 × ULN AND total bilirubin <2 × ULN 
and INR ≤1.5:

Perform liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and INR) 
and perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

If ALT ≥3 x ULN AND total bilirubin 
2 × ULN or INR >1.5 obtain the following in 
addition to the assessments listed above:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G or gamma globulins.

Serum acetaminophen adduct assay should 
be done (where available) to assess potential 
acetaminophen contribution to liver injury 
unless acetaminophen use is very unlikely in 
the preceding week (e.g. where the participant 
has been resident in the clinical 

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete Liver Imaging form.

Liver biopsy may be considered and 
discussed with local specialists if available, for 
instance:
o
In patients when serology raises the 
possibility of autoimmune hepatitis
o
In patients when suspected DILI 
progresses or fails to resolve on 
withdrawal of study intervention
o
In patients with acute or chronic 
atypical presentation.

If liver biopsy is conducted, then complete liver 
biopsy form
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, which is indicative of 
direct bilirubin elevations suggesting liver injury.
2.
All events of ALT 3 × ULN and total bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, 
which may indicate severe liver injury (possible “Hy’s Law”), must be reported to GSK as an SAE (excluding 
studies of hepatic impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving 
anticoagulants.
3.
Includes: hepatitis A immunoglobulin (IgM) antibody; hepatitis B surface antigen and hepatitis B core antibody; 
hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
heterophile antibody or monospot testing) and hepatitis E IgM antibody.
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw. If the date or time of the last dose is unclear, provide the participant’s best approximation. 
If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.

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10.7.
Appendix 7: Covid-19 
10.7.1.
Overall Rationale for this Appendix
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, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing.
This protocol appendix outlines measures that may be applicable for any 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 will remain in place until study completion.
10.7.2.
Study Procedures During COVID-19 Pandemic
During the special circumstances caused by the current COVID-19 pandemic, you 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 trial participants.
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants:

Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study 
conduct and 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 
participant notes and recorded as a COVID-19 protocol deviation.
10.7.3.
Protocol Defined Procedures/Visits:

The protocol defined interval for the collection of samples during the Follow-up 
visit (see Section 1.3 Schedule of Activities), may be extended up to a maximum 
length of 14 days. 

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10.7.4.
Data Management/Monitoring:

If a situation arises where on-site monitoring is no longer permitted, GSK will 
consider remote Source Data Verification/Source Document Review (SDV/SDR) 
where permitted by the clinical site/institution. Remote SDV/SDR will be proposed 
to study sites to meet a participant and/or critical quality need, e.g., to assess 
participant safety or to ensure data integrity. In case of remote SDV/SDR, GSK will 
work with the site to ensure participant privacy.

eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) 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 
PI may sign/re-sign the eCRF from any computer/location by accessing InForm (or 
other eDC platform) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly.
Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email approval 
can be accepted by replying to the relevant email that is sent by GSK.

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10.8.
Appendix 8: Clostridium difficile Testing Procedure and 
Algorithm
Note: This algorithm is subject to investigator discretion when the clinical presentation 
and time course of diarrhea (e.g., during or within 12 hours immediately after dosing) 
do not fit the Clostridium difficile associated diarrhea definition; consideration should 
be given to diarrhea occurring in this early time frame to be suggestive of a cholinergic 
effect.

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10.9.
Appendix 9: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity:
GRADE 1
Mild
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required
GRADE 2
Moderate
Mild to moderate limitation in activity – some assistance 
may be needed; no or minimal medical 
intervention/therapy required
GRADE 3
Severe
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible
GRADE 4
Life-
threatening
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DMID) and 
modified to better meet the needs of participants in 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.

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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/mL
>60 mcg/mL
Prothrombin Time (PT)
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated Partial Thromboplastin (APTT)
1.01 to 1.66 ULN
1.67 to 2.33 ULN
2.34 to 3 ULN
>3 ULN
Methemoglobin
5.0 to 9.9%
10.0 to 14.9%
15.0 to 19.9%
>20%
N/A=not applicable; ULN=upper limit of normal. 
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 or
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

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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia
(corrected for albumin)
10.6 to 11.5 mg/dL
11.6 to 12.5 mg/dL
12.6 to 13.5 mg/dL
>13.5 mg/dL or abnormal calcium 
with life-threatening arrhythmia
Hypomagnesemia
1.4 to 1.2 mEq/L
1.1 to 0.9 mEq/L
0.8 to 0.6 mEq/L
<0.6 mEq/L or abnormal magnesium 
with life-threatening arrhythmia
Hypophosphatemia
2.0 to 2.4 mg/dL
1.5 to 1.9 mg/dL or 
replacement Rx required
1.0 to 1.4 mg/dL
intensive therapy or 
hospitalization required
<1.0 mg/dL or abnormal phosphate 
with life-threatening arrhythmia
Hyperbilirubinemia (when accompanied 
by any increase in other liver function 
test)
1.1 to <1.25 ULN
1.25 to <1.5 ULN
1.5 to 1.75 ULN
>1.75 ULN
Hyperbilirubinemia (when other liver 
function tests are in the normal range)
1.1 to <1.5 ULN
1.5 to <2.0 ULN
2.0 to 3.0 ULN
>3.0 ULN
Blood urea nitrogen 
1.25 to 2.5 ULN
2.6 to 5 ULN
5.1 to 10 ULN
>10 ULN
Hyperuricemia (uric acid)
7.5 to 10.0 mg/dL
10.1 to 12.0 mg/dL
12.1 to 15.0 mg/dL
>15.0 mg/dL
Creatinine
1.1 to 1.5 ULN
1.6 to 3.0 ULN
3.1 to 6.0 ULN
>6 ULN or dialysis required
Rx=therapy; ULN=upper limit of normal.
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase (AST)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase (ALT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Gamma to glutamyl transferase (GGT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alkaline Phosphatase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Amylase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
Lipase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
ULN=upper limit of normal.

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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.
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 mm Hg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mm Hg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure 
<60 mm Hg 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; mm Hg = millimeters of mercury; N/A=not applicable; Rx=therapy.

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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.
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.

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
Slight incoordination 
dysdiadochokinesis
Intention tremor, dysmetria, slurred 
speech; nystagmus
Locomotor ataxia
Incapacitated
Psychiatric
Mild anxiety or depression
Moderate anxiety or depression; therapy 
required; change in normal routine
Severe mood changes requiring 
therapy; or suicidal ideation; or 
aggressive ideation
Acute psychosis requiring 
hospitalization; or suicidal 
gesture/attempt or hallucinations
Muscle strength
Subjective weakness; no objective 
symptoms/signs
Mild objective signs/symptoms; no 
decrease in function
Objective weakness; function limited
Paralysis
Paresthesia
(burning, tingling, 
etc.)
Mild discomfort; no treatment 
required
Moderate discomfort; non- narcotic 
analgesia required
Severe discomfort; or narcotic 
analgesia required with symptomatic 
improvement
Incapacitating; or not responsive 
to narcotic analgesia
Neurosensory
Mild impairment in sensation 
(decreased sensation, e.g., vibratory, 
pinprick, hot/cold in great toes) in 
focal area or symmetrical distribution; 
or change in taste, smell, vision, 
and/or hearing
Moderate impairment (moderately 
decreased sensation, e.g., vibratory, 
pinprick, hot/cold to ankles) and/or joint 
position or mild impairment that is not 
symmetrical
Severe impairment (decreased or loss 
of sensation to knees or wrists) or 
loss of sensation of at least moderate 
degree in multiple different body 
areas (i.e., upper and lower 
extremities)
Sensory loss involves limbs and 
trunk; paralysis; or seizures
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 pain; 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.

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SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
Erythema; pruritus
Diffuse, maculo-papular rash, dry 
desquamation
Vesiculation or moist desquamation 
or ulceration
Exfoliative dermatitis, mucous 
membrane involvement or 
erythema, multiforme or 
suspected Stevens-Johnson or 
necrosis requiring surgery
Induration
<15 mm
15 to 30 mm
>30 mm
N/A
Erythema
<15 mm
15 to 30 mm
>30 mm
N/A
Edema
<15 mm
15 to 30 mm
>30 mm
N/A
Rash at injection 
site
<15 mm
15 to 30 mm
>30 mm
N/A
Pruritus
Slight itching at injection site
Moderate itching at injection extremity
Itching over entire body
N/A
N/A=not applicable.
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic reaction
Pruritus without rash
Localized urticarial
Generalized urticarial; angioedema
Anaphylaxis
Headache
Mild, no treatment required
Transient, moderate; treatment required
Severe; responds to initial narcotic 
therapy
Intractable; requires repeated 
narcotic therapy
Fever: oral
37.7 to 38.5C or 100.0 to 101.5F
38.6 to 39.5C or 101.6 to 102.9F
39.6 to 40.5C or 103 to 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25% to 50% 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self

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11.
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