Clinical trial NCT04493931
Conditions: Infections, Bacterial
Keywords: Gepotidacin Drug Interaction Pharmacokinetic Safety Bacterial Infection Japanese Healthy Adults
Sponsor: GlaxoSmithKline
Start date: 2020-08-14; Completion date: 2020-12-21
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a drug-drug interaction (DDI), pharmacokinetics (PK), safety and tolerability study in adult healthy participants, including Japanese cohort. 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 Japanese participants in cohort 4. Food effect will also be evaluated in cohort 4.

Detailed description:

Arms: arm 1: This is a fixed sequence (Sequence AB) cohort. Participants will receive gepotidacin 1500 milligrams (mg) single dose (SD) on Day 1 of Period 1 (Treatment A); and Cimetidine 400 mg 4 times daily on Days 1 through 4 of Period 2 and gepotidacin 1500 mg single dose (Treatment B). Gepotidacin will be administered 1 hour after the first dose of cimetidine on Day 2 of Period 2. There will be 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. arm 2: This is a fixed sequence (Sequence CDE) cohort. Participants will receive gepotidacin 1500 mg single dose on Day 1 of Period 1 (Treatment C), 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 D); and gepotidacin 1500 mg single dose administered in the morning on Day 8 and 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 between Treatment C and Treatment D, and a follow-up visit 7 to 10 days after the last dose of rifampicin. arm 3: Participants will receive digoxin 0.5 mg and 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). There will be a washout of at least 10 days between treatments. 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. arm 4: Participants will receive gepotidacin two 3000 mg doses (given 12 hours apart) co-administered with digoxin 0.5 mg and midazolam 2 mg in Period 1 on Day 1, with the 2 probe drugs administered with the second daily dose of gepotidacin only (Treatment G) followed by digoxin 0.5 mg and midazolam 2 mg (Treatment F) in Period 2 on Day 1. A follow-up visit will occur 7 to 10 days after the last dose of study intervention in Period 2. arm 5: Cohort 4 will include Japanese participants. Participants will receive a single dose of gepotidacin 1500 mg under fed conditions in Period 1 (Treatment H), then a single dose of gepotidacin 1500 mg under fasted conditions in Period 2 (Treatment I), followed by two doses of gepotidacin up to 3000 mg (given 12 hours apart) under fed conditions in Period 3 (Treatment J). There will be 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. arm 6: Cohort 4 will include Japanese participants. Participants will receive a single dose of gepotidacin 1500 mg under fasted conditions in Period 1 (Treatment I), then a single dose of gepotidacin 1500 mg under fed conditions in Period 2 (Treatment H), followed by two doses of gepotidacin up to 3000 mg (given 12 hours apart) under fed conditions in Period 3 (Treatment J). There will be 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. arm 7: Cohort 4 will include Japanese participants. Participants will receive a single dose of placebo under fed conditions in Period 1, then a single dose of placebo under fasted conditions in Period 2, followed by two doses of placebo (given 12 hours apart) under fed conditions in Period 3. There will be a washout of at least 3 days between each period, and a follow-up visit 5 to 7 days after the last dose of placebo.
Interventions: intervention 1: Gepotidacin intervention 2: Cimetidine intervention 3: Rifampicin intervention 4: Midazolam intervention 5: Digoxin intervention 6: Placebo matching to gepotidacin
Intervention descriptions: intervention 1: Gepotidacin tablets will be available as unit dose strength 750 mg and will be administered orally. intervention 2: Cimetidine tablets will be available as unit dose strength 400 mg and will be administered orally. intervention 3: Rifampicin Capsules will be available as unit dose strength 300 mg and will be administered orally. intervention 4: Midazolam oral syrup 2 milligrams per milliliter (mg/mL) will be available to be administered orally. intervention 5: Digoxin tablets will be available as unit dose strength 0.25 mg and will be administered orally. intervention 6: Placebo matching to gepotidacin tablets will be administered orally.

Protocol documents:
Prot_000.pdf: 
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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
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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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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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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 
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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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
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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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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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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
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 
half-life of approximately 2 hours. Cimetidine tablets are rapidly absorbed after oral 


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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 
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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.
REFERENCES
Bax BD, Chan PF, Eggleston DS, et al. Type IIA topoisomerase inhibition by a new class 
of antibacterial agents. Nature. 2010:466(7309):935-940.
Bristol-Myers Squibb Company Document Control Number 930102301 Study AI468063. 
Effects of BMS-955176 on the single-dose pharmacokinetics of probe substrates 
(caffeine, metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, digoxin, and 
pravastatin) in healthy subjects. 2016.
Cimetidine prescribing information (Mylan Pharmaceuticals), July 2019.
Digoxin prescribing information (GlaxoSmithKline), November 2011.
Drug Interaction Solutions. University of Washington School of Pharmacy website. 
Updated 2020. https://www.druginteractionsolutions.org
Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug 
metabolizing enzymes and transporters in humans and their simultaneous use in the 
“cocktail” approach. Clin Pharmacol Ther. 2007:81(2):270-283.
GlaxoSmithKline Document Number 2014N198291_00 Study ID BTZ115198. A two 
part study to evaluate safety, tolerability, and pharmacokinetics of single and repeat IV 
doses of GSK2140944 in healthy adult subjects. 2014.
GlaxoSmithKline Document Number 2014N199850_00 Study ID BTZ117349. A 
single-center, three-part, open label study to evaluate the relative bioavailability of 
two formulations, food effect, and interaction with itraconazole following single dose of 
GSK2140944 in healthy subjects and effect of food on safety, tolerability, and 
pharmacokinetics following multiple doses of GSK2140944 in healthy elderly subjects. 
2015.
GlaxoSmithKline Document Number 2015N227098_00 Study ID BTZ115775.
Population pharmacokinetic-pharmacodynamic analysis of a Phase I, randomized, 
double-blinded, placebo- and moxifloxacin-controlled, 4-period crossover study to 
evaluate the effect of GSK2140944 on cardiac conduction as assessed by 12-lead 
electrocardiogram in healthy volunteers. 2015.
GlaxoSmithKline Document Number 2015N243789_00 Study ID BTZ116704. A 
Phase II, randomized, two-part, multicenter, dose-ranging study in adult subjects 
evaluating the safety, tolerability, and efficacy of GSK2140944 in the treatment of 
subjects with suspected or confirmed gram-positive acute bacterial skin and skin structure 
infections. 2015.
GlaxoSmithKline Document Number 2017N317989_01 Study ID BTZ116577. A 
Phase III, randomized, multicenter, open-label study in adolescent and adult participants 
comparing the efficacy and safety of gepotidacin to ceftriaxone plus azithromycin in the 
treatment of uncomplicated urogenital gonorrhea caused by neisseria gonorrhoeae. 2017. 


2020N434866_00
CONFIDENTIAL
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114
GlaxoSmithKline Document Number 2017N318043_01 Study ID 204989. A Phase III, 
randomized, multicenter, parallel-group, double-blind, double-dummy study in 
adolescent and adult female participants comparing the efficacy and safety of gepotidacin 
to nitrofurantoin in the treatment of uncomplicated urinary tract infection (acute cystitis). 
2017.
GlaxoSmithKline Document Number 2019N407320_01 Study ID 212390. A Phase III, 
randomized, multicenter, parallel-group, double-blind, double-dummy study in 
adolescent and adult female participants comparing the efficacy and safety of gepotidacin 
to nitrofurantoin in the treatment of uncomplicated urinary tract infection (acute cystitis). 
2019.
GlaxoSmithKline Document Number 2019N422403_00 Study ID 209611. A Phase I, 
double-blind, two-part, sequential study to evaluate the pharmacokinetics of gepotidacin 
tablets in healthy adult and adolescent participants. 18-May-2020.
GlaxoSmithKline Document Number CM2010/00033/06. Gepotidacin Investigator’s 
Brochure. 2019.
Heizmann P, Eckert M, Ziegler WH. Pharmacokinetics and bioavailability of midazolam 
in man. Br J Clin Pharmacol. 1983:16(Suppl 1):43S–49S
Huang SM, Temple R, Throckmorton DC, et al. Drug interaction studies: study design, 
data analysis, and implications for dosing and labeling: Current opinion. Clin Pharmacol 
Ther. 2007:81(2):298-304.
Midazolam hydrochloride syrup prescribing information (Roxane Laboratories, Inc), 
September 2012.
Nassr N, Huennemeyer A, Herzog R, et al. Effects of rifampicin on the pharmacokinetics 
of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol.
2009:68(4):580-587.
Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin 
clinical relevance. Clin Pharmacokinet. 2003:42(9):819-850.
Paulson SK, Wood-Horrall RN, Hoover R, et al. The pharmacokinetics of the CYP3A 
substrate midazolam after steady-state dosing of delafloxacin. Clin Ther. 
2017:39(6):1182-1190.
Rifampin capsules prescribing information (Sanofi-Aventis US LLC), February 2019.
Thummel KE, O’Shea D, Paine MF, et al. Oral first-pass elimination of midazolam 
involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol
Ther. 1996:59(5):491-502.

SAP_001.pdf: 
0 
 
 
 
Reporting and Analysis Plan 
Study ID:  213678 
Official Title of Study:  Reporting and Analysis Plan for A Pharmacokinetic, multicohort 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 
Date of Document: 16-DEC-2020 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
213678 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for 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 
Compound Number  : GSK2140944 
Effective Date  
: Refer to Document Date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol GSK213678. 
• 
This RAP is intended to describe the safety, tolerability, and pharmacokinetic 
(PK) analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) and Interim Analysis (IA) deliverable. 
 
RAP Author(s): 
 
Biostatistician (Biostatistics, Early Development Services, PPD) 
Senior Pharmacokineticist (Clinical Pharmacology, PPD) 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited.
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
213678 
 
2 
 
RAP Team Approvals: 
Approver 
Date 
Approval 
Method 
 MD 
08-Dec-2020 
E-mail 
Clinical Development Leader 
Clinical Development/ Specialty/ID 
 
09-Dec-2020 
E-mail 
Manager (Clinical Data Management) 
 
09-Dec-2020 
E-mail 
Director (CPMS) 
 
09-Dec-2020 
E-mail 
Programming Leader (Clinical Programming) 
 
09-Dec-2020 
E-mail 
Study Delivery Lead (Clinical Operations) 
 
09-Dec-2020 
E-mail 
Medical Director SERM (SMG Pharma Safety) 
  
10-Dec-2020 
E-mail 
Associate Statistician (Development Statistics) 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Approval Method 
  
Vault TMF e-
signature 
Manager (Development Statistics) 
 
Vault TMF e-
signature 
Director (Development Programming) 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
213678 
 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Analyses ..................................................................................... 16 
3. 
PLANNED ANALYSES .......................................................................................... 17 
3.1. 
Interim Analyses ......................................................................................... 17 
3.2. 
Final Analyses ............................................................................................ 17 
4. 
ANALYSIS POPULATIONS ................................................................................... 18 
4.1. 
Protocol Deviations ..................................................................................... 18 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 19 
5.1. 
Baseline Definitions .................................................................................... 19 
5.2. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 19 
6. 
STUDY POPULATION ANALYSES ....................................................................... 20 
6.1. 
Overview of Planned Study Population Analyses ........................................ 20 
7. 
PHARMACOKINETIC ANALYSES ......................................................................... 21 
7.1. 
Primary Pharmacokinetic Analyses ............................................................. 21 
7.1.1. 
Endpoint / Variables ..................................................................... 21 
7.1.1.1. 
Drug Concentration Measures .................................... 21 
7.1.1.2. 
Derived Pharmacokinetic Parameters......................... 21 
7.1.2. 
Summary Measure ...................................................................... 22 
7.1.3. 
Population of Interest ................................................................... 23 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 23 
7.1.5. 
Statistical Analyses / Methods ..................................................... 23 
7.1.5.1. 
Statistical Methodology Specification .......................... 23 
7.2. 
Secondary Pharmacokinetic Analyses ........................................................ 26 
7.2.1. 
Endpoint / Variables ..................................................................... 26 
7.2.1.1. 
Derived Pharmacokinetic Parameters......................... 26 
7.2.1.2. 
Derived Pharmacokinetic Parameters......................... 26 
7.2.2. 
Summary Measure ...................................................................... 27 
7.2.3. 
Population of Interest ................................................................... 28 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 28 
7.2.5. 
Statistical Analyses / Methods ..................................................... 28 
7.2.5.1. 
Statistical Methodology Specification .......................... 29 
7.3. 
Exploratory Pharmacokinetic Analyses ....................................................... 30 
7.3.1. 
Endpoint / Variables ..................................................................... 30 
7.3.1.1. 
Drug Concentration Measures .................................... 30 
7.3.1.2. 
Derived Pharmacokinetic Parameters......................... 30 
7.3.2. 
Summary Measure ...................................................................... 31 


 
CONFIDENTIAL 
 
 
 
213678 
 
4 
 
7.3.3. 
Population of Interest ................................................................... 31 
7.3.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 31 
7.3.5. 
Statistical Analyses / Methods ..................................................... 32 
7.3.5.1. 
Statistical Methodology Specification .......................... 32 
8. 
BIOMARKER ANALYSES ...................................................................................... 34 
8.1. 
Exploratory Biomarker Analyses ................................................................. 34 
8.1.1. 
Endpoint / Variables ..................................................................... 34 
8.1.1.1. 
Biomarker Concentration Measures ........................... 34 
8.1.1.2. 
Derived Biomarker Parameters................................... 34 
8.1.2. 
Summary Measure ...................................................................... 35 
8.1.3. 
Population of Interest ................................................................... 35 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 35 
8.1.5. 
Statistical Analyses / Methods ..................................................... 35 
8.1.5.1. 
Statistical Methodology Specification .......................... 35 
9. 
SAFETY ANALYSES ............................................................................................. 37 
9.1. 
Adverse Events Analyses ........................................................................... 37 
9.1.1. 
Adverse Events of Special Interest Analyses ............................... 37 
9.1.2. 
Potential Acetylcholinesterase-Inhibition AESIs ........................... 38 
9.2. 
Clinical Laboratory Analyses ....................................................................... 38 
9.3. 
Other Safety Analyses ................................................................................ 38 
9.4. 
Strategy for Intercurrent (Post-Randomization) Events ............................... 38 
10. REFERENCES ....................................................................................................... 39 
11. APPENDICES ........................................................................................................ 40 
11.1. 
Appendix 1: Schedule of Activities .............................................................. 40 
11.1.1. 
Protocol Defined Time and Events Table ..................................... 40 
11.1.2. 
Protocol Defined Safety and PK Assessments ............................. 49 
11.2. 
Appendix 2: Assessment Windows ............................................................. 56 
11.3. 
Appendix 3: Study Phases and Periods ...................................................... 57 
11.3.1. 
Treatment States ......................................................................... 57 
11.3.2. 
Treatment Period for Safety Summaries by Treatment 
Cohort .......................................................................................... 57 
11.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 59 
11.4.1. 
Study Treatment & Sub-group Display Descriptors ...................... 59 
11.4.2. 
Reporting Process & Standards ................................................... 60 
11.4.3. 
Reporting Standards for Pharmacokinetic .................................... 61 
11.5. 
Appendix 5: Derived and Transformed Data ............................................... 63 
11.5.1. 
General ........................................................................................ 63 
11.5.2. 
Study Population .......................................................................... 63 
11.5.3. 
Safety .......................................................................................... 64 
11.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 65 
11.6.1. 
Premature Withdrawals ................................................................ 65 
11.6.2. 
Handling of Missing Data ............................................................. 65 
11.6.2.1. Handling of Missing and Partial Dates ........................ 65 
11.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 67 
11.7.1. 
ECG ............................................................................................. 67 
11.7.2. 
Vital Signs .................................................................................... 67 
11.7.2.1. Normal Range for Vital Signs ..................................... 67 
11.8. 
Appendix 8: Adverse Event Assessement Criteria ...................................... 68 


 
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11.8.1. 
Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Events Assessments (2007) - 
Laboratory Values ........................................................................ 68 
11.8.2. 
List of Potential AEs for programming to be considered 
due to Acetylcholinesterase-Inhibition .......................................... 70 
11.9. 
Appendix 9: Multiple Comparisons & Multiplicity ......................................... 73 
11.9.1. 
Handling of Multiple Comparisons & Multiplicity ........................... 73 
11.10. Appendix 10: Abbreviations & Trade Marks ................................................ 74 
11.10.1. Abbreviations ............................................................................... 74 
11.10.2. Trademarks ................................................................................. 75 
11.11. Appendix 11: List of Data Displays.............................................................. 76 
11.11.1. Data Display Numbering .............................................................. 76 
11.11.2. Mock Example Shell Referencing ................................................ 76 
11.11.3. Deliverables ................................................................................. 76 
11.11.4. Study Population Tables .............................................................. 77 
11.11.5. Safety Tables ............................................................................... 78 
11.11.6. Pharmacokinetic Tables ............................................................... 80 
11.11.7. Biomarker Tables ......................................................................... 86 
11.11.8. Safety Figures ............................................................................. 87 
11.11.9. Pharmacokinetic Figures ............................................................. 88 
11.11.10. Biomarker Figures ....................................................................... 93 
11.11.11. ICH Listings ................................................................................. 94 
11.11.12. Non-ICH Listings .......................................................................... 97 
11.12. Appendix 12: Example Mock Shells for Data Displays .............................. 100 
 
 
 


 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the CSR for Protocol GSK213678 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The protocol states both within- and between-subject coefficient of variation (CV) will be 
calculated during statistical analysis of the PK data using linear mixed-effect models. It 
was subsequently determined that only within-subject CV is necessary. 
2.2. 
Study Objective(s) and Endpoint(s) 
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 
3000mg 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 
• 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 


 
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Objectives 
Endpoints 
adult participants 
 
 
 
 
 
• 
To evaluate the effect of a Japanese meal 
on the bioavailability of the gepotidacin 
tablet formulation 
the second dose; AUC(0-24), AUC(0-48), 
and AUC(0-t) of gepotidacin using the full 
profileb(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 
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 
 
• 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 
 
 


 
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Objectives 
Endpoints 
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 
• 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 
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 
 
• 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 


 
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Objectives 
Endpoints 
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 
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 
 
 
• 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 
• To evaluate concentrations of serum and 
urine creatinine after administration of 
gepotidacin with and without cimetidine in 
adult healthy participants 
 
 
• Serum and urine creatinine 
concentrations, as data permit 
• 1-NMN plasma and urine PK parameters 
normalized to creatinine, as data permit 
• To evaluate cimetidine PK to assess 
transporter inhibition in adult healthy 
participants 
• Cimetidine plasma PK concentrations, as 
data permit 
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 
coadministered 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 
• Plasma and urine concentrations and 
parameters for gepotidacin, as data permit 
 
 


 
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Objectives 
Endpoints 
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 
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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2.3. 
Study Design 
Overview of Study Design and Key Features 
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. 
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. 
  
  
  
  
                      
  
  
  
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Cohort 3 (Gepotidacin, Digoxin, and Midazolam) Study Design Schematic 
 
h = hour; PK = pharmacokinetic; SD = single dose; W = washout. 
• 
There will be a washout of at least 10 days between treatments. 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
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Overview of Study Design and Key Features 
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. 
  
  
  
                   
                    
              
  
  
  
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Design 
Features 
• Phase I, DDI, PK, safety, and tolerability, 4-cohort study in adult healthy 
participants. 
• 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. 
• 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 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.  
• 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. 
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. a 
participant who is randomized to gepotidacin receives gepotidacin in all periods 
and a participant randomized to placebo receives placebo in all periods. 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 


 
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Overview of Study Design and Key Features 
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. 
 
Dosing 
Cohort 1: 
• Treatment A: Gepotidacin 1500 mg 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 1 hour after the first dose of 
cimetidine on Day 2 of Period 2..  
Cohort 2: 
• 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.  
Cohort 3: 
• 
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. 
Cohort 4: 
• 
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 or placebo 
(given 12 hours apart) under fed conditions on Day 1. 
Time and 
Events 
• See Appendix 1: Schedule of Activities (SoA) 
Treatment 
Assignment 
• 
Cohort 1: Participants will receive the treatments in a fixed sequence 
(Sequence AB) 
• 
Cohort 2: Participants will receive the treatments in a fixed sequence 
(Sequence CDE) 


 
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• 
Cohort 3: Participants will be randomly assigned to receive 1 of 2 treatment 
sequences in a 1:1 ratio (Sequence FG or Sequence GF) 
• 
Cohort 4: Participants will be randomly assigned (11 active:3 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 
Interim 
Analysis 
No formal interim analysis is planned for this study.  
 
2.4. 
Statistical Analyses 
There is no formal research hypothesis that will be statistically tested in this study. 
 
 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No formal interim analysis is planned for this study. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol  
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met (for Cohort 4).  
4. Randomization codes have been distributed as per PPD procedures. 
 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• All participants who sign the informed consent 
form (ICF). 
• Study Population 
Enrolled 
• All participants who passed screening and 
entered the study. 
• Note screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the 
study. 
• Study Population 
Randomized 
• All participants who are randomized. (Cohorts 
3 and 4) 
• Study Population 
Safety 
• All participants who take at least 1 dose of 
study intervention. 
• Study Population 
• Safety 
PK 
• Participants who receive at least 1 dose of 
study intervention and have at least 1 
non-missing plasma or urine PK concentration. 
• PK and Biomarker 
Concentration 
PK Parameter 
• All participants in the PK population who 
received study intervention for whom valid and 
evaluable plasma or urine PK parameters are 
derived. 
• PK and Biomarker 
parameter 
• PK and Biomarker 
statistical analysis 
NOTES:  
• Please refer to Appendix 11: List of Data Displays which details the population to be used for 
each display being generated. 
4.1. 
Protocol Deviations 
Important (significant) protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 


 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the electronic case report form (eCRF). 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Baseline Definitions 
Both study baseline and period baseline will be used for this study.  
For 12-lead ECG and vital signs, period baseline will be used. The baseline for 12-lead 
ECG will be the mean of pre-dose assessments for each period. The baseline for vitals 
will be the pre-dose assessment for each period. If the pre-dose assessment for a period 
will be missing, then the baseline for the last period will be used. If Period 1 pre-dose are 
missing, the last available assessment prior to time of first study drug administration, 
including unscheduled and repeated measurements will be used. If period 1 baseline data 
are missing no derivation will be performed and baseline will be set to missing, unless 
otherwise stated. 
For all other safety assessment, study baseline will be used. The baseline value will be 
the last available assessment prior to time of first study drug administration, including 
unscheduled and repeated measurements, unless noted otherwise. If study baseline data 
are missing no derivation will be performed and baseline will be set to missing, unless 
otherwise stated. 
5.2. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
11.1 
Appendix 1: Schedule of Activities 
11.2 
Appendix 2: Assessment Windows 
11.3 
Appendix 3: Study Phases and Treatment Emergent Adverse Events 
11.4 
Appendix 4: Data Display Standards & Handling Conventions 
11.5 
Appendix 5: Derived and Transformed Data 
11.6 
Appendix 6: Reporting Standards for Missing Data 
11.7 
Appendix 7: Values of Potential Clinical Importance 
11.8 
Appendix 8: Adverse Event Assessment Criteria 
11.9 
Appendix 9: Multiple Comparisons and Multiplicity 
11.10 
Appendix 10: Abbreviations & Trade Marks 
11.11 
Appendix 11: List of Data Displays 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Screened, Enrolled, Randomized, or 
Safety population, unless otherwise specified. 
Study population analyses including analyses of subjects enrolled by Country and Site 
ID, subject’s disposition, screening failures, protocol deviations, demographic and 
baseline characteristics, prior and concomitant medications, and exposure will be based 
on GSK Core Data Standards. Details of the planned displays are presented in Appendix 
11: List of Data Displays. 
 
 


 
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7. 
PHARMACOKINETIC ANALYSES 
7.1. 
Primary Pharmacokinetic Analyses 
7.1.1. 
Endpoint / Variables 
7.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3 
Reporting Standards for Pharmacokinetic).  
7.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or using the currently supported version of SAS (9.4 or 
higher). All calculations of non-compartmental parameters will be based on actual 
sampling times. Primary pharmacokinetic parameters listed below will be determined 
from the plasma concentration-time data for gepotidacin, digoxin, and midazolam, as 
appropriate and as data permit. 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 (predose) to the last 
quantifiable concentration, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid 
(calculated for Cohorts 1 and 2: gepotidacin; Cohort 3: digoxin and midazolam; Cohort 4 (all 
periods): gepotidacin (using the full profile (both doses) in Period 3)). 
AUC(0-∞) 
Area under the concentration-time curve from time 0 (predose) extrapolated to infinite time, 
to be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid (calculated for Cohorts 1 and 2: 
gepotidacin; Cohort 3: digoxin and midazolam; Cohort 4 (periods 1 and 2 only): 
gepotidacin). 
AUC(0-24) 
Area under the plasma concentration-time curve from time 0 (predose) to the concentration 
at 24 hours postdose to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid (calculated for 
gepotidacin for Cohort 4 (all periods); the full profile (both doses) will be used for Period 3 ). 
AUC(0-48) 
Area under the plasma concentration-time curve from time 0 (predose) to the concentration 
at 48 hours postdose, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. (calculated for 
gepotidacin for Cohort 4 (all periods); the full profile (both doses) will be used for Period 3). 
AUC(0-τ) 
Area under the plasma concentration-time curve from time 0 (predose) to time tau (tau = 12 
h) (calculated for gepotidacin for Cohort 4, Period 3; separate estimates for each dose). 
Cmax 
Maximum observed plasma concentration, determined directly from the concentration-time 
data (calculated for Cohorts 1 and 2: gepotidacin; Cohort 3: digoxin and midazolam; Cohort 
4 (all periods): gepotidacin (separate estimates for each dose in Period 3)). 
Tmax 
Time to reach maximum observed plasma concentration (calculated for Cohorts 1 and 2: 
gepotidacin; Cohort 3: digoxin and midazolam; Cohort 4 (all periods): gepotidacin (separate 
estimates for each dose in Period 3)). 
Tlag 
Lag time before observation of drug concentration in plasma (calculated for Cohort 2: 
gepotidacin; Cohort 3: digoxin and midazolam; Cohort 4 (periods 1 and 2 only): 
gepotidacin). 


 
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Parameter 
Parameter Description 
t1/2 
Apparent plasma terminal phase half-life (plasma) (calculated for gepotidacin in Cohort 1 
only). 
RoAUC 
Accumulation ratio calculated as AUC(0-) after the second dose, where 0 is the timepoint 
prior to second dose, divided by AUC(0-) after the first dose, where 0 is the predose 
timepoint prior to the first dose (calculated for geptodacin in Cohort 4, Period 3 only). 
RoCmax 
Accumulation ratio calculated as Cmax after the second dose divided by Cmax after the first 
dose (calculated for geptodacin in Cohort 4, Period 3 only). 
NOTES: 
• 
Additional parameters may be included as required. 
 
7.1.2. 
 Summary Measure 
Cohort 1 
Plasma PK parameters Cmax, Tmax, t1/2, AUC(0-t), and AUC(0-∞) of gepotidacin 
following a single 1500 mg dose of gepotidacin alone (Period 1) and in the presence of 
cimetidine 400 mg QID (Period 2) in healthy adult participants will be summarized by 
treatment. Gepotidacin PK parameter estimates will be listed by participant and 
treatment. 
Cohort 2 
Plasma PK parameters Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-∞) of gepotidacin 
following a single 1500 mg dose of gepotidacin alone (Period 1) and in the presence of 
rifampin 600 mg QD (Period 2) in healthy adult participants will be summarized by 
treatment. Gepotidacin PK parameter estimates will be listed by participant and 
treatment. 
Cohort 3 
Plasma PK parameters Cmax, Tlag, Tmax, AUC(0-t), and AUC(0-∞) of digoxin and 
midazolam following a single dose (0.5 mg of digoxin and 2 mg of midazolam) alone and 
in the presence of gepotidacin (co-administered with the second dose of a two 3000 mg 
dose gepotidacin treatment) in healthy adult participants will be summarized by 
treatment. Digoxin and midazolam PK parameter estimates will be listed by participant 
and treatment. 
Cohort 4, Periods 1 and 2 
Plasma PK parameters Cmax, Tlag, Tmax, AUC(0-24), AUC(0-48), AUC(0-t), and 
AUC(0-∞) of gepotidacin following a single 1500 mg dose of gepotidacin under fasted or 
fed conditions in healthy adult Japanese participants will be summarized by treatment. 
Gepotidacin PK parameter estimates will be listed by participant and treatment. 
Cohort 4, Period 3  
The following gepotidacin PK parameters will be summarized following a two 3000 mg 
dose treatment in healthy adult Japanese participants: Cmax, Tmax, and AUC(0-τ) 


 
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(separately for dose 1 and dose 2); RoAUC and RoCmax (dose 2); AUC(0-24), 
AUC(0-48), and AUC(0-t) using the full profile (both doses). Gepotidacin PK parameter 
estimates will be listed by participant. 
7.1.3. 
Population of Interest 
The primary PK analyses will be based on the PK population for plasma PK 
concentrations and the PK parameter population for plasma PK parameters. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The intercurrent events identified are:  
• Treatment Discontinuation  
• Not consuming 100% food (Only for Cohort 4) 
 
The “while on treatment” strategy will be used to handle the intercurrent event “treatment 
discontinuation”. For this strategy, responses to treatment until the occurrence of the 
intercurrent event will be considered. PK parameters will not be derived once the subject 
discontinues the treatment so change to the protocol planned statistical model is not 
anticipated. 
The intercurrent event “not consuming 100% food” will handled by “Treatment Policy” 
strategy. Data will be considered regardless of whether or not the intercurrent event 
occurs so change to the protocol planned statistical model is not anticipated. 
7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Primary plasma PK parameters as described in Section 7.1.1 will be estimated for 
gepotidacin, digoxin, and midazolam. For each of these parameters the following 
summary statistics will be calculated by cohort and treatment: median, maximum, 
minimum, arithmetic mean, standard deviation, 95% confidence interval (CI) for the 
arithmetic mean, geometric mean, CV on geometric mean, 95% CI for the geometric 
mean, and SD of logarithmically transformed data. Parameters that are not 
logarithmically transformed are listed in Section 11.4.3.  
7.1.5.1. 
Statistical Methodology Specification 
The following PK statistical analyses will only be performed if sufficient data are 
available (i.e. if participants have well defined plasma profiles). 
For the linear mixed model analyses described below, the Kenward and Roger method for 
approximating the denominator degrees of freedom and correcting for bias in the 
estimated variance-covariance of the fixed effects will be used.  
 
 


 
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Endpoint / Variables 
• 
Plasma primary PK endpoints include plasma PK parameters for gepotidacin (Cohorts 1, 2, and 4) 
and plasma PK parameters for digoxin and midazolam (Cohort 3), as data permit. 
Model Specification 
Cohort 1 
• 
Analysis will be performed to compare the plasma 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-subject CV will be calculated as well. 
• 
The effect of cimetidine on gepotidacin Tmax will also be assessed. Nonparametric analysis using 
the Wilcoxon signed-rank test will be used to compute the point estimate for the above treatment 
comparison. 90% CIs for the median difference will also be computed. 
 
Cohort 2 
• 
A linear mixed model analysis will be performed to compare the plasma PK exposure of gepotidacin 
with and without rifampicin as described above for the Cohort 1. Analysis will be performed on the 
natural logarithms of plasma gepotidacin AUC(0-t), AUC(0-∞), and Cmax for the following treatment 
comparison: 
Gepotidacin + rifampicin versus gepotidacin alone 
• 
Wilcoxon signed-ranked test will be performed to compare the plasma Tmax and Tlag of gepotidacin 
with and without rifampicin as described above for the Cohort 1.  
 
Cohort 3 
• 
Analysis will be performed to compare the plasma 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-subject CV 
will be calculated as well. 
• 
A Wilcoxon signed-rank test will be performed to compare the plasma Tmax and Tlag of digoxin and 
midazolam with and without gepotidacin as described above for the Cohorts 1 and 2.  
 
Cohort 4 
• 
The effect of food on the plasma PK exposure of gepotidacin in Japanese participants (Periods 1 
and 2) will be similarly analyzed using a linear mixed-effect model as described above for Cohort 3. 


 
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Analysis will be performed on the natural logarithms of plasma gepotidacin AUC(0-t), AUC(0-∞), and 
Cmax for the following treatment comparison: 
Gepotidacin under fed conditions versus gepotidacin under fasted conditions 
• 
Wilcoxon signed-rank test will be performed to compare the plasma Tmax and Tlag of gepotidacin 
with and without food as described above for the Cohorts 1-3.  
 
All Cohorts 
• 
Summary statistics (arithmetic mean, geometric mean, median, 95% CI (arithmetic and geometric), 
standard deviation (arithmetic and geometric), minimum, maximum, and geometric CV) for primary 
plasma gepotidacin, and primary plasma digoxin and midazolam PK parameters will be summarized 
by treatment for each cohort, as applicable. 
• 
Should emesis occur the impact on PK will be assessed. If emesis causes differences on the PK 
exposure statistical analyses may be performed with and without data from participants that 
experience emesis, otherwise all data will be analyzed together, as appropriate. 
 
Model Checking & Diagnostics 
• 
Model assumptions will be checked before analysis. 
• 
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 seriously violated, then alternative data transformations will be explored. If no 
suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-rank 
test) will be performed. 
Model Results Presentation 
• 
Statistical analysis by linear mixed-effect models and Wilcoxon signed-rank test will be presented in 
tabular format for the following comparisons: 
Cohort 1: Gepotidacin + cimetidine versus gepotidacin alone 
Cohort 2: Gepotidacin + rifampicin versus gepotidacin alone 
Cohort 3: Gepotidacin + digoxin and midazolam versus digoxin and midazolam alone 
Cohort 4: Gepotidacin under fed conditions versus gepotidacin under fasted conditions in Japanese 
participants 
• 
For linear mixed-effect model tables, N, n, least squares GM values, GM ratios and associated 90% 
CIs, and within-subject CV will be presented. 
• 
For Wilcoxon signed-rank test the N, n, median values, median difference of the median values and 
associated 90% CIs will be presented (median difference and 90% CI of the median difference are 
from the Hodges-Lehmann estimate).  
• 
The gepotidacin geometric mean ratios and associated 90% CIs will also be presented in a forest 
plot for the DDI comparisons (Cohorts 1 and 2, Gepotidacin as a victim). PK data from BTZ117349 
(Gepotidacin + itraconazole versus gepotidacin alone) may be incorporated. In addition, a forest plot 
for Gepotidacin as a perpetrator, showing midazolam (potentially also with 1-hidroxymidazolam) and 
digoxin geometric mean ratios and associated 90% CIs might be included.  
 


 
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7.2. 
Secondary Pharmacokinetic Analyses 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Derived Pharmacokinetic Parameters 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3 
Reporting Standards for Pharmacokinetic) 
7.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or using the currently supported version of SAS (9.4 or 
higher). All calculations of non-compartmental parameters will be based on actual 
sampling times. Secondary pharmacokinetic parameters listed below will be determined 
from the plasma or urine concentration-time data for gepotidacin and the plasma 
concentration-time data for digoxin and midazolam, as appropriate and as data permit. 
Parameter 
Parameter Description 
Ae total 
Total amount excreted in urine (total amount of drug excreted in urine; concentration x 
volume), calculated by adding all the fractions of drug collected over all the allotted time 
intervals (calculated for gepotidacin for Cohort 1-4). 
Ae(t1-t2) 
Amount excreted in urine in a time interval (concentration x volume; calculated for 
gepotidacin for Cohort 1-4). 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 (predose) to the last 
quantifiable concentration, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid 
(calculated for gepotidacin for Cohort 3 using the full profile (both doses)). 
AUC(0-24) 
Area under the plasma or urine concentration-time curve from time 0 (predose) to the 
concentration at 24 hours, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid 
(calculated for gepotidacin for Cohorts 1-3 (plasma and urine) and Cohort 4 (urine only) 
(using the full profile when 2 doses are administered)). 
AUC(0-48) 
Area under the plasma or urine concentration-time curve from time 0 (predose) to the 
concentration at 48 hours postdose, to be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid 
(calculated for gepotidacin for Cohorts 1-3 (plasma and urine) and Cohort 4 (urine only) 
(using the full profile when 2 doses are administered)). 
AUC(0-τ) 
Area under the plasma or urine concentration-time curve from time 0 (predose) to time tau 
(tau = 12 h) (calculated for gepotidacin for Cohort 3 (plasma and urine) and Cohort 4, 
Period 3 (urine); separate estimates for each dose for plasma). 
Cmax 
Maximum observed plasma concentration, determined directly from the concentration-time 
data (calculated for gepotidacin for Cohort 3; separate estimates for each dose). 
Cmin 
Minimum observed plasma concentration, determined directly from the concentration-time 
data (calculated for digoxin and midazolam for Cohort 3). 
Tmax 
Time to reach maximum observed plasma concentration (calculated for gepotidacin for 
Cohort 3; separate estimates for each dose). 
Tlag 
Lag time before observation of drug concentrations in plasma (calculated for gepotidacin for 
Cohort 1, Cohorts 3 (first dose only), and 4 (first dose only)).  


 
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Parameter 
Parameter Description 
Vz/F 
Apparent plasma volume of distribution (calculated for Cohorts 1 and 2: gepotidacin; Cohort 
3: digoxin, midazolam, and gepotidacin; Cohort 4 (all periods): gepotidacin; calculated using 
the full profile when 2 doses are given). 
CL/F 
Apparent plasma oral clearance (calculated for Cohorts 1 and 2: gepotidacin; Cohort 3: 
digoxin, midazolam, and gepotidacin; Cohort 4 (all periods): gepotidacin; calculated using 
the full profile when 2 doses are given). 
t1/2 
Apparent plasma terminal phase half-life (calculated for Cohort 2: gepotidacin; Cohort 3: 
digoxin, midazolam, and gepotidacin; Cohort 4 (all periods): gepotidacin; calculated using 
the full profile when 2 doses are given). 
RoAUC 
Accumulation ratio calculated as AUC(0-τ) after the second dose, where 0 is the timepoint 
prior to second dose, divided by AUC(0-τ) after the first dose, where 0 is the predose 
timepoint prior to the first dose (calculated for gepotidacin for Cohort 3). 
RoCmax 
Accumulation ratio calculated as Cmax after the second dose divided by Cmax after the first 
dose (calculated for gepotidacin for Cohort 3). 
fe% 
Percentage of the given dose of drug excreted in urine, calculated as: 
fe% = (Ae total/Dose) × 100% (calculated for gepotidacin for Cohorts 1-4). 
CLr 
Renal clearance (of drug), calculated as: Ae total/AUC(0-t) (calculated for gepotidacin for 
Cohorts 1-4). 
NOTES: 
• 
Additional parameters may be included as required. 
 
7.2.2. 
Summary Measure 
Cohort 1 
Plasma PK parameters AUC(0-24), AUC(0-48), Tlag, Vz/F, and CL/F and urine PK 
parameters Ae total, Ae(t1-t2), fe%, AUC(0-24), AUC(0-48), and CLr of gepotidacin 
following a single 1500 mg dose of gepotidacin alone (Period 1) and in the presence of 
cimeditine 400 mg QID (Period 2) in healthy adult participants will be summarized by 
treatment. Gepotidacin PK parameter estimates will be listed by participant and 
treatment. 
Cohort 2 
Plasma PK parameters AUC(0-24), AUC(0-48), t1/2, Vz/F, and CL/F and urine 
pharmacokinetic parameters Ae total, Ae(t1-t2), fe%, AUC(0-24), AUC(0-48), and CLr 
of gepotidacin following a single 1500 mg dose of gepotidacin alone (Period 1) and in the 
presence of rifampin 600 mg QD (Period 2) in healthy adult participants will be 
summarized by treatment. Gepotidacin PK parameter estimates will be listed by 
participant and treatment. 
Cohort 3 
Plasma PK parameters Cmin, t1/2, Vz/F, and CL/F of digoxin and midazolam following a 
single dose (0.5 mg and 2 mg, respectively) alone and in the presence of gepotidacin (co-
administered with the second dose of a two 3000 mg dose gepotidacin treatment) in 
healthy adult participants will be summarized by treatment. Digoxin and midazolam PK 
parameter estimates will be listed by participant and treatment. 


 
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The following gepotidacin plasma PK parameters will be summarized following two 
3000 mg doses of gepotidacin in healthy adult participants in the presence of digoxin and 
midazolam following a single dose (0.5 mg and 2 mg, respectively): Tlag (dose 1 only); 
Cmax, Tmax, and AUC(0-τ) (separately for dose 1 and dose 2); RoAUC and RoCmax 
(dose 2); AUC(0-24), AUC(0-48), AUC(0- t), Vz/F, CL/F, and t1/2 using the full profile 
(both doses). Gepotidacin urine pharmacokinetic parameters Ae total, Ae(t1-t2), fe%, 
AUC(0-24), AUC(0-48), and CLr will be calculated using the full profile and 
summarized. Gepotidacin urine AUC(0-τ) will be calculated for the first dose and 
summarized. Gepotidacin PK parameter estimates will be listed by participant. 
Cohort 4, Periods 1 and 2 
Plasma pharmacokinetic parameters t1/2, Vz/F, and CL/F and urine pharmacokinetic 
parameters Ae total, Ae(t1-t2), fe%, AUC(0-24), AUC(0-48), and CLr of gepotidacin 
following a single 1500 mg dose of gepotidacin under fasted or fed conditions in healthy 
adult Japanese participants will be summarized by treatment. Gepotidacin PK parameter 
estimates will be listed by participant and treatment. 
Cohort 4, Period 3  
The following plasma gepotidacin PK parameters will be summarized following a two 
3000 mg dose gepotidacin treatment in healthy adult Japanese participants: Tlag (dose 1 
only); t1/2, Vz/F, and CL/F using the full profile (both doses). Gepotidacin urine 
pharmacokinetic parameters Ae total, Ae(t1-t2), fe%, AUC(0-24), AUC(0-48), and CLr 
will be calculated using the full profile and summarized. Gepotidacin urine AUC(0-τ) 
will be calculated for the first dose and summarized. Gepotidacin PK parameter estimates 
will be listed by participant 
7.2.3. 
Population of Interest 
The secondary PK analyses will be based on the PK population for plasma and urine PK 
concentrations and the PK parameter population for plasma PK parameters. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
For intercurrent events, see Section 7.1.4. 
7.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Secondary plasma and urine PK parameters as described in Section 7.2.1 will be 
estimated for gepotidacin, digoxin, and midazolam. For each of these parameters the 
following summary statistics will be calculated by cohort and treatment: median, 
maximum, minimum, arithmetic mean, standard deviation, 95% confidence interval (CI) 
for the arithmetic mean, geometric mean, CV on geometric mean, 95% CI for the 
geometric mean, and standard deviation of logarithmically transformed data. Parameters 
that are not logarithmically transformed are listed in Section 11.4.3. 


 
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7.2.5.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data are available (i.e. if participants have well defined plasma profiles). 
For the linear mixed model analyses described below, the Kenward and Roger method for 
approximating the denominator degrees of freedom and correcting for bias in the 
estimated variance-covariance of the fixed effects will be used.  
 
Endpoint / Variables 
• 
Plasma and urine secondary PK endpoints include plasma and urine PK parameters for gepotidacin 
(Cohorts 1, 2, 3, and 4) and plasma PK parameters for digoxin and midazolam (Cohort 3), as data 
permit. 
Model Specification 
Cohort 1 
• 
Analysis will be performed to compare the urine PK exposure of gepotidacin with and without 
cimetidine. Analysis will be performed on the natural logarithms of urine gepotidacin Ae total, AUC(0-
24), AUC(0-48), and CLr 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-subject CV will be calculated as well. 
 
Cohort 2 
• 
A linear mixed-effect model will be performed to compare the urine PK exposure of gepotidacin with 
and without rifampicin as described above for the Cohort 1. Analysis will be performed on the natural 
logarithms of urine gepotidacin Ae total, AUC(0-24), AUC(0-48), and CLr for the following treatment 
comparison: 
Gepotidacin + rifampicin versus gepotidacin alone 
 
Cohort 3 
• 
Analysis will be performed to compare the plasma PK exposure of digoxin and midazolam with and 
without gepotidacin. Analyses will be performed on the natural logarithms of plasma digoxin and 
midazolam Cmin, t1/2, Vz/F, and CL/F 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-subject CV 
will be calculated as well. 
 


 
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No Specific secondary analyses for Cohort 4 
 
All Cohorts 
• 
Summary statistics (arithmetic mean, geometric mean, median, 95% CI (arithmetic and geometric), 
standard deviation (arithmetic and geometric), minimum, maximum, and geometric CV) for 
secondary plasma and urine gepotidacin, and secondary plasma digoxin and midazolam PK 
parameters will be summarized by treatment for each cohort, as applicable. 
 
Model Checking & Diagnostics 
• 
Model assumptions will be checked before analysis. 
• 
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 seriously violated, then alternative data transformations will be explored. If no 
suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-rank 
test) will be performed. 
Model Results Presentation 
• 
Linear mixed-effect model results will be presented in tabular format for the following comparisons: 
Cohort 1: Gepotidacin + cimetidine versus gepotidacin alone 
Cohort 2: Gepotidacin + rifampicin versus gepotidacin alone 
Cohort 3: Gepotidacin + digoxin and midazolam versus digoxin and midazolam alone 
• 
The N, n, least squares GM values, GM ratios and associated 90% CIs, and within-subject CV will be 
presented. 
 
7.3. 
Exploratory Pharmacokinetic Analyses 
7.3.1. 
Endpoint / Variables 
7.3.1.1. 
Drug Concentration Measures  
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3 
Reporting Standards for Pharmacokinetic) 
7.3.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or using the currently supported version of SAS (9.4 or 
higher). All calculations of non-compartmental parameters will be based on actual 
sampling times. Exploratory plasma pharmacokinetic parameters listed below will be 
determined from the plasma concentration-time data for 1’-hydroxymidazolam for 
Cohort 3, as data permit. Exploratory urine pharmacokinetic parameters listed below will 
be determined from the urine concentration-time data for digoxin for Cohort 3, as data 
permit. Only Cohort 3 contains exploratory PK parameters. 


 
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Parameter 
Parameter Description 
Ae total 
Total amount excreted in urine (total amount of drug excreted in urine; concentration x 
volume), calculated by adding all the fractions of drug collected over all the allotted time 
intervals. 
AUC(0-t) 
Area under the plasma concentration-time curve from time 0 (predose) to the last 
quantifiable concentration, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.  
AUC(0-∞) 
Area under the plasma concentration-time curve from time 0 (predose) extrapolated to 
infinite time, to be calculated using the linear trapezoidal rule for each incremental trapezoid 
and the log trapezoidal rule for each decremental trapezoid.  
Cmax 
Maximum observed plasma concentration, determined directly from the concentration-time 
data.  
Cmin 
Minimum observed plasma concentration, determined directly from the concentration-time 
data. 
Tmax 
Time to reach maximum observed plasma concentration  
t1/2 
Apparent plasma terminal phase half-life  
AUC m/p1 
Metabolite-to-parent ratio based on AUC(0-∞) with correction for molecular weight. If data 
for AUC(0-∞) are insufficient then AUC(0-t) may be used.  
fe% 
Percentage of the given dose of drug excreted in urine, calculated as: 
fe% = (Ae total/Dose) × 100%. 
CLr 
Renal clearance (of drug), calculated as: Ae total/AUC(0-t). 
1Molecular weights by analyte: midazolam: 325.78, 1-hydroxymidazolam: 341.77. 
NOTES: 
• 
Additional parameters may be included as required. 
 
7.3.2. 
Summary Measure 
Cohort 3 
Plasma pharmacokinetic parameters Cmin, Cmax, Tmax, t1/2, AUC(0-t), AUC(0-∞) and 
AUC m/p for 1’-hydroxymidazolam and urine pharmacokinietic parameters Ae total, fe% 
and CLr for digoxin following a single dose (0.5 mg of digoxin and 2 mg of midazolam) 
alone and in the presence of gepotidacin (co-administered with the second dose of a two 
3000 mg dose gepotidacin treatment) in healthy adult participants will be summarized by 
treatment. PK parameter estimates will be listed by participant and treatment. 
7.3.3. 
Population of Interest 
The exploratory PK analyses will be based on the PK population for plasma and urine PK 
concentrations and the PK parameter population for plasma and urine PK parameters. 
7.3.4. 
Strategy for Intercurrent (Post-Randomization) Events 
For intercurrent events, see Section 7.1.4. 


 
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7.3.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Exploratory plasma and urine PK parameters as described in Section 7.3.1 will be 
estimated for 1’-hydroxylmidazolam and digoxin. For each of these parameters the 
following summary statistics will be calculated by cohort and treatment: median, 
maximum, minimum, arithmetic mean, standard deviation, 95% confidence interval (CI) 
for the arithmetic mean, geometric mean, CV on geometric mean, 95% CI for the 
geometric mean, and standard deviation of logarithmically transformed data. Parameters 
that are not logarithmically transformed are listed in Section 11.4.3. 
7.3.5.1. 
Statistical Methodology Specification 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data are available (i.e. if participants have well defined plasma profiles). 
 
For the linear mixed model analyses described below, the Kenward and Roger method for 
approximating the denominator degrees of freedom and correcting for bias in the 
estimated variance-covariance of the fixed effects will be used.  
 
Endpoint / Variables 
• 
Plasma exploratory PK endpoints include plasma PK parameters for 1’-hydroxymidazolam (Cohort 3) 
and urine PK parameters for digoxin (Cohort 3), as data permit. 
Model Specification 
Cohort 3 
• 
Upon review of the PK data, analysis may be performed to compare the plasma PK exposure of 1’-
hydroxymidazolam and urine PK exposure of digoxin with and without gepotidacin. Analyses will be 
performed on the natural logarithms of plasma 1’-hydroxymidazolam AUC(0-t), AUC(0-∞), Cmax, 
and AUC m/p and urine digoxin Ae total and CLr 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-subject CV 
will be calculated as well. 
• 
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 and urine digoxin 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 Western (non-
Japanese) participants (all-comers and Caucasians only) for the following: 


 
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Single dose: 
o Japanese participant data (Cohort 4, fed only) versus Western (non-Japanese) participant 
(all-comers and Caucasians only) data (Cohorts 1 and 2, Period 1 only) 
Multi-dose: 
o Japanese participant data (Cohort 4, Period 3 only) versus Western (non-Japanese) 
participant (all-comers and Caucasians only) data (Cohort 3).  
 
• 
Should emesis occur, Japanese and Western (non-Japanese) comparisons may be repeated with 
and without data from participants that experience emesis to evaluate the impact of emesis on PK 
exposure. 
 
• 
Japanese and Western (non-Japanese) participant data from BTZ117351 may be incorporated into 
summary outputs 
 
All Cohorts 
• 
Change from baseline in QTcF versus PK plasma concentrations of gepotidacin will be plotted 
separately by treatment. 
 
Model Checking & Diagnostics 
• 
Model assumptions will checked before analysis. 
• 
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 seriously violated, then alternative data transformations will be explored. If no 
suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-rank 
test) will be performed. 
Model Results Presentation 
• 
Linear mixed-effect model results will be presented in tabular format for the following comparison: 
Cohort 3: Gepotidacin + digoxin and midazolam versus digoxin and midazolam alone 
• 
The N, n, least squares GM values, GM ratios and associated 90% CIs, and within-subject CV will be 
presented. 
  
 
 
 


 
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8. 
BIOMARKER ANALYSES 
8.1. 
Exploratory Biomarker Analyses 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Biomarker Concentration Measures 
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 11.4.3 
Reporting Standards for Pharmacokinetic).  
8.1.1.2. 
Derived Biomarker Parameters 
Biomarker parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or using the currently supported version of SAS (9.4 or 
higher). All calculations of non-compartmental parameters will be based on actual 
sampling times. Exploratory biomarker parameters listed below will be determined from 
the baseline-corrected plasma or urine concentration-time data for N1-
methylnicotinamide (1-NMN) and serum or urine concentration-time data for creatinine 
for Cohort 1, as appropriate and as data permit. 
Parameter 
Parameter Description 
Ae total 
Total amount excreted in urine (total amount of biomarker excreted in urine), calculated by 
adding all the amounts excreted collected over all the allotted time intervals (1-NMN and 
creatinine). 
AUC(0-t) 
Area under the plasma or serum concentration-time curve from time 0 (predose) to the last 
quantifiable concentration, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid (1-NMN 
and creatinine). 
AUC(0-24) 
Area under the plasma concentration-time curve from time 0 (predose) to the concentration 
at 24 hours postdose, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid (1-NMN only). 
AUC(0-48) 
Area under the plasma concentration-time curve from time 0 (predose) to the concentration 
at 48 hours postdose, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid (1-NMN only). 
Cmax 
Maximum observed plasma concentration, determined directly from the concentration-time 
data (1-NMN only). 
Tmax 
Time to reach maximum observed plasma concentration (1-NMN only). 
C average 
Average concentration, calculated as AUC(0-48)/48 (1’-NMN only). 
Ctrough 
Trough plasma concentration (1-NMN only; 48 h post gepotidacin dose). 
CLr 
Renal clearance (of biomarker), calculated as: Ae total/AUC(0-t). (1-NMN and creatinine; 
CLr will also be reported for 1-NMN after normalization to creatinine CLr) 
NOTES: 
• 
Additional parameters may be included as required. 
 
 
 
 


 
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8.1.2. 
Summary Measure 
Cohort 1 
Plasma biomarker parameters C average, Cmax, Ctrough, Tmax, AUC(0-24), AUC(0-48) 
and AUC(0- t) of 1-NMN and urine biomarker parameters Ae total and CLr of 1-NMN 
following a single 1500 mg dose of gepotidacin alone (Period 1) and in the presence of 
cimeditine 400 mg QID (Period 2) in healthy adult participants will be summarized by 
treatment. Biomarker parameter estimates will be listed by participant and treatment. 
Creatinine Ae total, AUC(0-t) (serum), and CLr will similarly be summarized and listed. 
Estimated glomerular filtration rate (eGFR) will be summarized and listed for the predose 
time point. The Modification of Diet in Renal Disease formula will be used to derive 
eGFR:  
 
𝐞𝐆𝐅𝐑 ([𝐦𝐋/𝐦𝐢𝐧]/𝟏. 𝟕𝟑 𝐦𝟐)
= 175  × serum creatinine (mg/dL)−1.154 × age−0.203 
×  0.742 if female ×  1.212 if African American 
8.1.3. 
Population of Interest  
The exploratory biomarker analyses will be based on the PK population for plasma, 
serum, and urine biomarker concentrations and the PK parameter population for plasma, 
serum, and urine biomarker parameters. 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
For intercurrent events, see Section 7.1.4. 
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Exploratory biomarker parameters as described in Section 8.1.1 will be estimated for 1-
NMN and creatinine. For each of these parameters the following summary statistics will 
be calculated by treatment: median, maximum, minimum, arithmetic mean, standard 
deviation, 95% confidence interval (CI) for the arithmetic mean, geometric mean, CV on 
geometric mean, 95% CI for the geometric mean, and standard deviation of 
logarithmically transformed data.  
8.1.5.1. 
Statistical Methodology Specification 
The following biomarker statistical analyses will only be performed if sufficient data are 
available (i.e. if participants have well defined plasma profiles). 
 
 
 


 
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Endpoint / Variables 
• 
Biomarker exploratory endpoints include biomarker parameters for plasma and urine 1-NMN and 
serum and urine creatinine (Cohort 1), as data permit. 
Model Specification 
Cohort 1 
• 
Upon review of the biomaker data, analysis may be performed to compare the plasma and urine 
exposure of 1-NMN and the serum and urine exposure of creatinine with and without cimetidine. 
Analysis will be performed on the natural logarithms of plasma 1-NMN AUC(0-t), AUC(0-24), and 
Cmax, serum creatinine AUC(0-t), and urine 1-NMN and creatinine Ae total and CLr 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-subject CV will be calculated as well. 
 
• 
Summary statistics (arithmetic mean, geometric mean, median, 95% CI (arithmetic and geometric), 
standard deviation (arithmetic and geometric), minimum, maximum, and geometric CV) for 
exploratory biomarker plasma and urine 1-NMN (including those normalized to creatinine) and serum 
and urine creatinine parameters will be summarized by treatment. 
 
Model Checking & Diagnostics 
• 
Model assumptions will be checked before analysis. 
• 
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 seriously violated, then alternative data transformations will be explored. If no 
suitable transformation can be found, equivalent nonparametric analyses (ex. Wilcoxon signed-rank 
test) will be performed. 
Model Results Presentation 
• 
Linear mixed-effect model results will be presented in tabular format with geometric mean ratios for 
the following comparison: 
Cohort 1: Gepotidacin + cimetidine versus gepotidacin alone 
• 
The N, n, least squares GM values, GM ratios and associated 90% CIs, and within-subject CV will be 
presented. 
  
 
 


 
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9. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
9.1. 
Adverse Events Analyses 
The severity of AEs and SAEs will be determined by the investigator according to the US 
National Institute of Allergy and Infectious Diseases Division of Microbiology and 
Infectious Diseases (DMID) criteria for adult toxicity assessment. All reported AEs will 
be coded using MedDRA and summarized by system organ class (SOC) and preferred 
term (PT) and treatment. In Cohort 4, all the placebo arms will be summarized together, 
whether in the fed or fasted state. 
Adverse event severity is classified as mild (grade = 1), moderate (grade = 2), and severe 
(grade = 3), and Potentially Life-Threatening (grade = 4). Adverse events starting after 
the first dose of study treatment with a missing severity will be classified as severe. If a 
participant reports an AE more than once within an SOC/PT, the AE with the worst-case 
severity will be used in the corresponding severity summaries. 
Relationship to study treatment, as indicated by the investigator, is classified as “No” (not 
related) or “Yes” (related). Adverse events with a missing relationship to study treatment 
will be regarded as “Yes” to study treatment. If a participant reports the same AE more 
than once within an SOC/PT, the AE with the worst-case relationship to study treatment 
will be used in the corresponding relationship summaries. 
Adverse events analyses including the analysis of AEs, SAEs and other significant AEs 
will be based on GSK Core Data Standards. All AEs, study drug related AEs, SAEs, and 
AEs leading to discontinuation of study treatment or withdrawal from study will be 
provided in separate listings. The relationship between SOC and PT will be listed. 
Summary tables will be provided by SOC, PT, and maximum severity. 
In summary tables where AEs are presented by SOC, PT, and maximum severity, SOCs 
will be sorted in descending order of the total incidence then alphabetically, PTs will be 
sorted in descending order of the total incidence then alphabetically within the SOC.  
For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following Section 11.6.2.  
In addition, a summary of the number and percentage of participants with common AEs, 
defined as AEs occurring more than two times irrespective of treatment by cohort, will be 
presented in descending order of total incidence by PT. The details of the planned 
displays are provided in Appendix 11: List of Data Displays. 
9.1.1. 
Adverse Events of Special Interest Analyses 
Gastrointestinal AEs, Cardiovascular AEs, potential events related to 
Acetylcholinesterase inhibition as determined by algorithm, and Clostridium difficile 
infection events will be considered AEs of Special Interest (AESIs). AESIs except those 
for Acetylcholinesterase inhibition, are flagged in the eCRF and details of events are 


 
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collected on special eCRF pages. Potential acetylcholinesterase-Inhibition AESIs will be 
programmatically matched with the list of AEs specified in Section 9.1.2 In addition, 
there will be a manual review of AE listings to ensure accuracy and completeness of 
AESI reporting. 
9.1.2. 
Potential Acetylcholinesterase-Inhibition AESIs 
Any reported AE listed in the Section 11.8.2 with a start time after first dose of study 
treatment administered and no later than 12 hours after the last dose of the study 
treatment administered in each period, as evaluated by the investigator as per the DMID 
grading criteria provided in protocol Section 11.8.1: Division of Microbiology and 
Infectious Disease Adult Toxicity Tables for Adverse Event Assessment, will be 
programmatically identified as potential Acetylcholinesterase inhibition related AESI in 
Section 11.8.2 . 
AESIs will be listed and tabulated.  
The details of the planned displays are provided in Appendix 11: List of Data Displays. 
9.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. Division of Microbiology and Infectious Diseases (DMID) grading for all 
parameters as specified in the protocol will be assigned programmatically by PPD in the 
Laboratory Analysis Dataset. Summary of worst case of assessment results relative to 
normal range for clinical laboratory will be included. The details of the planned displays 
are in Appendix 11: List of Data Displays. 
9.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, including summary of worst case of assessment 
results relative to normal range for vital signs, unless otherwise specified. The details of 
the planned displays are presented in Appendix 11: List of Data Displays. 
9.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The only intercurrent event identified  for safety analyses is treatment discontinuation. A 
“while on treatment” strategy will be used . which attempts to estimate safety effects 
more likely to be attributable to the drug. 
 
 


 
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10. 
REFERENCES 
GlaxoSmithKline Document Numbers 2020N434866_00 (Original – 13-JUL-2020): 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 
(13-JUL-2020).


 
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11. 
APPENDICES 
11.1. 
Appendix 1: Schedule of Activities 
11.1.1. 
Protocol Defined Time and Events Table 
Table 1 
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 Protocol Section 8.2.5 – 
pregnancy testing for instruction 
on time points. 
Drug, alcohol, and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
See Protocol Table 16. 
Laboratory assessments 
X 
 
 
X 
 
 
 
X 
X 
X 
See Protocol Table 16.  


 
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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 
12-lead ECG3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Triplicate 12-lead ECGs will 
be measured on Pre-dose and 
Single ECGs on Day -1 and at all 
other timepoints  
Table 6 and Table 7 for timing of 
assessments. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Triplicate 12-lead ECGs will 
be measured on Pre-dose and 
Single ECGs on Day -1 and at all 
other timepoints  
Table 6 and Table 7 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. 
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. 


 
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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 
Blood collection for PK 
 
X 
X 
X 
 
X 
X 
X 
 
 
See Triplicate 12-lead ECGs will 
be measured on Pre-dose and 
Single ECGs on Day -1 and at all 
other timepoints  
Table 6 and Table 7 for timing of 
assessments. 
Urine collection for PK 
 
X 
X 
X 
 
X 
X 
X 
 
 
See Triplicate 12-lead ECGs will 
be measured on Pre-dose and 
Single ECGs on Day -1 and at all 
other timepoints  
Table 6 and Table 7 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 2 
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 Protocol Section 
8.2.5 – pregnancy testing 
for instruction on time 
points. 
Drug, alcohol, and 
cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol Table 16.  
Laboratory 
assessments 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
See Protocol Table 16. 
12-lead ECG3 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
See Table 8 for timing of 
assessments. 
Vital signs 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
See Table 8 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 8 for timing of 
assessments. 
Urine collection for 
gepotidacin PK 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
See Table 8 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 3 
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 Protocol Section 8.2.5 – 
pregnancy testing for instruction on 
time points. 
Drug, alcohol, 
and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Protocol Table 16. 
Laboratory 
assessments 
X 
 
 
 
 
 
D10 
 
 
 
 
X 
X 
X 
See Protocol Table 16. 
12-lead ECG5 
X 
X 
X 
X 
 
 
D10 
X 
X 
X 
 
 
X 
X 
See Table 9 and Table 10 for timing 
of assessments. 
Holter ECG 
monitoring 
X 
X 
 
 
 
 
D10 
X 
 
 
 
 
 
 
See Table 9 and Table 10 for timing 
of assessments. 
Vital signs 
X 
X 
X 
X 
 
 
D10 
X 
X 
X 
 
 
X 
X 
See Table 9 and Table 10 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 9 and Table 10 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 4 
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 Protocol Section 8.2.5 – 
pregnancy testing for instruction on 
time points. 
Drug, alcohol, and cotinine 
screen 
X 
 
 
 
 
 
 
 
 
See Protocol Table 16. 
Laboratory assessments 
X 
 
 
X 
 
 
X 
X 
X 
See Protocol Table 16. 
12-lead ECG4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Protocol Table 11 and 
Table 12 for timing of 
assessments. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Protocol Table 11 and 
Table 12 for timing of 
assessments. 


 
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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 
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. 
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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11.1.2. 
Protocol Defined Safety and PK Assessments 
Table 5 
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 6 
Safety and Pharmacokinetic Assessments - Cohort 1 (Relative to Gepotidacin) Period 2 
Procedure1 
 
 
Time point (hours) 
 
-1 Gepotidaci
n 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 7 
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 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 
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 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 sample4 
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 sample4,5 
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. 
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 24 hours, 24 to 36 hours, 36 to 48 hours, and 48 to 
60 hours after digoxin administration. 
 


 
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Table 10 
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 11 
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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11.2. 
Appendix 2: Assessment Windows 
• Actual times will be used in the derivation of PK parameters and in the individual 
concentration-time plots. Planned times will be used in the descriptive summaries and 
in mean and median plots 
• PK concentration listings shall have both the planned and actual times  
• Planned time will be used for all other analysis  


 
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11.3. 
Appendix 3: Study Phases and Periods 
11.3.1. 
Treatment States 
Treatment States for AE Data 
Treatment State 
Definition 
Pre-Treatment 
AE Start Date/Time < Study Treatment Start Date/Time 
Treatment 
AE Start Date/Time ≥ Study Treatment Start Date/Time  
In summaries of AEs by treatment, AEs will be summarized according to the most 
recent treatment received prior to the AE.  
Onset Time 
Since First Dose 
(Days) 
If Treatment Start Date/Time > AE Onset Date/Time = AE Onset Date - Treatment 
Start Date 
If Treatment Start Date/Time ≤ AE Onset Date/Time = AE Onset Date - Treatment 
Start Date +1 
Missing otherwise 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF OR value is missing 
NOTES:  
• 
If the study treatment stop date is missing then the AE will be considered to be On-Treatment. 
 
11.3.2. 
Treatment Period for Safety Summaries by Treatment Cohort 
The originally periods could refer to Section 11.1.1. The strategy for subject 
discontinuation is in Section 9.4.  
For AEs and Concomitant medications, the treatment period will be defined as the last 
treatment prior to the event. And event start datetime will be used instead of date (date 
will be used if datetime is missing) in below definition and table.  
For safety assessments other than AEs and Concomitant medications, the nominal periods 
are taken from Section 11.1.1. Time window will be used to determine period, and within 
each period, nominal visit will be used for summary purpose. The full definition of 
periods for safety summary are defined in below table. 
Treatment 
Cohort 
Period 
Start 
End 
Cohort 1 
1 
Date of first dose in nominal 
period 1 (inclusive) 
Date of first dose in nominal period 2 (not 
inclusive) if not missing 
Last Visit of Study if start date of period 2 
is missing 
 
2 
Date of first dose of nominal 
period 2 (inclusive) 
Last Visit of Study if start date of period 2 is 
not missing 
Cohort 2 
1 
Date of first dose in nominal 
period 1 (inclusive) 
Date of first dose in nominal period 2 (not 
inclusive) if not missing 


 
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Treatment 
Cohort 
Period 
Start 
End 
Last Visit of Study if start date of period 2 
is missing  
 
2  
Date of first dose in nominal 
period 2 administration 
(inclusive) 
Last Visit of Study if start date of period 2 is 
not missing 
Cohort 3 
1 
Date of dose in nominal 
period 1 (inclusive) 
Date of first dose in nominal period 2 (not 
inclusive) if not missing 
Last Visit of Study if start date of period 2 
is missing 
 
2 
Date of first dose in nominal 
period 2 (inclusive) 
Last Visit of Study if start date of period 2 is 
not missing 
Cohort 4 
1 
Date of dose in nominal 
period 1 (inclusive) 
Date of first dose in nominal period 2 (not 
inclusive) if not missing 
Last Visit of Study if start date of period 2 
is missing 
 
2 
Date of first dose in nominal 
period 2 administration 
(inclusive) 
Date of first dose in nominal period 3 (not 
inclusive) if not missing 
Last Visit of Study if start date of period 3 
is missing 
 
3 
Date of first dose in nominal 
period 3 administration 
(inclusive) 
Last Visit of Study if start date of period 3 is 
not missing 
 


 
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11.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
11.4.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
Study 
Cohort 
Treatment Group  
Data Displays for Reporting  
Code 
Description 
Description 
Order 
[1] 
1 
A 
Gepotidacin 1500 mg SD on Day 1 
of Period 1 
Gepotidacin 1500 mg 
1 
1 
B 
Cimetidine 400 mg 4 times daily 
Days 1 through 4 of Period 2 and 
gepotidacin 1500 mg SD. 
Cimetidine 400 mg + 
Gepotidacin 1500 mg 
2 
2 
C 
Gepotidacin 1500 mg SD on Day 1 
of Period 1 
Gepotidacin 1500 mg 
3 
2 
D 
Rifampicin 600 mg (administered 
in the evenings) once daily for 
7 days (Days 1 through 7) in 
Period 2. 
Rifampicin 600 mg 
4 
2 
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. 
Gepotidacin 1500 mg + 
Rifampicin 600 mg 
 
5 
3 
F 
Digoxin 0.5 mg and midazolam 2 
mg on Day 1. 
Midazolam and Digoxin 
6 
3 
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. 
Gepotidacin two 3000 mg + 
Midazolam and Digoxin 
7 
4 
H 
Gepotidacin 1500 mg SD under 
fed conditions on Day 1. 
Gepotidacin 1500 mg Fed 
9 
4 
I 
Gepotidacin 1500 mg SD under 
fasted conditions on Day 1. 
Gepotidacin 1500 mg Fasted 
10 
4 
J 
Two doses of gepotidacin up to 
3000 mg (given 12 hours apart) 
under fed conditions on Day 1. 
Gepotidacin 3000 mg Fed 
11 
4 
H/I/J 
Matching Placebo for H/I/J 
Placebo 
8 
NOTES: 
1. Order represents treatments being presented in TFL, as appropriate. 
 
 


 
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11.4.2. 
Reporting Process & Standards 
Reporting Process 
Software 
• 
The currently supported versions of SAS and WinNonlin software will be used. 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1]. 
• 
For creation of ADaM datasets (ADCM/ADC1/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• 
RTF files will be generated for all reporting efforts described in the RAP. 
 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
o 4.03 to 4.23: Principles for all displays 
o 5.01 to 5.09: Principles for Data Listings 
o 6.01 to 6.11: Principles for Summary Tables 
o 7.01 to 7.13: Principles for Graphics  
Formats 
• 
All data will be reported according to the actual treatment the subject received unless otherwise 
stated. 
• 
GSK IDSL Statistical Principles (4.23 & 6.9) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses : 
o Planned time relative to dosing will be used in figures (with the exception of individual PK 
concentration-time figures, where actual relative time will be used), summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will be considered when calculating baseline and in Table 2.8, Table 2.10, Table 
2.11, Table 2.12, Table 2.14, Table 2.15, and Table 2.18 but will not be included in any other 
summary tables. 
• 
Unscheduled visits will not be included in figures. 


 
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Reporting Standards 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
11.4.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (xpt format) for the non-compartmental analysis will be created 
according to SOP 314000(2.0).  
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
For continuous data: 
• 
NQs at the beginning of a participant profile (i.e. before the first incidence of a 
measurable concentration) are deemed to be zero as it is assumed that in this 
circumstance no drug is yet measurable in the blood. 
• 
For NQs at the end of the participant profile (i.e. after the last incidence of a 
measurable concentration); 
• 
for individual plots and pharmacokinetic analyses these are dropped (set 
to missing) as they do not provide any useful information (and can 
erroneously indicate that absolutely no drug is present) 
• 
for summary statistics, these are set to 0 (to avoid skewing of the 
summary statistics) 
• 
Individual NQs which fall between two measurable concentrations are set to 
missing (individual values of this nature are assumed to be an anomaly) 
If two or more NQ values occur in succession between measurable concentrations, 
the profile will be deemed to have terminated at the last measurable concentration 
prior to these NQs. For the purpose of individual participant plots, these NQs will be 
set to 0, and the subsequent measurable concentrations will be retained. For the 
derivation of pharmacokinetic parameters, these NQs and any subsequent 
measurable concentrations will be omitted (set to missing). 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
 


 
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Pharmacokinetic Parameter Data 
PK Parameter to be 
Derived by 
Programmer 
The following plasma PK and biomarker parameters will be derived by the 
Programmer:  
     RoCmax, RoAUC, AUC m/p, Ctrough, C average 
The following urine PK and biomarker parameters will be derived by the 
Programmer:  
     Ae total, Ae(t1-t2), fe%, CLr 
Note: Parameter definitions are found in Section 7.1.1.2, Section 7.2.1.2, Section 
7.3.1.2, and Section 8.1.1.2. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
N, n, arithmetic mean, 95% CI of arithmetic mean, geometric mean, 95% CI of 
geometric mean, standard deviation, standard deviation of logged data, CV (%), 
and between-subject geometric coefficient of variation (CVb (%)) will be reported. 
CVb (%) = √ (exp( standard deviation2) - 1) * 100 
(standard deviation = between-subject SD of Ln-eTransformed data)  
Within-subject CV for 
Statistical Analysis 
Tables 
Within-subject coefficient of variation (%CVw) will be reported. 
CVw (%) = √ (exp(σw2) - 1) * 100 
(σw2 is the mean squares estimate (MSE) from the statistical linear mixed model) 
Parameters Not 
Being Ln-
Transformed 
Tlag, Tmax, AUC%extrap. (percentage of the extrapolated area to infinity in ratio to 
the total area under the curve, calculated as: ((AUC0-∞ - AUC0-t) / AUC0-∞) × 
100), λz (apparent terminal elimination rate constant, estimated by linear regression 
of the terminal portion of the log-concentration by time curve), λz lower (lower limit 
on time for values to be included in the calculation of λz), λz upper (upper limit on 
time for values to be included in the calculation of λz), and λz no. of points (number 
of time points used in the calculation of λz). 
Parameters Not 
Being Summarized 
AUC%extrap., λz, λz lower, λz upper, and λz no. of points. 
Listings 
Include the first point, last point and number of points used in the determination of 
λz for listings. 
 
 
 


 
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11.5. 
Appendix 5: Derived and Transformed Data 
11.5.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented  
• 
For maximum grade increase summary and PCI summaries, each of the multiple measurements will 
be used to derive the subject worst case. 
Study Day 
• 
Calculated as the number of days from date of first study drug administration (Dose Date) for each 
cohort: 
• 
Ref Date = Missing        → Study Day = Missing  
• 
Ref Date < Dose Date   → Study Day = Ref Date – Dose Date  
• 
Ref Data ≥ Dose Date   → Study Day = Ref Date – (Dose Date) + 1 
Period Day 
• 
Calculated as the number of days from treatment start date for the respective period for each cohort:  
• 
Ref Date = Missing        → Period Day = Missing  
• 
Ref Date < Treatment Date   → Period Day = Ref Date – Treatment Date  
• 
Ref Data ≥ Treatment Date   → Period Day = Ref Date – (Treatment Date) + 1 
 
11.5.2. 
Study Population 
Demographics 
Age 
• 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows: 
o Only the year of birth will be collected. The date and month will be imputed as ‘30th June’. 
• 
Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)2] 
eGFR 
See Section 8.1.2. 
estimated creatine clearance (CLcr) 
The Cockcroft-Gault equation will be used to derive estimated creatine clearance (CLcr): 
CLcr (mL/min) = 
[140−age (years)]∗weight(kg) 
𝟕𝟐∗𝒔𝒆𝒓𝒖𝒎 𝒄𝒓𝒆𝒂𝒕𝒊𝒏𝒆 (𝒎𝒈/𝒅𝒍)  [∗0.85 𝑓𝑜𝑟 𝑓𝑒𝑚𝑎𝑙𝑒 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠] 
 


 
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11.5.3. 
Safety 
Adverse Events 
AE’S of Special Interest 
• 
Cardiovascular (CV) events 
• 
Gastrointestinal events 
• 
Potential Acetylcholinesterase inhibition events 
Adverse Events with Missing Relationship or Missing Serious Indicator 
• 
If the relationship to study treatment is missing for a treatment-emergent AE, it’ll be considered as 
related to the study treatment. 
• 
If the serious indicator “Was event serious?” is missing, the AE will be considered as SAE. 
• 
Adverse events with missing relationship or missing serious indicator will be presented as it is in listings 
but will be treated as related AEs or SAEs in summary tables. 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value.  
• 
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01 
• 
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1 
• 
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
ECG Parameters 
RR Interval 
• 
IF RR interval (millisecond [msec]) is not provided directly, then RR can be derived as: 
[1] If QTcB is machine read & QTcF is not provided, then: 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a collected 
value THEN do not derive. 
• 
Machine read values of RR should not be replaced with derived values. 
Corrected QT Intervals 
• 
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fridericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements. 
• 
IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:  
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
 
 


 
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11.6. 
Appendix 6: Reporting Standards for Missing Data 
11.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study including the follow-up visit. 
• 
Withdrawn participants may be replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Early termination visits will be summarized as early termination visits. 
11.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the CSR. 
11.6.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the date of 
first study treatment of the cohort; in this case the date of first study treatment 
date will be used. 
o Missing Stop Day: Last day of the month will be used, unless this is after the date 
of last visit of the cohort; in this case the last visit date of the cohort will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
If only the start date is completely missing, we assume that the medication has been 
taken from the beginning of the study for the participant.  


 
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Element 
Reporting Detail 
If only the stop date is missing, assume that the medication has been taken till the end 
of the compete study for the participant.  
• 
If both start and end date is missing, we assume that the medication has been taken 
for the duration of the study for the participant. 


 
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11.7. 
Appendix 7: Values of Potential Clinical Importance 
11.7.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval[3] 
msec 
> 450[1]  
 
> 450[2]  
≤ 480[2]  
> 480[2]  
≤ 500[2]  
> 500[2]  
 
Absolute PR Interval 
msec 
< 110[1]  
> 220[1]  
Absolute QRS Interval 
msec 
< 75[1]  
> 110[1]  
Change from Baseline 
Increase from Baseline QTc[3] 
msec 
≤ 30[2]  
 
msec 
> 30[2]  
≤ 60[2]  
msec 
> 60[1]  
 
NOTES: 
1. Represent standard ECG values of PCI for HV studies. 
2. Represent further subdivisions of ECG values for analysis. 
3. Qualifying QTc events, regardless whether QTcB or QTcF, will be captured. 
11.7.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
millimeters of 
mercury 
(mmHg) 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
11.7.2.1. 
Normal Range for Vital Signs 
 
 
Predose 
Postdose 
 
Temperature 
96.0-101.0 °F / 35.6-38.3°C 
96.0-101.0 °F / 35.6-38.3°C 
 
Respiratory Rate 
8-22 
8-22 
Supine 
Heart Rate 
40-110 (per GSK PCI Slides) 
40-110 (per GSK PCI Slides) 
 
BP 
<85 and >160 / <45 and >100 (per 
GSK PCI Slides) 
<85 and >160 / <45 and >100 
(per GSK PCI Slide) 
 
Pulse Oximetry 
94-99 
94-99 
 


 
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11.8. 
Appendix 8: Adverse Event Assessement Criteria 
11.8.1. 
Division of Microbiology and Infectious Diseases Adult Toxicity 
Tables for Adverse Events Assessments (2007) - Laboratory 
Values 
Parameter values are converted to use SI units. 
 
HEMATOLOGY 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
9.5 to 
10.5 gm/dL 
8.0 to 
9.4 gm/dL 
6.5 to 7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil 
Count 
1000 to 
1500 /mm3 
750 to 
999 /mm3` 
500 to 749 /mm3 
<500 /mm3 
Platelets 
75,000 to 
99,999 /mm3 
50,000 to 
74,999 /mm3 
20,000 to 
49,999 /mm3 
<20,000 /mm3 
White Blood Cells 
11,000 to 
13,000 /mm3 
13,000 to 
15,000 /mm3 
15,000 to 
30,000 /mm3 
>30,000 or <1000 /mm3 
% Polymorphonuclear 
Leukocytes + Band Cells 
>80% 
90 to 95% 
>95% 
N/A 
Abnormal Fibrinogen 
Low: 100 to 
200 mg/dL 
High: 400 to 
600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: <50 mg/dL 
High: N/A 
Fibrinogen associated with 
gross bleeding or with 
disseminated coagulation 
Fibrin Split Product 
20 to 40 mcg/mL 
41 to 
50 mcg/mL 
51 to 60 mcg/dL 
>60 mcg/dL 
Prothrombin Time (PT) 
1.01 to 
1.25  ULN 
1.26 to 
1.5  ULN 
1.51 to 3.0  ULN 
>3  ULN 
Activated Partial 
Thromboplastin (APTT) 
1.01 to 
1.66  ULN 
1.67 to 
2.33  ULN 
2.34 to 3  ULN 
>3  ULN 
Methemoglobin 
5.0 to 9.9% 
10.0 to 14.9% 
15.0 to 19.9% 
>20% 
N/A=not applicable; ULN=upper limit of normal.  
 
CHEMISTRIES 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130 to 
135 mEq/L 
123 to 
129 mEq/L 
116 to 122 mEq/L 
<116 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypernatremia 
146 to 
150 mEq/L 
151 to 
157 mEq/L 
158 to 165 mEq/L 
>165 mEq/L or abnormal 
sodium with mental status 
changes or seizures 
Hypokalemia 
3.0 to 3.4 mEq/L 
2.5 to 
2.9 mEq/L 
2.0 to 2.4 mEq/L or 
intensive replacement 
therapy of 
hospitalization 
required 
<2.0 mEq/L or abnormal 
potassium with paresis, 
ileus, or life-threatening 
arrhythmia 
Hyperkalemia 
5.6 to 6.0 mEq/L 
6.1 to 
6.5 mEq/L 
6.6 to 7.0 mEq/L 
>7.0 mEq/L or abnormal 
potassium with 
life-threatening arrhythmia 
Hypoglycemia 
55 to 64 mg/dL 
40 to 54 mg/dL 
30 to 39 mg/dL 
<30 mg/dL or abnormal 
glucose with mental status 
changes or coma 


 
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Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116 to 
160 mg/dL 
161 to 
250 mg/dL 
251 to 500 mg/dL 
>500 mg/dL or abnormal 
glucose with ketoacidosis 
or seizures 
Hypocalcemia 
(corrected for 
albumin) 
8.4 to 7.8 mg/dL 
7.7 to 
7.0 mg/dL 
6.9 to 6.1 mg/dL 
<6.1 mg/dL or abnormal 
calcium with life-threatening 
arrhythmia or tetany 
Hypercalcemia 
(corrected for 
albumin) 
10.6 to 
11.5 mg/dL 
11.6 to 
12.5 mg/dL 
12.6 to 13.5 mg/dL 
>13.5 mg/dL or abnormal 
calcium with life-threatening 
arrhythmia 
Hypomagnesemia 
1.4 to 1.2 mEq/L 
1.1 to 
0.9 mEq/L 
0.8 to 0.6 mEq/L 
<0.6 mEq/L or abnormal 
magnesium with 
life-threatening arrhythmia 
Hypophosphatemia 
2.0 to 2.4 mg/dL 
1.5 to 
1.9 mg/dL or 
replacement Rx 
required 
1.0 to 1.4 mg/dL 
intensive therapy or 
hospitalization 
required 
<1.0 mg/dL or abnormal 
phosphate with 
life-threatening arrhythmia 
Hyperbilirubinemia 
(when 
accompanied by 
any increase in 
other liver function 
test) 
1.1 to 
<1.25  ULN 
1.25 to 
<1.5  ULN 
1.5 to 1.75  ULN 
>1.75  ULN 
Hyperbilirubinemia 
(when other liver 
function tests are in 
the normal range) 
1.1 to 
<1.5  ULN 
1.5 to 
<2.0  ULN 
2.0 to 3.0  ULN 
>3.0  ULN 
Blood urea nitrogen  1.25 to 
2.5  ULN 
2.6 to 5  ULN 
5.1 to 10  ULN 
>10  ULN 
Hyperuricemia (uric 
acid) 
7.5 to 
10.0 mg/dL 
10.1 to 
12.0 mg/dL 
12.1 to 15.0 mg/dL 
>15.0 mg/dL 
Creatinine 
1.1 to 1.5  ULN 
1.6 to 
3.0  ULN 
3.1 to 6.0  ULN 
>6  ULN or dialysis 
required 
Rx=therapy; ULN=upper limit of normal. 
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. 
11.8.2. 
List of Potential AEs for programming to be considered due to 
Acetylcholinesterase-Inhibition 
Abdominal discomfort 
Abdominal pain 
Abdominal pain lower 
Abdominal pain upper 
Abdominal symptom 
Abdominal tenderness 
Asthma 
Atonic seizures 
Atypical benign partial epilepsy 
Autonomic seizure 
Bradyarrhythmia 
Bradycardia 
Bronchial hyperreactivity 
Bronchospasm 
Clonic convulsion 
Cold sweat 
Convulsions local 
Convulsive threshold lowered 
Defaecation urgency 
Diarrhoea 
Drooling 
Dyspnoea 
Dyspnoea at rest 
Dyspnoea exertional 
Epigastric discomfort 
Epilepsy 
Epilepsy with myoclonic-atonic seizures 
Faeces soft 
Febrile convulsion 


 
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Febrile infection-related epilepsy syndrome 
Flatulence 
Focal dyscognitive seizures 
Frequent bowel movements 
Frontal lobe epilepsy 
Gastrointestinal disorder 
Gastrointestinal pain 
Gastrointestinal tract irritation 
Generalised non-convulsive epilepsy 
Generalised tonic-clonic seizure 
Heart rate decreased 
Hyperhidrosis 
Hyperkinesia 
Hypocalcaemic seizure 
Hypoglycaemic seizure 
Hyponatraemic seizure 
Idiopathic generalised epilepsy 
Idiopathic partial epilepsy 
Irregular breathing 
Lacrimation increased 
Lafora's myoclonic epilepsy 
Lennox-Gastaut syndrome 
Myoclonic epilepsy 
Nausea 
Night sweats 
Partial seizures 
Partial seizures with secondary generalisation 
Petit mal epilepsy 
Psychomotor hyperactivity 
Retching 
Salivary hypersecretion 
Seizure 
Seizure cluster 
Simple partial seizures 
Status asthmaticus 
Status epilepticus 
Sweat gland disorder 
Syncope 


 
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Tonic clonic movements 
Tonic convulsion 
Unilateral bronchospasm 
Vomiting 
Vomiting projectile 
Wheezing 
 


 
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11.9. 
Appendix 9: Multiple Comparisons & Multiplicity 
11.9.1. 
Handling of Multiple Comparisons & Multiplicity 
No adjustments for multiplicity will be made. 
 
 
 


 
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11.10. 
Appendix 10: Abbreviations & Trade Marks 
11.10.1. 
Abbreviations 
z 
terminal phase rate constant 
ADaM 
Analysis Data Model 
AE 
adverse event 
AESI 
adverse event of special interest 
Ae total 
total amount excreted in urine (drug or biomarker) 
Ae (t1-t2) 
amount excreted in urine in a time interval (drug) 
AUC 
area under the concentration-time curve 
AUC(0-∞) 
area under the concentration-time curve from time 0 (predose) extrapolated to 
infinite time (plasma) 
AUC(0-24) 
area under the concentration-time curve from time 0 (predose) to 24 hours post 
dose administration following the first dose (plasma or urine) 
AUC(0-48) 
area under the concentration-time curve from time 0 (predose) to 48 hours post 
dose administration following the first dose (plasma or urine) 
AUC(0-t) 
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration (plasma, serum, or urine) 
AUC(0-τ) 
area under the concentration-time curve from time 0 (predose) to time tau 
(plasma or urine) 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
Apparent plasma oral clearance  
CLr 
renal clearance (drug or biomarker) 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CSR 
Clinical Study Report 
DDI 
drug-drug interaction 
DMID 
Division of Microbiology and Infectious Diseases 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
fe% 
percentage of the given dose of drug excreted in urine 
GSK 
GlaxoSmithKline 
ICF 
informed consent form 
IA 
Interim Analysis 
IDSL 
Integrated Data Standards Library 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
mmHg 
millimeters of mercury 
msec 
millisecond 
PK 
pharmacokinetic 
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 
RAP 
Reporting and Analysis Plan 
RoAUC 
accumulation ratio based on AUC(0-) (plasma) 
RoCmax 
accumulation ratio based on Cmax (plasma) 
SAC 
Statistical Analysis Complete 


 
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SAE 
serious adverse event 
SAS 
Statistical Analysis Software 
SD 
single dose 
SoA 
schedule of activities 
t1/2 
Apparent plasma terminal phase half life 
Tlag 
lag time before observation of drug concentration in plasma 
Tmax 
time to reach maximum observed plasma concentration 
Vz/F 
Apparent plasma volume of distribution  
11.10.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group 
of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
GSKDrug 
 
MedDRA 
 
 
SAS 
 
 
WHODrug 
 
 
WinNonlin 
 
 
 


 
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11.11. 
Appendix 11: List of Data Displays 
11.11.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.10 
NA 
Safety 
2.1 to 2.22 
2.1 to 2.5 
Pharmacokinetic 
3.1 to 3.33 
3.1 to 3.37 
Biomarker 
4.1 to 4.5 
4.1 to 4.3 
Section 
Listings 
ICH Listings 
1 to 46 
Other Listings 
47 to 65 
 
11.11.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
11.11.3. 
Deliverables 
Delivery  
Description 
SAC 
Final Statistical Analysis Complete 


 
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11.11.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition and Analysis Sets 
1.1 
Enrolled 
NS1 
Summary of Number of Subjects Enrolled by Country and Site 
ID 
 
SAC [1] 
1.2 
Safety 
ES1xo 
Summary of Subject Disposition  
 
SAC [1] 
1.3 
Enrolled 
ES4 
Summary of Subject Disposition at Each Study Period 
Cohorts 3 and 4 only 
SAC [1] 
1.4 
Screened 
ES6 
Summary of Reasons for Screening Failures  
 
SAC [1] 
1.5 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
 
SAC [1] 
1.6 
Enrolled 
DV1 
Summary of Important Protocol Deviations  
 
SAC [1] 
Demographics and Baseline Characteristics 
1.7 
Safety 
DM1xo 
Summary of Demographic Characteristics  
 
SAC [1] 
1.8 
Safety 
DM6xo 
Summary of Race and Racial Combinations 
 
SAC [1] 
1.9 
Enrolled 
DM11xo 
Summary of Age Ranges 
 
SAC [1] 
1.10 
Safety 
MH4 
Summary of Current Cardiovascular and Liver Disease Related 
Medical Conditions 
 
SAC [1] 
 
 


 
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11.11.5. 
Safety Tables 
Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Adverse Events 
2.1 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class and Preferred 
Term and Maximum Grade 
 
SAC [1] 
2.2 
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade 
 
SAC [1] 
2.3 
Safety 
AE15 
Summary of Common Non-serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and Occurrences)  
 
SAC [1] 
2.4 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences)  
 
SAC[1] 
2.5 
Safety 
AE5B 
Summary of Potential Acetylcholinesterase-Inhibition Adverse Events of 
Special Interest by System Organ Class and Preferred Term and 
Maximum Grade 
 
SAC [1] 
2.6 
Safety 
SAFE_T1 
Summary of Cumulative Grades of Potential Acetylcholinesterase-
Inhibition Adverse Events of Special Interest 
 
SAC[1] 
Laboratory Measurements 
2.7 
Safety 
LB1 
Summary of Chemistry Change from Baseline  
 
SAC [1] 
2.8 
Safety 
LB15 
Summary of Worst Case Chemistry Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
 
SAC [1] 
2.9 
Safety 
LB1 
Summary of Hematology Change from Baseline  
 
SAC [1] 
2.10 
Safety 
LB15 
Summary of Worst Case Hematology Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
 
SAC [1] 
2.11 
Safety 
UR1 
Summary of Worst Case Urinalysis Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
 
SAC [1] 


 
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Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
2.12 
Safety 
LIVER1 
Summary of Liver Stopping Event Reporting 
 
SAC [1] 
Electrocardiograms 
2.13 
Safety 
EG1 
Summary of ECG Findings  
 
SAC [1] 
2.14 
Safety 
EG11 
Summary of Maximum QTc Values Post-Baseline ECG Parameter 
Corrected QTc Interval  
 
SAC [1] 
2.15 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post- Baseline Relative 
to Baseline by Category  
 
SAC [1] 
2.16 
Safety 
EG2 
Summary of Change from Baseline in ECG Values  
 
SAC [1] 
Vital Signs 
2.17 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs  
 
SAC [1] 
2.18 
Safety 
VS3 
Summary of Worst Case Vital Sign Results Relative to Normal Range 
Post- Baseline Relative to Baseline  
 
SAC [1] 
Cardiovascular Risk Factors 
2.19 
Safety 
FH1 
Summary of Family History of Cardiovascular Risk Factors 
 
SAC [1] 
2.20 
Safety 
SU1 
Summary of Substance Use 
 
SAC [1] 
2.21 
Safety 
EG2 
Summary of QTcF Values 
 
SAC[1] 
COVID-19 
2.22 
Safety 
PAN1 
Summary of COVID-19 Assessment 
 
SAC [1] 
 
 


 
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11.11.6. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
PK Concentration Data 
3.1.  
PK  
PKCT1 
Summary of Gepotidacin Plasma Pharmacokinetic 
Concentration-Time Data (ug/mL) by Cohort and Treatment  
Cohorts 1, 2, and 4; Paginate by 
treatment; For Cohort 4 only 
show periods 1/2 (fasted v fed) 
SAC [1] 
3.2.  
PK  
PKCT1 
Summary of Cimetidine Plasma Pharmacokinetic 
Concentration-Time Data (units)  
Cohort 1 (Period 2 only) 
SAC [1] 
3.3.  
PK  
PKCT1 
Summary of Digoxin Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment  
Paginate by treatment; Cohort 3 
SAC [1] 
3.4.  
PK  
PKCT1 
Summary of Midazolam and 1-Hydoxymidazolam Plasma 
Pharmacokinetic Concentration-Time Data (units) by 
Treatment  
Paginate by treatment; by-
variable for analyte; Cohort 3 
SAC [1] 
3.5.  
PK  
PKCT1 
Summary of Gepotidacin Plasma Pharmacokinetic 
Concentration-Time Data (ug/mL) for 1500 mg Dose: 
Japanese versus Western Participants 
Japanese: Cohort 4 (single dose 
fed only); Western: Cohorts 1 
and 2 (Gepo-only period – Period 
1); Paginate by ethnicity. 
SAC [1] 
3.6.  
PK  
PKCT1 
Summary of Gepotidacin Plasma Pharmacokinetic 
Concentration-Time Data (ug/mL) for Two 3000 mg Doses: 
Japanese versus Western Participants 
Japanese: Cohort 4 (Period 3); 
Western: Cohort 3; 
Paginate by ethnicity. 
SAC [1] 
3.7.  
PK  
PKCT1 
Summary of Gepotidacin Urine Pharmacokinetic 
Concentration-Time Data (ug/mL) by Treatment by Cohort 
and Treatment 
Cohorts 1, 2, and 4; Paginate by 
treatment; For Cohort 4 only 
show period 1/2 (fasted v fed) 
SAC [1] 
3.8.  
PK  
PKCT1 
Summary of Gepotidacin Urine Pharmacokinetic 
Concentration-Time Data (ug/mL) for 1500 mg Dose: 
Japanese versus Western Participants 
Japanese: Cohort 4 (single dose 
fed only); Western: Cohorts 1 
and 2 (Gepo-only period – Period 
SAC [1] 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
1); Paginate by ethnicity. 
3.9.  
PK  
PKCT1 
Summary of Gepotidacin Urine Pharmacokinetic 
Concentration-Time Data (ug/mL) for Two 3000 mg Doses: 
Japanese versus Western Participants 
Japanese: Cohort 4 (Period 3); 
Western: Cohort 3; 
Paginate by ethnicity. 
SAC [1] 
PK Derived Parameters 
3.10. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Plasma 
Pharmacokinetic Parameters by Treatment by Cohort and 
Treatment 
Cohorts 1, 2, and 4; Parameters 
with units. Do not ln-transform 
Tmax or Tlag; Treatments side-
by-side; For Cohort 4 only show 
period 1/2 (fasted v fed) 
SAC [1] 
3.11. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Digoxin Plasma 
Pharmacokinetic Parameters by Treatment  
Parameters with units. Do not ln-
transform Tmax or Tlag; 
Treatments side-by-side; Cohort 
3 
SAC [1] 
3.12. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Midazolam and 1-
Hydroxymidazolam Plasma Pharmacokinetic Parameters by 
Treatment  
Parameters with units. Do not ln-
transform Tmax or Tlag;. 
Treatments side-by-side; Cohort 
3; by-variable for analyte. 
SAC [1] 
3.13. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Plasma 
Pharmacokinetic Parameters for 1500 mg Dose: Japanese 
versus Western Participants 
Parameters with units. Do not ln-
transform Tmax or Tlag; Ethnicity 
side-by-side; Japanese: Cohort 4 
(single dose fed only); Western: 
Cohorts 1 and 2 (Gepo-only 
period – Period 1) 
SAC [1] 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
3.14. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Plasma 
Pharmacokinetic Parameters for Two 3000 mg Doses: 
Japanese versus Western Participants 
Parameters with units. Do not ln-
transform Tmax or Tlag; Ethnicity 
side-by-side; Japanese: Cohort 4 
(Period 3); Western: Cohort 3; 
by-variable for dose number 
SAC [1] 
3.15. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Urine 
Pharmacokinetic Parameters by Cohort and Treatment 
Parameters with units; 
Treatments side-by-side; by-
variable for Cohort; Cohorts 1, 2, 
and 4; for Cohort 4 period 1/2 
(fasted/fed) only 
SAC [1] 
3.16 
PK Parameter 
PKPT4 
Summary Statistics of Derived Digoxin Urine 
Pharmacokinetic Parameters by Treatment  
Parameters with units; 
Treatments side-by-side; Cohort 
3. 
SAC [1] 
3.17 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Urine 
Pharmacokinetic Parameters for 1500 mg Dose: Japanese 
versus Western Participants 
Parameters with units. Ethnicity 
side-by-side; Japanese: Cohort 4 
(single dose fed only); Western: 
Cohorts 1 and 2 (Gepo-only 
period – Period 1) 
SAC [1] 
3.18 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Urine 
Pharmacokinetic Parameters for Two 3000 mg Doses: 
Japanese versus Western Participants 
Parameters with units. Do not ln-
transform Tmax or Tlag; Ethnicity 
side-by-side; Japanese: Cohort 4 
(Period 3); Western: Cohort 3; 
by-variable for dose number 
SAC [1] 
PK Analysis 
3.19 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma and Urine 
Pharmacokinetic Parameters: Parametric Analysis – Cohort 1 
 Linear mixed-effect model: 
plasma: AUCs, Cmax, t1/2; urine: 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
AUCs, Ae total, CLr; contains 
inferential analysis 
3.20 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma Pharmacokinetic 
Parameters: Non-parametric Analysis – Cohort 1 
 Wilcoxon signed-rank test: 
Tmax; contains inferential 
analysis 
SAC 
3.21 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma and Urine 
Pharmacokinetic Parameters: Parametric Analysis – Cohort 2 
 Linear mixed-effect model: 
plasma: AUCs, Cmax; urine: 
AUCs Ae total, CLr; contains 
inferential analysis 
SAC 
3.22 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma Pharmacokinetic 
Parameters: Non-parametric Analysis – Cohort 2 
 Wilcoxon signed-rank test: 
Tmax and Tlag; contains 
inferential analysis 
SAC 
3.23 
PK Parameter 
PKPT3 
Statistical Analysis of Digoxin Plasma and Urine 
Pharmacokinetic Parameters: Parametric Analysis – Cohort 3 
 Linear mixed-effect model: 
plasma: AUCs, Cmax, t1/2, 
Cmin, Vz/F, CL/F; urine: Ae total 
and CLr; contains inferential 
analysis 
SAC 
3.24 
PK Parameter 
PKPT3 
Statistical Analysis of Midazolam and 1’-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters: Parametric Analysis – 
Cohort 3 
 Linear mixed-effect model: 
plasma: AUCs, Cmax, t1/2, 
Cmin, Vz/F, CL/F; contains 
inferential analysis,  
SAC 
3.25 
PK Parameter 
PKPT3 
Statistical Analysis of Digoxin Plasma Pharmacokinetic 
Parameters: Non-parametric Analysis – Cohort 3 
 Wilcoxon signed-rank test: 
Tmax and Tlag; contains 
inferential analysis 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
3.26 
PK Parameter 
PKPT3 
Statistical Analysis of Midazolam and 1’-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters: Non-parametric 
Analysis – Cohort 3 
 Wilcoxon signed-rank test: 
Tmax and Tlag; contains 
inferential analysis 
SAC 
3.27 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma Pharmacokinetic 
Parameters: Food Effect, Parametric Analysis – Cohort 4 
 Linear mixed-effect model: 
plasma: AUC(0-t), AUC(0-∞), 
Cmax; Periods 1 and 2 only; 
contains inferential analysis 
SAC 
3.28 
PK Parameter 
PKPT3 
Statistical Analysis of Gepotidacin Plasma Pharmacokinetic 
Parameters: Food Effect, Non-parametric Analysis – Cohort 4 
 Wilcoxon signed-rank test: 
Tmax and Tlag; Periods 1 and 2 
only; contains inferential analysis 
SAC 
Emesis vs. No Emesis 
3.29 
PK Parameter 
PKPT4 
Summary Statistics of Derived Gepotidacin Plasma 
Pharmacokinetic Parameters by Cohort and Treatment for 
Participants with Emesis and Participants without Emesis   
Emesis v No Emesis side-by-
side; Cohort 3 and Cohort 4 
(period 3). 
SAC 
3.30 
PK Parameter 
PKPT3 
Statistical Analysis of Digoxin Plasma and Urine 
Pharmacokinetic Parameters Excluding Participants with 
Emesis: Parametric Analysis – Cohort 3 
 Linear mixed-effect model: 
plasma: AUCs, Cmax, t1/2, 
Cmin, CL/F, and Vz/F; urine: Ae 
total, CLr; contains inferential 
analysis 
SAC 
3.31 
PK Parameter 
PKPT3 
Statistical Analysis of Midazolam and 1’-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters Excluding Participants 
with Emesis: Parametric Analysis – Cohort 3 
 Linear mixed-effect model: 
plasma: AUCs, Cmax, t1/2, 
Cmin, CL/F, Vz/F; contains 
inferential analysis,  
SAC 
3.32 
PK Parameter 
PKPT3 
Statistical Analysis of Digoxin Plasma Pharmacokinetic 
Parameters Excluding Participants with Emesis: Non-
parametric Analysis – Cohort 3 
 Wilcoxon signed-rank test: 
Tmax and Tlag; contains 
inferential analysis 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
3.33 
PK Parameter 
PKPT3 
Statistical Analysis of Midazolam and 1’-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters Excluding Participants 
with Emesis: Non-parametric Analysis – Cohort 3 
 Wilcoxon signed-rank test: 
Tmax and Tlag; contains 
inferential analysis 
SAC 
 


 
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11.11.7. 
Biomarker Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Biomarker Concentration Data 
4.1 
PK  
PKCT1 
Summary of Biomarker Concentration-Time Data (units) by 
Treatment  
Cohort 1; Creatinine (serum), 1-
NMN (plasma), eGFR; Paginate by 
treatment; Baseline-corrected 
values 
SAC [1] 
Biomarker Derived Parameters 
4.2 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Biomarker Parameters by 
Treatment  
Cohort 1; Parameters with units. 
Treatments side-by-side. 
SAC [1] 
4.3 
PK 
Parameter 
PKPT4 
Summary Statistics of Derived Biomarker Urine Parameters by 
Treatment  
Cohort 1; Parameters with units. 
Treatments side-by-side; include 
creatinine-normalized parameters. 
SAC [1] 
Statistical Analysis 
4.4 
PK 
Parameter 
PKPT3 
Statistical Analysis of 1-NMN Plasma and Urine Biomarker 
Parameters: Parametric Analysis – Cohort 1 
 Linear mixed-effect model: 
plasma: AUCs, Cmax; urine: Ae 
total and CLr; contains inferential 
analysis 
SAC 
4.5 
PK 
Parameter 
PKPT3 
Statistical Analysis of Creatinine Serum and Urine Biomarker 
Parameters: Parametric Analysis – Cohort 1 
 Linear mixed-effect model: 
plasma: AUC and Cmax; urine: Ae 
total and CLr; contains inferential 
analysis 
SAC 
 
 
 


 
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11.11.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
2.1 
Safety 
AE10 
Gastrointestinal Adverse Events of Special Interest Adverse 
Events  
 
SAC [1] 
2.2 
Safety 
SAFE_F1 
Plot of Distribution of Cumulative Grades of 
Acetylcholinesterase-Inhibition Adverse Events of Special 
Interest 
 
SAC [1] 
2.3 
Safety 
SAFE_F2 
Plot of duration and severity of Adverse Events for Individual 
Participants 
 
SAC [1] 
2.4 
Safety 
EG8 
Distribution of QTcF Change By Time And Treatment 
 
SAC [1] 
2.5 
Safety 
SAFE_F3 
Individual and Mean Plot of QTcF Over Time And Treatment 
 
SAC [1] 
 
 
 


 
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11.11.9. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.1.  
PK  
PKCF1P 
Individual Gepotidacin Plasma Concentration-Time Plots by 
Cohort and Treatment (Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ; 
Participants Overlaid; By-variable 
for Cohort; all cohorts 
SAC [1] 
3.2.  
PK  
PKCF1P 
Individual Digoxin Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ; 
Participants Overlaid; Cohort 3 
SAC [1] 
3.3.  
PK  
PKCF1P 
Individual Midazolam and 1’-Hydroxymidazolam Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ; 
Participants Overlaid; by-variable 
for analyte; Cohort 3 
SAC [1] 
3.4.  
PK  
PKCF1P 
Individual Gepotidacin Urine Concentration-Time Plots by 
Cohort and Treatment (Linear and Semi Logarithmic) 
Paginate by Treatment; Dashed 
line represents the LLQ; 
Participants Overlaid; By-variable 
for Cohort; All cohorts; Plot 
based on the actual relative mid-
point time for each interval. 
SAC [1] 
Mean / Median Concentration Plots 
3.5.  
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Plasma 
Concentration-Time Plots by Cohort and Treatment (Linear 
and Semi-Logarithmic) 
Treatments Overlaid; By-variable 
for Cohort; Cohorts 1, 2, and 4. 
For Cohort 4 only show period 
1/2 (fasted v fed) 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.6.  
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Plasma 
Concentration-Time Plots for Japanese Participants (Linear 
and Semi-Logarithmic) 
Cohort 4 – single dose fed and 
two doses (period 3) overlaid.  
SAC [1] 
3.7.  
PK  
PKCF2 
Mean (± Standard Deviation) Digoxin Plasma Concentration-
Time Plots by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid; Cohort 3 
SAC [1] 
3.8.  
PK  
PKCF2 
Mean (± Standard Deviation) Midazolam and 1-
Hydoxymidazolam Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid; By-variable 
for analyte; Cohort 3 
SAC [1] 
3.9.  
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Plasma 
Concentration-Time Plots for 1500 mg Dose: Japanese 
versus Western Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (single dose fed only); 
Western: Cohorts 1 and 2 (Gepo-
only period). 
SAC [1] 
3.10. 
 
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Plasma 
Concentration-Time Plots for Two 3000 mg Doses: Japanese 
versus Western Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (Period 3); Western: 
Cohort 3. 
SAC [1] 
3.11. 
 
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Urine 
Concentration-Time Plots by Cohort and Treatment (Linear 
and Semi-Logarithmic) 
Treatments Overlaid; By-variable 
for Cohort; For Cohort 4 only 
show period 1/2 (fasted v fed). 
Cohorts 1, 2, and 4; Plot based 
on the planned relative mid-point 
time for each interval. 
SAC [1] 
3.12. 
 
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Urine 
Concentration-Time Plots for Japanese Participants (Linear 
and Semi-Logarithmic) 
Cohort 4 – single dose fed and 
two doses (period 3) overlaid; 
Plot based on the planned 
relative mid-point time for each 
interval. 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.13. 
 
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Urine 
Concentration-Time Plots for 1500 mg Dose: Japanese 
versus Western Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (single dose fed only); 
Western: Cohorts 1 and 2 (Gepo-
only period); Plot based on the 
planned relative mid-point time 
for each interval. 
SAC [1] 
3.14. 
 
PK  
PKCF2 
Mean (± Standard Deviation) Gepotidacin Urine 
Concentration-Time Plots for Two 3000 mg Doses: Japanese 
versus Western Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (Period 3); Western: 
Cohort 3; Plot based on the 
planned relative mid-point time 
for each interval. 
SAC [1] 
3.15. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Plasma Concentration-Time 
Plots by Cohort and Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid; By-variable 
for Cohort; For Cohort 4 only 
show period 1/2 (fasted v fed); 
Cohorts 1, 2, and 4. 
SAC [1] 
3.16. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Plasma Concentration-Time 
Plots for Japanese Participants (Linear and Semi-
Logarithmic) 
Cohort 4 – single dose fed and 
two doses (period 3) overlaid 
SAC [1] 
3.17. 
 
PK  
PKCF3 
Median (Range) Digoxin Plasma Concentration-Time Plots 
by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid; Cohort 3 
SAC [1] 
3.18. 
 
PK  
PKCF3 
Median (Range) Midazolam and 1-Hydoxymidazolam Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid; By-variable 
for analyte; Cohort 3 
SAC [1] 
3.19. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Plasma Concentration-Time 
Plots for 1500 mg Dose: Japanese versus Western  
Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (single dose fed only); 
Western: Cohorts 1 and 2 (Gepo-
only period). 
SAC [1] 
3.20. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Plasma Concentration-Time 
Plots for Two 3000 mg Doses: Japanese versus Western 
Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (Period 3); Western: 
Cohort 3. 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.21. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Urine Concentration-Time Plots 
by Cohort and Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid; By-variable 
for Cohort; For Cohort 4 only 
show period 1/2 (fasted v fed); 
Cohorts 1, 2, and 4; Plot based 
on the planned relative mid-point 
time for each interval. 
SAC [1] 
3.22. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Urine Concentration-Time Plots 
for Japanese Participants (Linear and Semi-Logarithmic) 
Cohort 4 – single dose fed and 
two doses (period 3) overlaid; 
Plot based on the planned 
relative mid-point time for each 
interval. 
SAC [1] 
3.23. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Urine Concentration-Time Plots 
for 1500 mg Dose: Japanese versus Western Participants 
(Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (single dose fed only); 
Western: Cohorts 1 and 2 (Gepo-
only period). 
SAC [1] 
3.24. 
 
PK  
PKCF3 
Median (Range) Gepotidacin Urine Concentration-Time Plots 
for Two 3000 mg Doses: Japanese versus Western 
Participants (Linear and Semi-Logarithmic) 
Ethnicities overlaid; Japanese: 
Cohort 4 (Period 3); Western: 
Cohort 3. 
SAC [1] 
3.25. 
 
PK 
Parameter 
PK25 
Spaghetti and Box Plots of Gepotidacin PK Parameters With 
and Without Cimetidine 
Cohort 1; Primary PK parameters 
SAC [1] 
3.26. 
 
PK 
Parameter 
PK25 
Spaghetti and Box Plots of Gepotidacin PK Parameters With 
and Without Rifampin 
Cohort 2; Primary PK parameters 
SAC [1] 
3.27. 
 
PK 
Parameter 
PK25 
Spaghetti and Box Plots of Digoxin PK Parameters With and 
Without Gepotidacin 
Cohort 3; Primary PK parameters 
SAC [1] 
3.28. 
 
PK 
Parameter 
PK25 
Spaghetti and Box Plots of Midazolam and 1-
Hydroxymidazolam PK Parameters With and Without 
Gepotidacin 
Cohort 3; Primary PK parameters 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.29. 
 
PK 
Parameter 
EFF_F1 
Box Plot of Gepotidacin PK Parameters With and Without 
Food in Japanese Participants 
Cohort 4 Period 1/2; Primary PK 
parameters 
SAC [1] 
3.30. 
 
PK 
Parameter 
EFF_F1 
Box Plot of Gepotidacin PK Parameters for 1500 mg Dose: 
Japanese versus WesternParticipants 
Ethnicity side-by-side; Japanese: 
Cohort 4 (single dose fed only); 
Western: Cohorts 1 and 2 (Gepo-
only period); Include data from 
BTZ117351 
SAC [1] 
3.31. 
 
PK 
Parameter 
EFF_F1 
Box Plot of Gepotidacin PK Parameters for Two 3000 mg 
Doses: Japanese versus Western Participants 
Ethnicity side-by-side; Japanese: 
Cohort 4 (Period 3); Western: 
Cohort 3; by-variable for dose 
number 
SAC [1] 
3.32. 
 
PK 
Parameter 
EFF_F2 
Mean Urinary Gepotidacin Excretion With and Without 
Cimetidine 
Cohort 1 
SAC [1] 
3.33. 
 
PK 
Parameter 
EFF_F3 
Geometric Mean Treatment Ratio and 90% Confidence 
Interval of Gepotidacin Pharmacokinetic Parameters 
Cohorts 1 and 2; Include data 
from BTZ117349 
SAC [1] 
3.34. 
 
PK 
Parameter 
EFF_F3 
Geometric Mean Treatment Ratio and 90% Confidence 
Interval of Digoxin, Midazolam, and 1-Hydroxymidazolam 
Pharmacokinetic Parameters 
Cohort 3 
SAC [1] 
3.35. 
 
Safety 
PKPF2 
Change from Baseline QTcF Data Versus Gepotidacin 
Plasma Concentrations  
Combine gepotidacin-only data 
from Cohorts 1, 2, 3 and 4; 
indicate cohort and ethnicity in 
legend; contains inferential 
analysis 
 SAC [1] 
Emesis vs No Emesis 
3.36. 
 
PK 
PKCF1P 
Individual Gepotidacin Plasma Concentration-Time Plots by 
Treatment for Participants with Emesis and Participants 
without Emesis (Linear and Semi-Logarithmic) 
Cohorts 3 and 4 (Period 3); only 
programmed if emesis is 
observed 
SAC [1] 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.37. 
 
PK 
PKCF2 
Mean (± Standard Deviation) Gepotidacin Plasma 
Concentration-Time Plots by Treatment for Participants with 
Emesis and Participants without Emesis (Linear and Semi-
Logarithmic) 
Cohorts 3 and 4 (Period 3); only 
programmed if emesis is 
observed 
SAC [1] 
 
11.11.10. Biomarker Figures 
Biomarker: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
4.1 
PK  
PKCF1P 
Individual Biomarker Concentration-Time Plots by Treatment 
(Linear) 
Paginate by treatment; Dashed 
line represents the LLQ; 
Participants Overlaid; Cohort 1 
SAC [1] 
Mean / Median Concentration Plots 
4.2 
PK  
PKCF2 
Mean (± Standard Deviation) Biomarker Concentration-Time 
Plots by Treatment (Linear) 
Treatments Overlaid; Cohort 1 
SAC [1] 
4.3 
PK  
PKCF3 
Median (Range) Biomarker Concentration-Time Plots by 
Treatment (Linear) 
Treatments Overlaid; Baseline-
corrected data; Cohort 1 
SAC [1] 
 
 


 
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11.11.11. ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Randomization 
1 
Enrolled 
TA1xo 
Listing of Randomised and Actual Treatment 
 
SAC [1] 
Subject Disposition 
2 
Safety 
ES2xo 
Listing of Reasons for Study Withdrawal 
 
SAC [1] 
3 
Safety 
SD2xo 
Listing of Reasons for Study Treatment Discontinuation 
 
SAC [1] 
4 
Randomized 
BL1xo 
Listing of Subjects for Whom the Treatment Blind was Broken 
During the Study 
 
SAC [1] 
5 
Screened 
ES7 
Listing of Reasons for Screening Failure 
 
SAC [1] 
6 
Enrolled 
DV2xo 
Listing of Important Protocol Deviations 
 
SAC [1] 
7 
Screened 
IE3xo 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC [1] 
8 
Enrolled 
SP3xo 
Listing of Subjects Excluded from Any Population 
 
SAC [1] 
Demographics 
9 
Safety 
DM2xo 
Listing of Demographic Characteristics 
Include height, 
weight and BMI 
and childbearing 
potential 
SAC [1] 
10 
Safety 
DM9xo 
Listing of Race 
 
SAC [1] 
Medical Conditions and Concomitant Medications 
11 
Safety 
MH2xo 
Listing of Medical Conditions  
 
SAC [1] 
12 
Safety 
CM3xo 
Listing of Concomitant Medications  
 
SAC [1] 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Exposure 
13 
Safety 
EX3xo 
Listing of Exposure Data 
 
SAC [1] 
Safety 
14 
Safety 
AE2 
Listing of Relationship Between System Organ Class and Verbatim 
Text 
 
SAC[1] 
15 
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC [1] 
16 
Safety 
AE8xo 
Listing of All Adverse Events 
 
SAC [1] 
17 
Safety 
AE8xo 
Listing of Study Drug Related Adverse Events 
 
SAC [1] 
18 
Safety 
AE8xo 
Listing of Serious Adverse Events 
 
SAC [1] 
19 
Safety 
AE8xo 
Listing of Adverse Events Leading to Withdrawal from Study 
 
SAC [1] 
20 
Safety 
AE8xo 
Listing of Cardiovascular Adverse Events of Special Interest 
Conditional display 
SAC [1] 
21 
Safety 
AE8xo 
Listing of Gastrointestinal Adverse Events of Special Interest 
Conditional display 
SAC [1] 
22 
Safety 
AE8xo 
Listing of Potential Acetylcholinesterase-Inhibition Adverse Events 
of Special Interest 
Conditional display 
SAC [1] 
23 
Safety 
AE8xo 
Listing of Liver Adverse Events 
Conditional display 
SAC [1] 
24 
Safety 
SAFE_L2 
Listing of Clostridium Difficile Testing 
Conditional display 
SAC [1] 
Laboratory Measurements 
25 
Safety 
LB5xo 
Listing of All Chemistry Data for Subjects with Any Value 
 
SAC [1] 
26 
Safety 
LB5xo 
Listing of All Chemistry Data for Subjects with Toxicities of Grade 3 
or Higher 
 
SAC [1] 
27 
Safety 
LB5xo 
Listing of All Hematology Data for Subjects with Any Value 
 
SAC [1] 
28 
Safety 
LB5xo 
Listing of All Hematology Data for Subjects with Toxicities of Grade 
3 or Higher 
 
SAC [1] 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
29 
Safety 
UR2xo 
Listing of All Urinalysis Data for Subjects with Any Value 
 
SAC [1] 
30 
Safety 
UR2xo 
Listing of All Urinalysis Data for Subjects with Toxicities of Grade 3 
or Higher 
 
SAC [1] 
ECGs 
31 
Safety 
EG5xo 
Listing of Abnormal ECG Findings 
 
SAC [1] 
32 
Safety 
EG5xo 
Listing of All ECG Findings for Subjects with an Abnormal Finding 
 
SAC [1] 
33 
Safety 
HM10 
Listing of Clinically Significant Holter Abnormalities 
 
SAC [1] 
34 
Safety 
EG3xo 
Listing of ECG Values of Potential Clinical Importance 
 
SAC [1] 
35 
Safety 
EG3xo 
Listing of ECG Change from Baseline of Potential Clinical 
Importance 
 
SAC [1] 
36 
Safety 
EG3xo 
Listing of All ECG Values for Subjects with Any Value of Potential 
Clinical Importance 
 
SAC [1] 
37 
Safety 
EG4 
Listing of ECG Values 
 
 
Vital Signs 
38 
Safety 
VS4xo 
Listing of Vital Signs of Potential Clinical Importance 
 
SAC [1] 
39 
Safety 
VS4xo 
Listing of All Vital Signs for Subjects with Potential Clinical 
Importance Values 
 
SAC [1] 
66 
Safety 
VS4xo 
Listing of Vital Signs Values 
 
SAC [1] 
Liver Events 
40 
Safety 
LIVER5 
Listing of Liver Stopping Event Reporting 
Conditional display 
SAC [1] 
41 
Safety 
LIVER10 
Listing of Hepatobiliary Laboratory Abnormalities 
Conditional display 
SAC [1] 
42 
Safety 
MH2x 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
Conditional display 
SAC [1] 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
43 
Safety 
PKCL1X 
Listing of Plasma Concentration Data for Subjects with Liver 
Stopping Events 
Conditional display 
SAC [1] 
44 
Safety 
SAFE_L3 
Listing of Alcohol Intake at Onset of Liver Event 
Conditional display 
SAC [1] 
45 
Safety 
SAFE_L4 
Listing of Liver Biopsy Details 
Conditional display 
SAC [1] 
46 
Safety 
SAFE_L5 
Listing of Liver Imaging Details 
Conditional display 
SAC [1] 
 
11.11.12. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
COVID-19 
47 
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessment 
 
SAC [1] 
Pharmacokinetics 
48 
PK  
PKCL1P 
Listing of Gepotidacin Plasma Concentrations (ug/mL) by 
Cohort and Treatment 
All Cohorts 
SAC [1] 
49 
PK  
PKCL1P 
Listing of Cimeditine Plasma Concentrations (units)  
Cohort 1 (Period 2 only) 
SAC [1] 
50 
PK  
PKCL1P 
Listing of Digoxin Plasma Concentrations (units) by Treatment  Cohort 3 
SAC [1] 
51 
PK  
PKCL1P 
Listing of Midazolam and 1-Hydroxymidazolam Plasma 
Concentrations (units) by Treatment  
Cohort 3 
SAC [1] 
52 
PK  
PKUL1P 
Listing of Gepotidacin Urine Concentrations (ug/mL) by Cohort 
and Treatment 
All Cohorts 
SAC [1] 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
53 
PK  
PKUL1P 
Listing of Digoxin Urine Concentrations (units) by Treatment  
Cohort 3 
SAC [1] 
54 
PK 
Parameter 
PKPL1P 
Listing of Gepotidacin Plasma Pharmacokinetic Parameters by 
Cohort and Treatment 
All cohorts; Include by-variable 
for dose number for Cohorts 3/4 
SAC [1] 
55 
PK 
Parameter 
PKPL1P 
Listing of Digoxin Plasma Pharmacokinetic Parameters by 
Treatment  
Cohort 3 
SAC [1] 
56 
PK 
Parameter 
PKPL1P 
Listing of Midazolam and 1-Hydroxymidazolam Plasma 
Pharmacokinetic Parameters by Treatment  
By-variable for analyte; Cohort 3 
SAC [1] 
57 
PK 
Parameter 
PKPL1P 
Listing of Gepotidacin Urine Pharmacokinetic Parameters by 
Cohort and Treatment 
All cohorts 
SAC [1] 
58 
PK 
Parameter 
PKPL1P 
Listing of Digoxin Urine Pharmacokinetic Parameters by 
Treatment  
Cohort 3 
SAC [1] 
Biomarker 
59 
PK  
PKCL1P 
Listing of Biomarker Concentrations (units) by Treatment  
Creatinine (serum) and 1-NMN 
(plasma); Cohort 1; by-variable 
for analyte; include eGFR for 
predose time point 
SAC [1] 
60 
PK  
PKUL1P 
Listing of Biomarker Urine Concentrations (units) by 
Treatment  
Creatinine and 1-NMN; Cohort 
1; by-variable for analyte 
SAC [1] 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
61 
PK 
Parameter 
PKPL1P 
Listing of Biomarker Parameters by Treatment  
Creatinine (serum) and 1-NMN 
(plasma); Cohort 1; by-variable 
for analyte 
SAC [1] 
62 
PK 
Parameter 
PKPL1P 
Listing of Biomarker Urine Parameters by Treatment  
Creatinine and 1-NMN; include 
creatinine-normalized 
parameters; Cohort 1; by-
variable for analyte 
SAC [1] 
63 
Safety 
SAFE_L4 
Listing of Subject Recruitment by Country and Site Number  
 
SAC [1] 
64 
Safety 
SU2 
Listing of Substance Use 
 
SAC [1] 
65 
Safety 
SAFE_L1 
Listing of Subjects in Previous Clinical Trial 
 
SAC [1] 


 
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11.12. 
Appendix 12: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 


Signature Page for  213678 TMF-8687321 v1.0
Signature Page for TMF-8687321 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 16-Dec-2020 05:21:43 GMT+0000
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 16-Dec-2020 14:14:39 GMT+0000
PPD
PPD