A Phase I; Multi-Center; Open-Label (Parts 1 and 2); Randomized, Double-Blind, Placebo-Controlled (Part 3); Single-Dose; 3-Part Study to Evaluate the Relative Bioavailability of Three Formulations in Healthy Subjects, Food Effect on Tablet Formulation in Healthy Subjects, and Pharmacokinetics of Gepotidacin (GSK2140944) in Japanese Subjects in Fasted and Fed States
Phase: PHASE1
Conditions: Infections, Bacterial
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
BTZ117351
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I; Multi-Center; Open-Label (Parts 1 and 2); 
Randomized, Double-Blind, Placebo-Controlled (Part 3); 
Single-Dose; 3-Part Study to Evaluate the Relative 
Bioavailability of Three Formulations in Healthy Subjects, Food 
Effect on Tablet Formulation in Healthy Subjects, and 
Pharmacokinetics of Gepotidacin (GSK2140944) in Japanese 
Subjects in Fasted and Fed States
Compound Number:
GSK2140944
Development Phase:
I
Effective Date:
05-SEP-2017
Protocol Amendment Number:  02
Author (s):
GSK Authors:
 (Clinical Pharmacology Modeling and Simulation), 
 (ID, Medicines Discovery and Development), 
 (Clinical 
Statistics), and 
 (Projects Clinical Platforms and Sciences)
PPD Authors: 
 (Pharmacokineticist), 
 (Biostatistician), and 
(Medical Writer)
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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BTZ117351
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N281831_00
2016-JUL-12
Original
2016N281831_01
2017-MAR-16
Amendment No. 1
The purpose of this amendment is to remove the Chinese cohort and introduce a second 
oral dose for Japanese subjects in Part 2 in a fixed sequence design. Japanese subjects 
will receive a single 1500-mg dose in Period 1 followed by a single 3000-mg dose in 
Period 2. Blood and urine samples (Part 2 only) will also be collected for 
pharmacokinetic analysis of gepotidacin concentrations in Japanese subjects.
2016N281831_02
2017-SEP-05
Amendment No. 2
The purpose of this amendment is to introduce an additional part to the study (Part 3),
and an additional cohort of Japanese subjects will be enrolled in a fixed sequence design.
Japanese subjects in the fed state will receive single escalating doses of gepotidacin 
(1500 mg, 2250 mg, and 3000 mg) in Periods 1, 2, and 3, respectively, or placebo. This 
amendment provides additional guidelines for managing subjects in Part 3 who 
experience adverse events of diarrhea.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone Number 
and E-mail 
Address
After-Hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor and 
SAE Contact 
Information
MD
Safety Hotline:
PPD
929 N Front St
Wilmington, NC 
28401
Secondary 
Medical 
Monitor
MD
Safety Hotline:
PPD
7551 Metro Center
Austin, TX 78744
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address: 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089
Collegeville, PA 19426-0989
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): IND 111885
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BTZ117351
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351 .................................................9
2.
INTRODUCTION....................................................................................................16
2.1.
Study Rationale ..........................................................................................16
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................23
4.6.
Benefit:Risk Assessment ............................................................................24
4.6.1.
Risk Assessment .........................................................................26
4.6.2.
Benefit Assessment.....................................................................28
4.6.3.
Overall Benefit:Risk Conclusion...................................................28
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............28
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................30
5.3.
Screening/Baseline/Run-In Failures............................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................32
5.4.1.
Liver Chemistry Stopping Criteria ................................................33
5.4.2.
QTc Stopping Criteria ..................................................................33
5.4.3.
Gastrointestinal Stopping Criteria ................................................33
5.4.4.
Rash/Hypersensitivity Stopping Criteria .......................................34
5.5.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Investigational Product and Other Study Treatment....................................34
6.2.
Treatment Assignment................................................................................36
6.3.
Planned Dose Adjustments.........................................................................36
6.4.
Blinding.......................................................................................................36
6.5.
Packaging and Labeling..............................................................................37
6.6.
Preparation/Handling/Storage/Accountability..............................................37
6.7.
Compliance With Study Treatment Administration ......................................38
6.8.
Treatment of Study Treatment Overdose....................................................38
6.9.
Treatment After the End of the Study..........................................................39
6.10.
Lifestyle and/or Dietary Restrictions............................................................39
6.10.1.
Meals and Dietary Restrictions ....................................................39
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................39
6.10.3.
Activity .........................................................................................40
6.11.
Concomitant Medications and Non-Drug Therapies....................................40
6.11.1.
Permitted Medications and Non-Drug Therapies..........................40
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................40
 
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
7.1.
Time and Events Table...............................................................................42
7.2.
Screening and Critical Baseline Assessments ............................................44
7.3.
Safety .........................................................................................................44
7.3.1.
Adverse Events and Serious Adverse Events..............................44
7.3.1.1.
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
information .................................................................44
7.3.1.2.
Method of Detecting Adverse Events and 
Serious Adverse Events .............................................45
7.3.1.3.
Follow-Up of Adverse Events and Serious 
Adverse Events ..........................................................45
7.3.1.4.
Regulatory Reporting Requirements for 
Serious Adverse Events .............................................45
7.3.2.
Pregnancy ...................................................................................45
7.3.3.
Physical Exams ...........................................................................46
7.3.4.
Vital Signs....................................................................................46
7.3.5.
Electrocardiogram........................................................................46
7.3.6.
Clinical Safety Laboratory Assessments ......................................46
7.4.
Pharmacokinetics .......................................................................................47
7.4.1.
Blood Sample Collection..............................................................47
7.4.2.
Urine Sample Collection ..............................................................48
7.4.3.
Sample Analysis ..........................................................................48
7.5.
Genetics .....................................................................................................48
8.
DATA MANAGEMENT ...........................................................................................48
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................49
9.1.
Hypotheses.................................................................................................49
9.2.
Sample Size Considerations.......................................................................49
9.2.1.
Sample Size Assumptions ...........................................................49
9.2.2.
Sample Size Re-Estimation or Adjustment...................................50
9.3.
Data Analysis Considerations .....................................................................50
9.3.1.
Analysis Populations....................................................................50
9.3.2.
Interim Analysis ...........................................................................50
9.4.
Key Elements of Analysis Plan ...................................................................51
9.4.1.
Primary Analyses.........................................................................51
9.4.2.
Secondary Analyses ....................................................................53
10. STUDY GOVERNANCE CONSIDERATIONS........................................................54
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............54
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................54
10.3.
Quality Control (Study Monitoring) ..............................................................55
10.4.
Quality Assurance.......................................................................................55
10.5.
Study and Site Closure ...............................................................................55
10.6.
Records Retention......................................................................................56
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................57
11. REFERENCES.......................................................................................................58
 
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12. APPENDICES........................................................................................................60
12.1.
Appendix 1: Abbreviations and Trademarks................................................60
12.2.
Appendix 2: Liver Chemistry Stopping Criteria............................................62
12.3.
Appendix 3: Liver Safety Required Actions and Follow-Up 
Assessments ..............................................................................................63
12.4.
Appendix 4: Genetic Research ...................................................................65
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting of Adverse Events..............................................68
12.5.1.
Definition of Adverse Events........................................................68
12.5.2.
Definition of Serious Adverse Events...........................................69
12.5.3.
Recording of Adverse Events and Serious Adverse Events .........70
12.5.4.
Evaluating Adverse Events and Serious Adverse Events.............71
12.5.5.
Reporting of Serious Adverse Events to GSK..............................72
12.6.
Appendix 6: Division of Microbiology and Infectious Disease Adult 
Toxicity Tables for Adverse Event Assessment...........................................73
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential and Collection of 
Pregnancy Information................................................................................81
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential.........................81
12.7.2.
Collection of Pregnancy Information ............................................82
12.8.
Appendix 8: Follow-Up for Gastrointestinal Findings...................................84
12.9.
Appendix 9: Clostridium Difficile Testing Procedure and Algorithm .............85
12.10. Appendix 10: Country-Specific Requirements.............................................86
12.11. Appendix 11: Protocol Changes..................................................................87
 
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1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351
Rationale
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet
granulation [HSWG]) compared with the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK), safety, and tolerability
data in Part 1a, a decision will be made whether to proceed with the remainder of the 
study.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349 will be 
used to guide dosing recommendations with food.
Part 2 will evaluate the pharmacokinetics, safety, and tolerability of 2 different doses of 
the tablet formulation selected from Part 1a in Japanese subjects. Testing gepotidacin in 
this specific population will provide PK data and enable future pivotal Phase III studies in 
Japan.
Part 3 will evaluate the pharmacokinetics, safety, and tolerability of 3 different doses of 
the tablet formulation selected from Part 1a in Japanese subjects in the fed state. Testing 
gepotidacin in this specific population will provide PK data under fed conditions and 
enable future pivotal Phase III studies in Japan.
 
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Objectives/Endpoints
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared 
with the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from 
Part 1a
Part 2

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects
Part 3

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose, a single 2250-mg (3 × 750 mg) 
dose, and a single 3000-mg (4 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) in Japanese subjects
in the fed state
Parts 1a, 2, and 3

Plasma gepotidacin AUC(0-), 
AUC(0-t), Frel (for Part 1a only), Cmax, 
Tmax, tlag and t1/2, as data permit

Urine endpoints include Ae total, 
Ae(t1-t2), AUC(0-12), AUC(0-24), 
AUC(0-48), fe%, and CLr of 
gepotidacin, as data permit
Part 1b

Plasma gepotidacin AUC(0-), 
AUC(0-t), Cmax, Tmax, tlag, and t1/2, 
as data permit
Secondary
Part 1a

To assess the safety and tolerability of a single 1500-mg 
dose of gepotidacin tablet formulations (RC and HSWG; 
2 × 750 mg) compared with the reference capsule 
formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a when administered with a
moderate fat meal
Part 2

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose followed by a single 
3000-mg (4 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a in Japanese subjects
Part 3

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose, a single 2250-mg (3 × 750 mg) 
dose, and a single 3000-mg (4 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from 
Part 1a in Japanese subjects in the fed state
Parts 1, 2, and 3

Clinical safety data from AEs, clinical 
laboratory tests, vital signs (systolic and 
diastolic blood pressure and heart rate), 
and 12-lead ECG readings

Plasma gepotidacin AUC(0-) and 
Cmax, as data permit (for Parts 2 and 3
only)
 
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Objectives
Endpoints

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose, a single 2250-mg 
(3 × 750 mg) dose, and a single 3000-mg (4 × 750 mg) 
dose of gepotidacin tablets (RC or HSWG) selected 
from Part 1a in Japanese subjects in the fed state
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related compound.
Overall Design
This is a Phase I, multi-center, single-dose, 3-part study. Parts 1 and 2 are open-label, and 
Part 3 is a randomized, double-blind, placebo-controlled study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared with the reference capsule formulation under fasted conditions. 
Based upon PK, safety and tolerability data obtained from Part 1a, a decision will be 
made whether to use the free base RC or HSWG tablet formulation for the remainder of 
the study. Part 1b will evaluate the bioavailability of the selected tablet formulation under 
fasted and fed conditions. Part 2 will evaluate pharmacokinetics of 2 different doses of 
the selected tablet formulation in Japanese subjects under fasted conditions. Part 3 will
evaluate pharmacokinetics of 3 single escalating doses of the selected tablet formulation 
in Japanese subjects in the fed state.
Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a 
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC 
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA).
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations. Blood and urine samples will be 
collected up to approximately 48 hours after dosing.
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
formulation selected from Part 1a. If both formulations of the free base tablet exhibit 
similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349 will be 
used to guide dosing recommendations with food.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations. Blood samples will be collected up to 
approximately 48 hours after dosing.
 
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Part 2: Pharmacokinetics in Japanese Subjects
Part 2 is a 2-period, fixed-sequence study and will evaluate the pharmacokinetics of a 
single dose of 1500 mg followed by a single dose of 3000 mg gepotidacin tablet 
formulation selected from Part 1a in a cohort of Japanese subjects under fasted 
conditions.
Subjects will participate in 2 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations. Blood and urine samples will be 
collected up to approximately 48 hours after dosing.
Part 3: Pharmacokinetics in Japanese Subjects - Fed State
Part 3 is a 3-period, randomized, double-blind, placebo-controlled, fixed-sequence study 
and will evaluate the safety, tolerability, and pharmacokinetics of single ascending doses 
of 1500 mg, 2250 mg, and 3000 mg gepotidacin tablet formulation selected from Part 1a 
or placebo in a cohort of Japanese subjects in the fed state.
Subjects will be stratified by gender in a 1:1 ratio and randomly assigned
(10 active: 2 placebo) to receive gepotidacin or placebo. For each period, a sentinel group 
of up to 4 subjects will be dosed with study drug and evaluated for safety and tolerability 
prior to dosing the remaining subjects. The adverse event profiles will be reviewed before 
escalating to the next dose. Subjects will participate in 3 treatment periods and blood and 
urine samples will be collected for PK analysis of gepotidacin concentrations. Blood and 
urine samples will be collected up to approximately 48 hours after dosing.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets

Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
 
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Based on PK, safety, and tolerability data from Part 1a, subjects may be enrolled for the 
remainder of the study.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Part 2: Pharmacokinetics in Japanese Subjects

Treatment B or C: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets, 
respectively

Treatment F: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets
On Day 1 (Period 1), subjects will receive a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablet (RC or HSWG) selected from Part 1a. On Day 1 of Period 2, subjects 
will receive a single 3000-mg (4 × 750 mg) dose of gepotidacin tablet (RC or HSWG) 
selected from Part 1a. There will be a washout period of at least 3 days between doses. 
Subjects will remain in the clinical research unit from Day –1 until Day 3 of Period 2
after all scheduled PK and safety assessments have been completed, and will return to the 
clinic for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. 
The duration of the study (from Screening to the Follow-up visit) will be approximately 
41 days.
Part 3: Pharmacokinetics in Japanese Subjects - Fed State

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets - fed

Treatment G: Gepotidacin 2250 mg (3 × 750 mg) RC or HSWG tablets - fed

Treatment H: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets - fed

Treatment I: Placebo tablets - fed
Subjects will be stratified by gender in a 1:1 ratio and randomly assigned
(10 active: 2 placebo) to receive gepotidacin tablet (RC or HSWG) selected from Part 1a
in an ascending manner (Treatments E, G, and H) on Day 1 of Periods 1, 2, and 3, 
respectively, or placebo. For each period, a sentinel group of up to 4 subjects will be 
dosed with study drug and evaluated for safety and tolerability prior to dosing the 
remaining subjects. There will be a washout period of at least 3 days between doses. The 
adverse event profiles will be reviewed before escalating to the next dose. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
 
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scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK 
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Part 2, approximately 10 Japanese subjects will be enrolled.
For Part 3, approximately 12 Japanese subjects (ideally 6 male, 6 female) will be 
enrolled.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
Analysis
Plasma concentrations of gepotidacin will be analyzed (as data permit) by 
noncompartmental PK analysis to determine the following PK metrics: area under the 
plasma concentration-time curve (AUC) from time 0 extrapolated to infinite time 
[AUC(0-)], AUC from time 0 to time of last quantifiable concentration [AUC(0-t)], 
maximum observed concentration (Cmax), relative bioavailability of drug (Frel; Part 1a 
only), terminal phase half-life (t1/2), lag time before observation of drug concentrations 
in sampled matrix (tlag), and time to first occurrence of Cmax (Tmax). AUC(0-∞) and 
Cmax following single dose may be used for assessment of dose proportionality (Parts 2
and 3 only).
Urine (Parts 1a, 2, and 3 only) concentrations of gepotidacin will be analyzed (as data 
permit) by noncompartmental PK analysis to determine the following PK metrics: total 
unchanged drug (Ae total), amount of drug excreted in urine [Ae(t1-t2)], AUC from 
time 0 to 12 hours after dosing [AUC(0-12)], AUC from time 0 to 24 hours after dosing 
[AUC(0-24)], AUC from time 0 to 48 hours after dosing [AUC(0-48)], percentage of the 
given dose of drug excreted in urine (fe%), and renal clearance of drug (CLr). 
Plasma and urine (Parts 1a, 2, and 3 only) concentrations of gepotidacin and the 
associated PK parameters will be listed, and summary statistics (n, mean, median, 
standard deviation, minimum, maximum, and coefficient of variation) will be presented 
by day and treatment. Mean and individual plasma concentration versus time profiles will 
be presented graphically on linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed-effect terms for sequence, period, and regimen, and treating subject within 
sequence as a random effect. Point estimates and 90% confidence intervals (CIs) for the 
differences of interest (RC tablets and HSWG tablets versus capsules) will be constructed 
 
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15
using the residual variance. Point and interval estimates will then be exponentially
back-transformed to construct point and 90% CI estimates for the ratios of interest (RC 
tablets and HSWG tablets versus capsules).
Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
For Parts 2 and 3, dose proportionality of AUC(0-∞) and Cmax will be explored
separately and/or pooled together as a single model.
For the bioavailability assessment, Tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
Safety endpoints will include monitoring adverse events, clinical laboratory results, vital 
sign measurements, 12-lead electrocardiogram measurements, and physical examination 
findings.
 
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2.
INTRODUCTION
Gepotidacin is a novel type II triazaacenaphthylene bacterial topoisomerase inhibitor, 
which inhibits bacterial DNA replication and has in vitro activity against susceptible and 
drug resistant pathogens associated with a range of conventional and biothreat infections.
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 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 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
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet 
granulation [HSWG]) compared with the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK), safety, and tolerability
data in Part 1a, a decision will be made whether to proceed with the remainder of the 
study.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349 
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Part 2 will evaluate the pharmacokinetics, safety, and tolerability of 2 different doses of 
the tablet formulation selected from Part 1a in Japanese subjects. Testing gepotidacin in 
this specific population will provide PK data and enable future pivotal Phase III studies in 
Japan.
Part 3 will evaluate the pharmacokinetics, safety, and tolerability of 3 different doses of 
the tablet formulation selected from Part 1a in Japanese subjects in the fed state. Testing 
gepotidacin in this specific population will provide PK data under fed conditions and 
enable future pivotal Phase III studies in Japan.
2.2.
Brief Background
Gepotidacin has been administered to healthy subjects in 7 Phase I studies and 2 Phase II 
studies. Gepotidacin has demonstrated clinical efficacy in a Phase II study for acute 
bacterial skin and skin structure infections, and is currently being evaluated in a Phase II 
 
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study for gonorrhea. Additional details can be found in the Investigator’s Brochure (IB; 
GlaxoSmithKline Document Number CM2010/00033/04).
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared 
with the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from Part 1a
Part 2

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects
Part 3

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose, a single 2250-mg (3 × 750 mg) dose, 
and a single 3000-mg (4 × 750 mg) dose of gepotidacin 
tablets (RC or HSWG) in Japanese subjects in the fed 
state
Parts 1a, 2, and 3

Plasma gepotidacin 
AUC(0-), AUC(0-t), Frel (for 
Part 1a only), Cmax, Tmax, 
tlag and t1/2, as data permit

Urine endpoints include Ae 
total, Ae(t1-t2), AUC(0-12), 
AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as 
data permit
Part 1b

Plasma gepotidacin 
AUC(0-), AUC(0-t), Cmax, 
Tmax, tlag, and t1/2, as data 
permit
Secondary
Part 1a

To assess the safety and tolerability of a single 
1500-mg dose of gepotidacin tablet formulations (RC 
and HSWG; 2 × 750 mg) compared with the reference 
capsule formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a when administered 
with a moderate fat meal
Part 2

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose followed by a single 
3000-mg (4 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a in Japanese subjects

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose followed by a single 
3000-mg (4 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a in Japanese subjects
Parts 1, 2, and 3

Clinical safety data from AEs, 
clinical laboratory tests, vital 
signs (systolic and diastolic 
blood pressure and heart rate), 
and 12-lead ECG readings

Plasma gepotidacin AUC(0-) 
and Cmax, as data permit (for 
Parts 2 and 3 only)
 
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Objectives
Endpoints
Part 3

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose, a single 2250-mg 
(3 × 750 mg) dose, and a single 3000-mg (4 × 750 mg) 
dose of gepotidacin tablets (RC or HSWG) selected 
from Part 1a in Japanese subjects in the fed state

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose, a single 2250-mg  
(3 × 750 mg) dose, and a single 3000-mg (4 × 750 mg) 
dose of gepotidacin tablets (RC or HSWG) selected 
from Part 1a in Japanese subjects in the fed state
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related 
compound.
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I, multi-center, single-dose, 3-part study. Parts 1 and 2 are open-label, and 
Part 3 is a randomized, double-blind, placebo-controlled study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared with the reference capsule formulation under fasted conditions. 
Based upon PK, safety, and tolerability data obtained from Part 1a, a decision will be 
made whether to use the free base RC or HSWG tablet formulation for the remainder of 
the study. Part 1b will evaluate the bioavailability of the selected tablet formulation under 
fasted and fed conditions. Part 2 will evaluate pharmacokinetics of 2 different doses of 
the selected tablet formulation in Japanese subjects under fasted conditions. Part 3 will 
evaluate pharmacokinetics of 3 single escalating doses of the selected tablet formulation 
in Japanese subjects in the fed state.
Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a 
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA). See 
the study schematic in Table 1 for more details.
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Time and Events 
Table (Table 9). Blood and urine samples will be collected up to approximately 48 hours 
after dosing.
 
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Table 1
Part 1a Relative Bioavailability Study Design Schematic
Treatment
Cross-over
Follow-up
Capsule 
(reference)a
Period 1
Wash-out
At least 3 days
Period 2
Wash-out
At least 3 days
Period 3
5 to 7 days after 
final dose
RC and 
HSWG tabletb
Sequence 1
A
B
C
Sequence 2
C
A
B
Sequence 3
B
C
A
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 3 × 500-mg capsules (Treatment A; reference formulation)
b
1500 mg single dose given as 2 × 750-mg RC (Treatment B) or HSWG (Treatment C) tablets
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
formulation selected from Part 1a. If both formulations of the free base tablet exhibit 
similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349 
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food. See the study schematic in Table 2 for 
more details.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations according to the Time and Events Table 
(Table 9). Blood samples will be collected up to approximately 48 hours after dosing.
Table 2
Part 1b Food Effect Study Design Schematic
Treatment
Cross-over
Follow-up
RC or HSWG tablet fasteda
Period 1
Wash-out
At least 3 days
Period 2
5 to 7 days after 
final dose
RC or HSWG tablet feda
Sequence 4
D
E
Sequence 5
E
D
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750 mg tablets fasted (Treatment D) and fed (Treatment E)
Part 2: Pharmacokinetics in Japanese Subjects
Part 2 is a 2-period, fixed-sequence study and will evaluate the pharmacokinetics of a 
single dose of 1500 mg followed by a single dose of 3000 mg gepotidacin tablet 
formulation selected from Part 1a in a cohort of Japanese subjects under fasted 
conditions. See the study schematic in Table 3 for more details.
 
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Subjects will participate in 2 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Time and Events 
Table (Table 9). Blood and urine samples will be collected up to approximately 48 hours 
after dosing.
Table 3
Part 2 Pharmacokinetic Study Design Schematic
Treatment
Fixed-sequence
Follow-up
RC or HSWG 
tableta
Period 1
Wash-out
At least 3 days
Period 2
Wash-out
At least 3 days
5 to 7 days after 
final dose
Sequence 6
B or C
F
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750-mg RC (Treatment B) or HSWG (Treatment C) tablets; 3000 mg single 
dose given as 4 × 750-mg RC or HSWG tablets (Treatment F)
Part 3: Pharmacokinetics in Japanese Subjects - Fed State
Part 3 is a 3-period, randomized, double-blind, placebo-controlled, fixed-sequence study 
and will evaluate the safety, tolerability, and pharmacokinetics of single ascending doses 
of 1500 mg, 2250 mg, and 3000 mg gepotidacin tablet formulation selected from Part 1a
or placebo in a cohort of Japanese subjects in the fed state. See the study schematic in 
Table 4 for more details.
Table 4
Part 3 Pharmacokinetic Study Design Schematic - Fed State
Treatment
Fixed-sequence
Follow-up
RC, HSWG, or 
placebo tablet 
- feda
Period 1
Wash-out
At least 3 days
Period 2
Wash-out
At least 3 days
Period 3
5 to 7 days 
after final dose
Sequence 7
E or I
G or I
H or I
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750-mg RC or HSWG (Treatment E) tablets – fed; 2250 mg single dose given 
as 3 × 750-mg RC or HSWG (Treatment G) tablets – fed; 3000 mg single dose given as 4 × 750-mg RC or HSWG 
(Treatment H) tablets – fed; or placebo (Treatment I) tablets – fed
Subjects will be stratified by gender in a 1:1 ratio and randomly assigned 
(10 active: 2 placebo) to receive gepotidacin or placebo. For each period, a sentinel group 
of up to 4 subjects will be dosed with study drug and evaluated for safety and tolerability 
prior to dosing the remaining subjects. The adverse event profiles will be reviewed before 
escalating to the next dose. Subjects will participate in 3 treatment periods and blood and 
urine samples will be collected for PK analysis of gepotidacin concentrations according 
to the Time and Events Table (Table 9). Blood and urine samples will be collected up to 
approximately 48 hours after dosing.
 
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4.2.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets

Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
Based on PK, safety, and tolerability data from Part 1a, subjects may be enrolled for the 
remainder of the study.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Part 2: Pharmacokinetics in Japanese Subjects

Treatment B or C: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets, 
respectively

Treatment F: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets
On Day 1 (Period 1), subjects will receive a single 1500-mg (2 × 750 mg) dose of
gepotidacin tablet (RC or HSWG) selected from Part 1a. On Day 1 of Period 2, subjects 
will receive a single 3000-mg (4 × 750 mg) dose of gepotidacin tablet (RC or HSWG) 
selected from Part 1a. There will be a washout period of at least 3 days between doses. 
 
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Subjects will remain in the clinical research unit from Day –1 until Day 3 of Period 2
after all scheduled PK and safety assessments have been completed, and will return to the 
clinic for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. 
The duration of the study (from Screening to the Follow-up visit) will be approximately 
41 days.
Part 3: Pharmacokinetics in Japanese Subjects - Fed State

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets - fed

Treatment G: Gepotidacin 2250 mg (3 × 750 mg) RC or HSWG tablets - fed

Treatment H: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets - fed

Treatment I: Placebo tablets - fed
On Day 1 (Period 1), subjects will be stratified by gender in a 1:1 ratio and randomly 
assigned (10 active: 2 placebo) to receive gepotidacin tablet (RC or HSWG) selected 
from Part 1a in an ascending manner (Treatments E, G, and H) on Day 1 of Periods 1, 2, 
and 3, respectively, or placebo. For each period, a sentinel group of up to 4 subjects will 
be dosed with study drug and evaluated for safety and tolerability prior to dosing the 
remaining subjects. There will be a washout period of at least 3 days between doses. The 
adverse event profiles will be reviewed before escalating to the next dose. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
4.3.
Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK 
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Part 2, approximately 10 Japanese subjects will be enrolled.
For Part 3, approximately 12 Japanese subjects (ideally 6 male, 6 female) will be 
enrolled.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
4.4.
Design Justification
The study design for Part 1a is commonly used when evaluating relative bioavailability 
of a drug entity in subjects. It is based on recommendations given in the US Food and 
Drug Administration (FDA) draft guidance for industry, Bioavailability and 
Bioequivalence Studies Submitted in NDAs or INDs — General Considerations 
[DHHS, 2014].
 
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The study design for Part 1b is commonly used when evaluating the effect of food on a 
drug entity in subjects. It is based on recommendations given in the US FDA draft 
guidance for industry, Food-Effect Bioavailability and Fed Bioequivalence Studies 
[DHHS, 2002].
The study design for Part 2 is commonly used when evaluating pharmacokinetics of a 
drug entity in subjects from different ethnic groups. The fixed-sequence design allows for 
dosing of a lower dose followed by a higher dose within a subject and requires fewer 
subjects for PK evaluation compared with a parallel cohort. Pharmacokinetic data 
obtained from this group would satisfy regulatory guidelines and provide dosing 
recommendations for future Phase III studies in Japanese subjects.
The study design for Part 3 is commonly used when evaluating pharmacokinetics of a 
drug entity in subjects from different ethnic groups. The fixed-sequence design allows for 
dosing of a lower dose followed by escalating doses within a subject and requires fewer 
subjects for PK evaluation compared with a parallel cohort. The fed state will evaluate 
whether food improves tolerability at higher doses of gepotidacin. Pharmacokinetic data 
obtained from this group would satisfy regulatory guidelines and provide dosing 
recommendations under fed conditions for future Phase III studies in Japanese subjects.
Gepotidacin exhibits linear and time-independent pharmacokinetics, which indicates a 
single-dose study is adequate to achieve study objectives. A multiple-dose study is not 
necessary since there are no safety concerns with metabolites of this study drug.
4.5.
Dose Justification
The 1500-mg dose of gepotidacin is considered to be the likely dose used for future 
Phase III studies and will be evaluated in all parts of this study. The 3000-mg dose of 
gepotidacin will be evaluated in Parts 2 and 3 of this study to evaluate PK, safety, and 
tolerability for planned use in future Phase III studies. The 2250-mg dose of gepotidacin 
will be evaluated in Part 3 of this study as an intermediate dose that may have utility for 
future Phase III studies. Selection of dose and dosing frequency for this study is justified 
based on observed safety and PK data following oral single (100 to 3000 mg) and repeat 
twice daily (400 to 2300 mg) and 3 times daily (1500 to 2000 mg) capsule doses in 
healthy subjects in Studies BTZ114595 and BTZ116778, and single 1500-mg doses of 
the capsule and RC tablet formulations in Study BTZ117349. The 1500-mg dose (PK 
data for Study BTZ116778 [Table 5] and Study BTZ117349 [Table 6]) and 3000-mg 
dose (PK for Study BTZ114595 [Table 7]) achieve the projected therapeutic target 
plasma concentration and will be evaluated in all parts of the study. A moderate fat meal 
should only have a minimal effect on PK after administration of the tablet formulation 
since only a minimal food effect on PK was previously observed in Studies BTZ114595 
and BTZ117349 [Table 6].
 
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Table 5
Selected PK Parameters of Gepotidacin After Single and Repeat BID 
Dose of 1500 mg Orally (Study BTZ116778)
AUC(0-)a 
(µg.hr/mL)
Cmax (µg/mL)a
Tmax (hr)b
t1/2 (hr)a
Single Dose PK
[Day 1] (N=12)
20.1 (21.5%)
4.08 (40.3%)
2.0
[1.5 – 4.0]
12.0 (17.9%)
AUC(0-12)a
(µg.hr/mL)
Cmax1 (µg/mL)a
Tmax (hr)b
Roa
Repeat BID Dose PK
[Day 14] (N=12)
22.4 (29.6%)
5.41 (31.1%)
2.0
[1.5 – 4.0]
1.30 (34.9%)
BID = twice daily, CVb% = percent coefficient of variation, PK = pharmacokinetic, Ro = accumulation ratio.
a
Geometric mean (CVb%) [range]
b
Median [range]
Table 6
Selected Gepotidacin PK Parameters After Single Dose Oral Capsule 
and Tablet Administration Under Fasted and Fed Conditions 
(Study BTZ117349)
Gepotidacin 
1500-mg 
Capsule/Fasted
(N=15)
Gepotidacin 
1500 mg RC 
Tablet/Fasted
(N=14)
Gepotidacin 
1500 mg RC 
Tablet/Fed
(N=13)
AUC(0-)(µg.hr/mL)a
13.6 (28.8%)
15.8 (20.3%)
16.9 (16.2%)
Cmax (µg/mL)a
3.77 (58.1%)
4.37 (24.7%)
3.73 (29.1%)
Tmax (hr)b
1.5 (0.5 – 6.0)
1.75 (1.0 – 3.0)
3.0 (1.5 – 4.0)
t1/2 (hr)c
12.1 (27.3)
11.8 (19.2)
11.7 (18.6)
CVb% = percent coefficient of variation, PK = pharmacokinetic.
a
Geometric mean (CVb%)
b
Median [range]
c
Arithmetic mean (CVb%)
Table 7
Selected Gepotidacin PK Parameters After Single Oral Capsule 
Administration of 3000 mg (Study BTZ114595)
AUC(0-)
(µg.hr/mL)a
Cmax (µg/mL)a
Tmax (hr)b
t1/2 (hr)b
Single Dose PK
[Day 1] (N=6)
33.1 (31.5%)
9.03 (36.0%)
1.25
[1.00 – 2.00]
10.8
[8.66 – 13.90]
CVb% = percent coefficient of variation, PK = pharmacokinetic.
a
Geometric mean (CVb%)
b
Median [range]
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
gepotidacin can be found in the IB (GlaxoSmithKline Document 
Number CM2010/00033/04).
 
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Section 4.6.1 outlines the risk assessment and mitigation strategy for this study 
(GlaxoSmithKline Document Number 2013N174977).
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product Gepotidacin
Gastrointestinal (GI) Effects
Lower GI effects (soft stools, flatulence, and diarrhea) are the most 
common GI-associated adverse events (AEs) reported in human 
subjects dosed with gepotidacin. Additional events of heme + stool 
have been observed.
In the Phase I studies, out of approximately 400 healthy subjects 
who have received gepotidacin, Clostridium difficile has been 
reported in 8 subjects.
In an acute bacterial skin and skin structure infection study of 
122 patients from 13 sites in the USA, the most frequently reported 
AEs were in the GI system including diarrhea, nausea, and 
abdominal cramping (see GlaxoSmithKline Document 
Number 2015N243789_00 Study ID BTZ116704). Events were 
usually mild in severity with fewer of moderate severity. No patients 
experienced severe GI AEs and none withdrew due to GI AEs.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Subjects with significant GI symptoms will obtain the 
appropriate work-up (Appendix 8).
Subject stopping criteria: Subjects experiencing Grade 3 or 
Grade 4 AEs will have permanent discontinuation of the 
investigational product and will be followed as appropriate 
until resolution of the AE.
For Part 3, subjects experiencing Grade 3 or Grade 4 
diarrhea will be managed as described in Table 8
Cardiovascular Effects
Reversible increase in QT prolongation and a 
mild increase in heart rate in human subjects.
In Study BTZ115775 [see GlaxoSmithKline Document Number 
2015N227098_00 Study ID BTZ115775], the infusion of gepotidacin 
at a dose of 1000 mg and 1800 mg over 2 hours caused a mild heart 
rate effect of approximately 6 beats per minute to 10 beats per 
minute and a QT prolongation, measured as ∆∆QTcF, of 12 msec to 
22 msec. 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.
The 1500 mg oral dose yields a Cmax of 4.8 µg/mL with predicted 
ΔΔQTcF (90% CI) of 7.5 msec (6.8 to 8.3 msec) compared with that 
observed after the therapeutic 1,000 mg intravenous (IV) dose 
(Cmax of 7.3 µg/mL) administered in the thorough QTc study.
Exclusion criteria, oral dosing of capsule and tablet 
formulations will have lower Cmax compared with IV doses 
in the thorough QTc study, close monitoring of clinical 
parameters, and AEs will be conducted and stopping 
criteria will be utilized to mitigate and assess 
cardiovascular effects.
Note: Subjects with a QRS duration <70 and >120 msec 
will be excluded. 
Subject stopping criteria: Subjects 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
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 total drug concentration).
At higher doses, some subjects have experienced effects consistent 
with increased cholinergic tone, including central nervous system 
and GI effects (including dizziness, abdominal pain, salivary 
hypersecretion, hot flush, diarrhea, fatigue, and nausea). These 
effects appear to be related to Cmax and are significantly attenuated 
when Cmax is below 14 g/mL.
Coadministration of anticholinergics and administration in 
subjects 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. The Cmax will be below 14 g/mL in this study.
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was seen in 3 of 
8 subjects following 10 days of dosing 1500 mg 3 times daily (see 
GlaxoSmithKline Document Number 2014N198291_00
Study ID BTZ115198)
Rash was reported as an AE for 4 of 122 subjects (3%) and 
consisted of mild, related urticaria; moderate, related rash 
maculopapular; mild, related rash; mild, related urticaria; and mild, 
not related arthropod bite (see GlaxoSmithKline Document Number 
2015N243789_00 Study ID BTZ116704).
There has been no other evidence of hypersensitivity in human 
subjects 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 GlaxoSmithKline medical 
monitor, contraindicates their participation.
Subject monitoring:
Patients will be monitored closely for cutaneous effects 
throughout the study, and specialist advice will be sought 
as needed to evaluate any clinically significant finding.
Subject stopping criteria:
Grade 3 or higher rash or Grade 2 rash with evidence of 
systemic involvement.
 
 
 
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4.6.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy subjects, there is no direct clinical 
benefit to study subjects. Participation in this study will contribute to the process of 
developing new antibiotic therapies in areas of growing unmet need.
4.6.3.
Overall Benefit:Risk Conclusion
The risk of adverse events (AEs) is minimized for the populations being investigated in 
the proposed study by careful selection of dose and subjects for the study; the relatively 
short duration of study drug exposure; and the extent of safety monitoring incorporated 
into the study.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB (GlaxoSmithKline Document 
Number CM2010/00033/04).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Male or female subjects between 18 and 64 years of age inclusive, at the time of 
signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator based on medical history, clinical 
laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign 
measurements, 12-lead electrocardiogram (ECG) results, and physical examination 
findings. A subject with a 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 subjects (Parts 2 and 3):

The subject was a non-naturalized Japanese citizen and held a Japanese passport.

The subject had 2 Japanese parents and 4 Japanese grandparents who were all 
 
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non-naturalized Japanese citizens, as confirmed by interview.

The subject had been living outside of Japan for up to 10 years as confirmed by 
interview.
WEIGHT
4. Body weight:

Subjects in Part 1a and Part 1b: 50 kg and body mass index (BMI) within the 
range 19 and 32 kg/m2, inclusive.

Japanese subjects (Parts 2 and 3): 50 kg and BMI within the range 18 and 
32 kg/m2, inclusive.
SEX
5. Male or female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin test, not lactating, and at least one of the 
following conditions applies:
a.
Nonreproductive potential defined as:

Premenopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented bilateral oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea (in 
questionable cases a blood sample with simultaneous follicle-stimulating 
hormone [FSH] and estradiol levels consistent with menopause [refer to 
laboratory reference ranges for confirmatory levels]). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the 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 prior to study 
enrollment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (Appendix 7) from 30 days prior to the first dose of study 
medication and until completion of the Follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
 
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INFORMED CONSENT
6. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Subject has a clinically significant abnormality in past medical history or at the 
Screening physical examination that in the investigator’s opinion may place the 
subject at risk or interfere with outcome variables of the study. This includes, but is 
not limited to, history or current cardiac, hepatic, renal, neurologic, 
gastrointestinal (GI), respiratory, hematologic, or immunologic disease.
2. Subject has any surgical or medical condition (active or chronic) that may interfere 
with drug absorption, distribution, metabolism, or excretion of the study drug, or any 
other condition that may place the subject at risk, in the opinion of the investigator.
3. Corrected QT (QTc) >450 msec.
4. Use of a systemic antibiotic within 30 days of Screening.
5. Within 2 months before Screening, either a confirmed history of Clostridium difficile
diarrhea infection or a past positive Clostridium 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 sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
uses heparin to maintain intravenous cannula patency).
CONCOMITANT MEDICATIONS
8. Subjects cannot use any over-the-counter, or prescription medication (except for 
hormonal contraceptives and/or acetaminophen; see Section 6.11 for more details), 
vitamin supplement, or herbal medication within 7 days (or 5 half-lives, whichever is 
longer) before dosing and during the study.
RELEVANT HABITS
9. 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.
 
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10. Urinary cotinine level indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months before screening.
CONTRAINDICATIONS 
11. History of sensitivity to any of the study medications, or components thereof, or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
13. Female subject has a positive pregnancy test result or is lactating at Screening or upon 
admission to the clinic.
14. Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN)
15. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. Urinalysis positive for blood without other cause identified.
17. A positive pre-study drug/alcohol screen.
18. A positive test for human immunodeficiency virus (HIV) antibody.
19. Subject has clinically significant abnormal findings in serum chemistry, hematology, 
or urinalysis results obtained at Screening or Day –1.
20. Donation of 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.
21. Previous exposure to gepotidacin within 12 months prior to the first dosing day.
22. Exclusion criteria for screening and baseline 12-lead ECG (a single repeat is allowed 
for eligibility determination):
Males
Females
Heart rate
<40 and >100 beats per minute
<50 and >100 beats per minute
PR interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcB or QTcF interval
>450 msec
QTcB = corrected QT interval using Bazett’s formula, QTcF = corrected QT interval using 
Fridericia’s formula.

Evidence of previous myocardial infarction (does not include ST segment changes 
associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, atrioventricular block [second degree or higher], 
Wolf-Parkinson-White syndrome), sinus pauses >3 seconds, non-sustained or 
sustained ventricular tachycardia (≥3 consecutive ventricular ectopic beats) or any 
significant arrhythmia which, in the opinion of the principal investigator and GSK 
medical monitor, will interfere with the safety of the individual subject.
 
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23. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
24. Subject is unable to comply with all study procedures, in the opinion of the
investigator.
25. The subject should not participate in the study, in the opinion of the investigator or
sponsor.
5.3.
Screening/Baseline/Run-In Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials publishing requirements, 
and respond to queries from regulatory authorities, a minimal set of screen failure 
information is required including demographics, screen failure details, eligibility criteria, 
and serious AEs (SAEs).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The clinic must attempt to contact the subject and reschedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow-up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 
3 telephone calls and if necessary a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “lost to follow-up”.
A subject may withdraw from study treatment 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 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
 
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5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
guidance, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” 
[DHHS, 2009].
Study treatment will be stopped if the following liver chemistry stopping criterion is met:

ALT 3 × ULN
For details of the required assessments if a subject meets the above criteria, refer to 
Appendix 2, Liver Chemistry Stopping Criteria.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on the QTcF, then 
the QTcF must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, 
the same formula must continue to be used for that subject 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 triplicate 
ECGs obtained over a brief (e.g., 5 to 10 minute) recording period.
A subject who meets either bulleted criterion below will be withdrawn from the study:

QTc >500 msec

Increase from baseline of QTc >60 msec
For subjects with underlying bundle branch block, the following discontinuation criteria 
will be used instead:
Baseline QTc With Bundle Branch Block
Discontinuation QTc With Bundle Branch Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec
5.4.3.
Gastrointestinal Stopping Criteria
Subjects experiencing Grade 3 or Grade 4 AEs (confluent pseudomembranes or 
ulcerations OR mucosal bleeding with minor trauma; tissue necrosis OR diffuse 
spontaneous mucosal bleeding OR life-threatening consequences, e.g., aspiration, 
choking) will be followed as appropriate until resolution of the AE(s).
 
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Furthermore, subjects who experience diarrhea or enteritis should be evaluated with 
additional fecal occult blood tests and stool cultures as deemed appropriate by the 
investigator as outlined in Appendix 8 and Appendix 9.
For Part 3, subjects who experience diarrhea should also be evaluated using the 
guidelines detailed in Table 8
Table 8
Part 3 Management of Gastrointestinal Symptoms - Diarrhea
Diarrhea
Treatment Strategy
Grade 1
Initiate supportive care including loperamide.
Grade 2
Initiate supportive care including loperamide. Consider discontinuation of subject from the 
study upon discussion with medical monitor.
Grades 3 or 4
Above plus consider IV hydration, hospital admission and prophylactic antibiotics as 
appropriate. Withhold study drug(s) until diarrhea has resolved to ≤Grade 1, continue 
diarrheal prophylaxis. Discontinue subject from the study upon discussion with medical 
monitor.
5.4.4.
Rash/Hypersensitivity Stopping Criteria
A subject 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).
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
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Study Treatment
Product name:
Gepotidacin 
(GSK2140944) 
capsule
Gepotidacin 
(GSK2140944B) 
RC tablet
Gepotidacin 
(GSK2140944B) 
HSWG tablet
Placebo tablet
Formulation 
description:
Immediate release 
capsules containing 
gepotidacin 
(mesylate salt) and 
inactive formulation 
excipients
Immediate 
release tablets 
containing 
gepotidacin (free 
base) and 
inactive 
formulation 
excipients
Immediate 
release tablets 
containing 
gepotidacin (free 
base) and 
inactive 
formulation 
excipients
Immediate 
release tablets 
containing only 
inactive 
formulation 
excipients
Dosage form:
Capsule
Tablet
Tablet
Tablet
Unit dose
strength/
Dosage level:
500 mg/
1500 mg 
(3 × 500 mg)
750 mg/
1500 mg 
(2 × 750 mg)
2250 mg 
(3 × 750 mg)
3000 mg 
(4× 750 mg)
750 mg/
1500 mg 
(2 × 750 mg)
Not applicable
Route of 
Administration:
Oral
Oral
Oral
Oral
Dosing 
instructions:
Dose with 240 mL 
of water. Up to an 
additional 100 mL 
of water may be 
given to assist in 
swallowing 
capsules.
Dose with 
240 mL of water. 
Up to an 
additional 
100 mL of water 
may be given to 
assist in 
swallowing 
tablets.
Dose with 
240 mL of water. 
Up to an 
additional 
100 mL of water 
may be given to 
assist in 
swallowing 
tablets.
Dose with 
240 mL of water. 
Up to an 
additional 
100 mL of water 
may be given to 
assist in 
swallowing 
tablets.
Physical 
description:
Pink Gelatin size 00 
capsule with no 
identifying markings 
containing slightly 
agglomerated pale 
yellow to grayish 
yellow to yellowish 
gray powder.
A capsule-shape 
white film-coated 
tablet with no 
identifying 
markings.
An oval shape 
white film-coated 
tablet with no 
identifying 
markings.
A capsule-shape 
white film-coated 
tablet with no 
identifying 
markings.
Manufacturer/
Source of 
procurement:
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
 
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6.2.
Treatment Assignment
Subjects in Part 1a will be assigned to a treatment sequence to receive gepotidacin 
(GSK2140944) capsules, RC tablets, and HSWG tablets in accordance with the 
randomization schedule generated by PPD before the start of the study, using validated 
internal software. Based upon PK, safety, and tolerability data obtained from Part 1a, a 
decision will be made whether to use the free base RC or HSWG tablet formulation for 
the remainder of the study. Subjects in Part 1b will be assigned to a treatment sequence to 
receive the selected tablet formulation under fasted and fed conditions. Japanese subjects 
in Part 2 will receive 2 different doses of the selected tablet formulation. Japanese 
subjects in Part 3 will be stratified by gender in a 1:1 ratio and randomized 
(10 active: 2 placebo) to receive the selected tablet formulation in a fixed sequence or 
placebo under fed conditions.
A description of each regimen for all study parts is provided in the table below:
Part 
Treatment 
Code
Treatment
1a
A
Gepotidacin 1500 mg (3 × 500 mg) capsules
1a
B
Gepotidacin 1500 mg (2 × 750 mg) RC tablets
1a
C
Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
1b
D
Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fasted
1b
E
Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fed
2
B or C
Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets, respectively
2
F
Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets
3
E
Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets – fed
3
G
Gepotidacin 2250 mg (3 × 750 mg) RC or HSWG tablets – fed
3
H
Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets – fed
3
I
Placebo tablets - fed
Subjects will be given a subject number that will be a unique identifier. Once a subject 
number has been assigned, the number will not be reused even if the subject withdraws 
from the study before receiving gepotidacin.
6.3.
Planned Dose Adjustments
Planned dose adjustments are not allowed during this study.
6.4.
Blinding
Parts 1 and 2 will be an open-label study.
Part 3 will be a double-blind (sponsor unblinded) study. The subjects will be completely 
blinded and the site staff will be blinded to subject-specific treatment assignment. The 
GSK study team will be unblinded at the aggregate level for decision making throughout 
the study (e.g. to support dose escalations and use of Bayesian predictive techniques). 
 
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Where possible, the GSK/clinical research organization personnel will not have access to 
subject-specific treatment assignment so as to not potentially introduce bias in 
discussions with the study site. The pharmacokineticists, statisticians, programmers, and 
data managers, however, will need access to subject randomization during the course of 
the study for analysis purposes to support dose adjustments and escalations. Other GSK 
staff may be included in discussions around dose adjustments and progression if it is 
deemed necessary and relevant by the above mentioned GSK study team members.
During dosing of a specific cohort, the investigator or treating physician may unblind a 
subject’s treatment assignment only in the case of an emergency, when knowledge of the 
study treatment is essential for the appropriate clinical management or welfare of the 
subject. Whenever possible, the investigator must first discuss options with the GSK 
medical monitor or appropriate GSK study personnel before unblinding the subject’s 
treatment assignment. If this is impractical, the investigator must notify GSK as soon as 
possible, but without revealing the treatment assignment of the unblinded subject, unless 
that information is important for the safety of subjects currently in the study. The date 
and reason for the unblinding must be recorded in the electronic data capture system. In 
this situation, the subject will be withdrawn from further treatment if the subject’s 
treatment code is unblinded by the investigator or treating physician. The primary reason 
for discontinuation (the event or condition which led to the unblinding) will be recorded 
in the electronic data capture system. GSK’s Global Clinical Safety and 
Pharmacovigilance staff may unblind the treatment assignment for any subject with an 
SAE. If the SAE requires that an expedited regulatory report be sent to 1 or more 
regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, 
may be sent to the investigator in accordance with local regulations and/or GSK policy.
During the dose escalation safety review, the GSK clinical team and the investigator will 
review safety data in a blinded aggregate form. In the event of concern over a potential 
safety signal, the GSK clinical team and the investigator may review unblinded treatment 
assignments for the purposes of safety review and dose selection without study 
interruption. If a safety signal is determined to indicate findings in subjects who received 
gepotidacin, the findings will be escalated for assessment by the GSK safety team and 
actions taken as appropriate including review of study for possible halting of further 
dosing.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are to be reported and resolved before use of the study treatment.
 
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
Only subjects enrolled in the study may receive study treatment and only 
authorized clinic staff may supply or administer study treatment. All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized clinic staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to clinic staff.

A Material Safety Data Sheet or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request 
from GSK.
6.7.
Compliance With Study Treatment Administration
When subjects are dosed at the clinic, they will receive study treatment 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 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the clinic staff other than the person administering the study treatment. Study 
site personnel will examine each subject’s mouth to ensure that the study treatment was 
ingested.
6.8.
Treatment of Study Treatment Overdose
Gepotidacin (all parts) or placebo (Part 3 only) will be administered at the clinic, thus 
limiting the risk of overdose. In the unlikely event that an overdose with gepotidacin 
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 subject’s clinical 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 subject for AEs/SAEs and laboratory abnormalities until 
gepotidacin can no longer be detected systemically (at least 3 days for gepotidacin).
 
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3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment 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 eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on a clinical evaluation of the subject.
6.9.
Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Standard meals will be provided during the study dosing period at specified times.
Subjects will refrain from consumption of red wine, Seville oranges, grapefruit, or 
grapefruit juice (and/or pummelos, exotic citrus fruits, or grapefruit hybrids) from 7 days 
prior to the first dose of study medication until after the final dose.
For Parts 1a and 2, subjects will fast from food and drink (except water) for at least 
10 hours before dosing on Day 1 of each period. For the fed group of the food effect 
evaluation in Part 1b, study drug will be administered within 30 minutes after the 
completion of a moderate fat meal. For Part 3, study drug (gepotidacin or placebo) will 
be administered within 30 minutes after the completion of a standard Japanese meal.
Fasting requirements may be modified, relaxed, or removed based on emerging safety, 
tolerability, and PK data from Part 1a. If fasting requirements are removed, then Part 1b 
may be conducted as a single-period study with drug administered only under fed 
conditions. In the event that the formulation tested for Part 1b is not tolerated in the 
fasting state, subjects may receive the formulation with a meal after consultation with the 
sponsor and investigator.
6.10.2.
Caffeine, Alcohol, and Tobacco
Subjects will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to the start of dosing until 
collection of the final PK sample. 
During each dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final PK sample.
Use of tobacco products is not allowed from 3 months before Screening until after the 
final Follow-up visit.
 
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6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. Subjects may participate in light recreational activities during 
the study (e.g., watch television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Hormonal contraceptives and/or acetaminophen, at doses of ≤2 grams/day are permitted 
for use. Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor.
All concomitant medication use will be documented on the concomitant medication page 
in the eCRF.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Subjects 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) prior to the first dose of 
study medication until completion of the Follow-up visit, unless in the opinion of the 
investigator and sponsor the medication will not interfere with the study.
Since gepotidacin is known to have some prolongation of QTc, any drugs known to 
increase QTc interval should be avoided when treating an AE.
Due to the potential for acetylcholinesterase inhibition with gepotidacin, the following 
medications are prohibited:

Succinylcholine or other depolarizing muscle relaxants

Acetylcholinesterase inhibitors as required for myasthenia gravis including 
edrophonium, pyridostigmine, neostigmine, etc
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 9), are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table (Table 9).
The following points must be noted: 
 
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
If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
5. 12-lead ECG
6. vital signs
7. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety and PK 
assessments, may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which will be approved by the relevant 
GSK study team member and then archived in the study sponsor and clinic study 
files, but this will not constitute a protocol amendment. 

The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the informed consent form.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
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7.1.
Time and Events Table
Table 9
Time and Events Table: All Parts
Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Part 2 – Pharmacokinetics: Periods 1 and 2
Part 3 - Pharmacokinetics - Fed State: Periods 1, 2, and 3
Follow-up
(5 to 
7 days 
post last 
dose)
Day
–1a
Day 1
Day 2
Day 3
Predose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Admission to unit
X
Informed consent
X
Demographics including BMI
X
Full physical examination including 
height and weightb
X
Brief physical examinationb
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECGc
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
Drug/alcohol/cotinine screen
X
X
Serum pregnancy, FSH, and estradiol 
(women)
X
X
X
HIV antibody, HBsAg, and hepatitis C 
antibody screen
X
Safety laboratory testse
X
X
X
X
Study drug administrationf
X
Pharmacokinetic sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for pharmacokinetics 
(Parts 1a, 2, and 3 only)g
X
X
X
X
X
X
X
X
X
 
 
 
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Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Part 2 – Pharmacokinetics: Periods 1 and 2
Part 3 - Pharmacokinetics - Fed State: Periods 1, 2, and 3
Follow-up
(5 to 
7 days 
post last 
dose)
Day
–1a
Day 1
Day 2
Day 3
Predose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Pharmacogenetic sampleh
========================================================================
AE/SAE Review
X
==================================================================================
X
Concomitant medication review
X
========================================================================
X
Dischargei
X
Outpatient visit
X
X
AE = adverse event, BMI = body mass index, ECG = electrocardiogram, FSH = follicle-stimulating hormone, h = hour, HBsAg = hepatitis B surface antigen, HIV = human 
immunodeficiency virus, SAE = serious adverse event.
a
The Day –1 visit occurs in Period 1 only. Periods 2 (all parts) and 3 (Parts 1a and 3 only) begin on Day 1.
b
A complete physical examination will include at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal, 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).
c
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured in 
semi-supine position after 5 minutes rest at all other time points during the study
d
Single vital signs will be measured in semi-supine position after 5 minutes rest and will include systolic and diastolic blood pressure, and heart rate. Body temperature and 
respiratory rate will be collected at Screening only.
e
Safety laboratory tests include serum chemistry, hematology, and urinalysis.
f
Subjects will fast from food and drink (except water) for at least 10 hours before study drug administration on Day 1 of each period. For the fed group of the food effect evaluation 
in Part 1b, study drug will be administered within 30 minutes after the completion of a moderate fat meal. For Part 3, study drug will be administered within 30 minutes after 
completion of a standard Japanese meal.
g
Urine collection intervals (Parts 1a, 2, and 3 only) for subjects include 0 (predose), 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.
h
For subjects who consent only: collect 1 pharmacogenetic sample after the start of dosing (preferably Day 1). Informed consent for optional pharmacogenetics research must be 
obtained before collecting a sample.
i
For Parts 1a and 3, subjects will be discharged from the clinical research unit on Day 3 of Period 3. For Parts 1b and 2, subjects will be discharged on Day 3 of Period 2.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Table 9). Additional time points for safety tests such as vital signs, physical exams, and 
laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.
7.3.1.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

AEs will be collected from the time informed consent is obtained until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Table 9).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
 
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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5.
7.3.1.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
Follow-Up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.3.1.4.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for noninterventional post marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met.
GlaxoSmithKline has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a product under clinical investigation. 
GlaxoSmithKline will comply with country specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC, and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of dosing and until the Follow-up visit.
 
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If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
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.
7.3.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
systolic and diastolic blood pressure, and heart rate. Body temperature and respiratory 
rate will be collected at Screening only.
7.3.5.
Electrocardiogram
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured 
in semi-supine position after 5 minutes rest at all other time points during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 5.4.2 for QTc stopping criteria and additional QTc 
readings that may be necessary.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 10, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Table 
(Table 9). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/center number, and visit date. 
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
 
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Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 10.
Table 10
Protocol-Required Safety Laboratory Assessments
Hematology
Platelet count 
RBC indices:
WBC count with differential:
RBC count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Eosinophils
Basophils
Serum Chemistrya
Blood urea nitrogen
Potassium 
Aspartate aminotransferase
Total and direct bilirubin
Creatinine
Sodium
Alanine aminotransferase
Total protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Creatine kinase
Bicarbonate
Chloride
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
Hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing potential only)
Serum test for human chorionic gonadotropin (as needed in women of childbearing potential)
Alcohol (via urine, blood alcohol, or breathalyzer test), cotinine, and drug screen (via serum, urine, or saliva) to include, 
at a minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines).
Fecal occult blood test and stool cultures as appropriate for gastrointestinal adverse events (Appendix 8)
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; RBC = red blood cell; WBC = white blood cell.
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 5.4.1 and Appendix 3.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation should be repeated until the values return to normal or baseline. If 
such values do not return to normal within a period judged reasonable by the investigator, 
the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for PK analysis of gepotidacin will be collected at the time points 
indicated in the Time and Events Table (Table 9). The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.
For each sample, 3 mL of blood will be drawn via an indwelling catheter and/or direct 
venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. Details of 
PK blood sample processing, storage, and shipping procedures are provided in the SRM.
 
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7.4.2.
Urine Sample Collection
Pharmacokinetic urine samples for the analysis of gepotidacin (Parts 1a, 2, and 3 only) 
will be collected at the time points listed in the Time and Events Table (Table 9). The 
actual date and time of each urine sample collection will be recorded. The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.
Details of PK urine sample processing, storage, and shipping procedures are provided in 
the SRM.
7.4.3.
Sample Analysis
Plasma and urine analysis will be performed under the control of PTS-DMPK/Scinovo, 
GSK, the details of which will be included in the SRM. Concentrations of gepotidacin 
will be determined in plasma and urine samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM). 
Since plasma protein binding of gepotidacin is low (33%), only total drug concentrations 
will be reported for the PK analysis.
Once the plasma and urine samples have been analyzed for gepotidacin, any remaining 
plasma and urine samples may be analyzed for other compound-related metabolites and 
the results reported under a separate PTS-DMPK/Scinovo, GSK protocol.
7.5.
Genetics
Depending on the clinical study results, exploratory pharmacogenomics analyses may be 
performed to examine the potential relationship between genetic variants and clinical 
endpoints.
The pharmacogenomics samples will be collected according to the Time and Events 
Table (Table 9). Information regarding genetic research is included in Appendix 4.
8.
DATA MANAGEMENT

For this study, subject data will be entered via an eCRF into Oracle Clinical Remote 
Data Capture System. Subject data will be available for viewing through access to the 
Oracle Clinical Remote Data Capture System. Data provided from other sources will 
be received, reconciled, combined, and transferred to GSK at predetermined time 
points.

Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity and quality of the data 
(e.g., removing errors and inconsistencies in the data). Adverse events and 
concomitant medications terms will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and a validated medication dictionary, GSKDrug.
 
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
The eCRFs (including queries and audit trails) will be sent at the end of the study in 
electronic format to GSK to be retained. Each investigator will receive a copy of their 
site specific data in the same format to maintain as the investigator copy. In all cases, 
subject initials will not be collected or transmitted.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
All statistical analyses will be performed by PPD using SAS (SAS Institute Inc., Cary, 
North Carolina, USA), version 9.2 or higher. Pharmacokinetic parameters will be 
calculated using Phoenix WinNonlin (Certara USA Inc., Princeton, New Jersey, USA), 
version 6.2.1 or higher.
Before database lock, a reporting and analysis plan (RAP) will be issued as a separate 
document, providing detailed methods for the analyses outlined below.
Any deviations from the planned analyses will be described in a RAP addendum and 
justified in the final integrated clinical study report.
9.1.
Hypotheses
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the relative bioavailability of the gepotidacin RC and HSWG tablet 
formulations relative to the reference gepotidacin capsule formulation in healthy subjects 
(Part 1a), estimate the effect of food on the tablet formulation selected from Part 1a 
(Part 1b), and to evaluate the pharmacokinetics of the tablet formulation selected from
Part 1a in Japanese subjects (Parts 2 and 3).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size is largely based on feasibility; however, some justification is provided 
below.
Part 1a – Relative Bioavailability:
The sample size of 24 PK parameter population subjects will be used based on feasibility 
to address the objectives of Part 1a of the study.
There are no estimates for the coefficient of variation (CV) of HSWG for any PK 
parameters. An assumed CV of 27.5% for a PK parameter implies that the sample size of 
24 PK parameter evaluable subjects will provide at least 80% power to demonstrate 
equivalence of the PK parameter. Equivalence is demonstrated when 90% confidence 
interval (CI) for the ratio of Test:Reference of the PK parameter will be within 0.8 to 
1.25 following log transformation.
Two different test formulations are being used in this study. No adjustment for 
pre-planned multiple comparisons are made.
 
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The total sample size of 27 subjects (9 subjects in 3 sequences) will be randomized to 
ensure 24 PK parameter evaluable subjects with PK parameter estimates from the 
reference and at least one test formulation.
Part 1b – Food Effect:
A sample size of 16 subjects will be randomized (8 per sequence) based on feasibility to 
address the objectives of Part 1b of the study.
This sample size will ensure equivalence (as specified in sample size assumption in 
Part 1a) with 80% power with an assumed CV of 22%.
Part 2 – Pharmacokinetics:
A sample size of approximately 10 subjects will be used in Part 2 based on feasibility to 
address the objectives of Part 2 of the study.
Part 3 – Pharmacokinetics - Fed State:
A sample size of 12 subjects (ideally 6 male, 6 female) will be randomized 
(10 active: 2 placebo) based on feasibility to address the objectives of Part 3 of the study.
9.2.2.
Sample Size Re-Estimation or Adjustment
Not applicable.
9.3.
Data Analysis Considerations
In general, descriptive summaries will include number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum for continuous variables; and percent 
for categorical variables. Summaries will present data by group, and where appropriate, 
by assessment time.
9.3.1.
Analysis Populations
The Safety Population will consist of all subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.
The PK Population will consist of all subjects who received at least 1 dose of 
gepotidacin and have evaluable PK data for gepotidacin. 
The PK Parameter Population will consist of all subjects in the PK Population, for 
whom valid and evaluable PK parameters were derived. This population will be used in 
the assessment and characterization of PK parameters.
9.3.2.
Interim Analysis
No formal interim analyses are planned for this study. However, all preliminary safety, 
tolerability, and available PK data will be reviewed by the study team after completing 
Part 1a of the study to select the formulation for Part 1b, Part 2, and Part 3, and also to 
 
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determine if the effect of food on the selected formulation needs to be studied (Part 1b). 
At the time of finalization of Protocol Amendment 1, Part 1b is no longer needed based 
on data from Part 1a. The team will review unblinded data from Part 1a of this open-label 
study to select the appropriate formulation.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Pharmacokinetic Analyses
Plasma and urine concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods. Based on the individual concentration time data the 
following parameters will be estimated:
Plasma:
AUC(0-)
Area under the concentration-time curve (AUC) from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
the last quantifiable concentration
Cmax
Maximum observed concentration
Frel
Relative bioavailability of drug, calculated as:
[AUC(0-)tablet]/[AUC(0-)capsule] (Part 1a only)
t1/2
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled matrix
Tmax
Time to first occurrence of Cmax
Urine (Parts 1a, 2, and 3 only):
Ae total
Total unchanged drug (total amount of drug excreted in urine), calculated 
by adding all the fractions of drug collected over all the allotted time 
intervals
Ae(t1-t2)
Amount of drug excreted in urine in time intervals of predose, 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 for subjects
AUC(0-12)
Area under the concentration-time curve from time 0 (predose) to 12 hours 
after dosing
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 24 hours 
after dosing
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 48 hours 
after dosing
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)
 
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Plasma (all subjects) and urine (Parts 1a, 2, and 3 only) concentrations of gepotidacin and 
the associated PK parameters will be listed, and summary statistics (n, mean, median, SD, 
minimum, maximum, and CV) will be presented by day and treatment. Mean and 
individual plasma concentration versus time profiles will be presented graphically on 
linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed-effect terms for sequence, period, and regimen, and treating subject within 
sequence as a random effect. Point estimates and 90% CIs for the differences of interest 
(RC tablets and HSWG tablets versus capsules) will be constructed using the residual 
variance. Point and interval estimates will then be exponentially back-transformed to 
construct point and 90% CI estimates for the ratios of interest (RC tablets and HSWG 
tablets versus capsules).
Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
For the bioavailability assessment, Tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
For Parts 2 and 3, dose proportionality of AUC(0-∞) and Cmax will be explored 
separately and/or pooled together as a single model based on dose normalized parameters 
(log transformed parameters) using reference dose. The lower dose group (1500 mg) 
would be chosen as the reference dose.
The dose proportionality of AUC(0-∞) and Cmax will be summarized by descriptive 
statistics (including 90% confidence interval).
Detailed descriptions of the analyses in this study will be presented in the RAP.
 
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9.4.2.
Secondary Analyses
Safety Analyses
The following safety evaluations will be performed:

Monitoring for AEs

Changes in routine clinical laboratory parameters including serum chemistry, 
hematology, and urinalysis

Clinically significant changes in vital sign measurements or physical examination 
findings 

Changes in 12-lead ECG measurements
Safety endpoints will include AEs, clinical laboratory results (serum chemistry [including 
liver function parameters], hematology, and urinalysis), vital sign measurements (systolic 
and diastolic blood pressure and heart rate), 12-lead ECG measurements, and physical 
examination findings.
All safety data will be presented in the data listings. Subject demographics, medical 
history, and prior and concomitant medications will be summarized by group using 
descriptive statistics. For continuous variables, these summaries will include sample size, 
mean, median, SD, minimum, and maximum.
For categorical variables, the summaries will include frequencies and corresponding 
percentages. No inferential hypothesis testing will be performed on the safety variables.
Adverse events will be coded using the MedDRA classification system. 
Treatment-emergent AEs will be defined as any AEs, regardless of relationship to 
investigational product, that occur after the dose of investigational product. All AEs will 
be summarized by group at AE onset for the overall number of AEs and the percentage of 
subjects who experience them. The total number of AEs will be summarized by group 
and overall. Listings for the subsets of SAEs and treatment-related SAEs will be 
provided. The number of SAEs will be summarized. The incidence of AEs will also be 
summarized by system organ class and preferred term.
Clinical laboratory results, vital sign measurements (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG results will be summarized by change from baseline. 
Clinical laboratory values that are outside of the reference ranges will be flagged and 
evaluated for clinical significance by the investigator. Any ECG abnormalities, including 
but not limited to a QTc >500 msec or increase in QTc from the baseline ECG of 
≥60 msec, will be summarized by group.
Detailed descriptions of the analyses in this study will be presented in the RAP.
 
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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.

Obtaining signed informed consent.

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to the IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IRB/IEC, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
 
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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP and GSK/PPD 
procedures, GSK/PPD monitors will contact the clinic prior to the start of the 
study to review the following with the clinic staff: the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK/PPD requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
GSK/PPD will monitor the study and clinic activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees 
to allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the clinic records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit, or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct 
access to all relevant documents and to allocate their time and the time of their 
staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any 
findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK/PPD 
monitor will conduct clinic closure activities with the investigator or clinic staff, 
as appropriate, in accordance with applicable regulations including GCP, and 
GSK/PPD standard operating procedures.

GSK/PPD reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical 
issues or severe noncompliance. For multi-center studies, this can occur at 1 or 
more or at all clinics.

If GSK/PPD determines such action is needed, GSK/PPD will discuss the reasons 
for taking such action with the investigator or the head of the medical institution 
(where applicable). When feasible, GSK/PPD will provide advance notification to 
 
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the investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, 
GSK/PPD will promptly inform all investigators, heads of the medical institutions 
(where applicable) and/or institution(s) conducting the study. GSK/PPD will also 
promptly inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all clinic study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.

The records must be maintained to allow easy and timely retrieval when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with an assessment of the facility, supporting systems, and relevant 
clinic staff.

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including regenerating a hard copy, if required. Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK/PPD will inform the investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to that clinic for the 
study, as dictated by any institutional requirements or local laws or regulations, 
GSK/PPD standards/procedures, and/or institutional requirements.

The investigator must notify GSK/PPD of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the clinic.
 
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
 
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11.
REFERENCES
Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA 
topoisomerase inhibition by a new class of antibacterial agents. Nature. 
2010;466(7309):935-40.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in age-related macular 
degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a 
meta-analysis. PloS ONE. 2012; 7: e42464.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in 
NDAs or INDs — General Considerations. March 2014. [29 screens]. Available from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm389370.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. July 2009. [28 screens]. Available from: 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Drug Evaluation and Research 
(US). Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence 
Studies. December 2002. [12 screens.] Available from: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126833.pdf
GlaxoSmithKline Document Number 2013N176846_01 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. 
2014.
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 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.
 
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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 CM2010/00033/04. GSK2140944 Investigator’s 
Brochure. 2016.
GlaxoSmithKline Document Number 2013N174977. Benefit Risk Management Plan 
Version 3. 2015.
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th ed. Atlanta, Georgia: Ardent Media, Inc., 2011: 
50. Table 3-2.
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
M3 (R2); June 2009. [31 screens]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplina
ry/M3_R2/Step4/M3_R2__Guideline.pdf
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et. al. 
Pharmacokinetics of acetaminophen-adducts in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos 2009; 37(8):1779-84.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
adverse event
Ae total
total unchanged drug
Ae (t1-t2)
amount of drug excreted in urine in a time interval
ALT
alanine aminotransferase 
AUC
area under the plasma concentration-time curve
AUC(0-)
area under the concentration-time curve from time 0 
(predose) extrapolated to infinite time
AUC(0-t)
area under the concentration-time curve from time 0 
(predose) to time of the last quantifiable concentration
BMI
body mass index
CI
confidence interval
CLr
renal clearance of drug
Cmax
maximum observed concentration
CV
coefficient of variation
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fe%
percentage of the given dose of drug excreted in urine
Frel
relative bioavailability of drug
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HSWG
high shear wet granulation
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
IRB
institutional review board
MedDRA
Medical Dictionary for Regulatory Activities
mm Hg
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 Bazett’s formula
 
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QTcF
corrected QT interval using Fridericia’s formula
RAP
reporting and analysis plan
RC
related compound
SAE
serious adverse event
SD
standard deviation
SRM
Study Reference Manual
t1/2
terminal phase half-life
tlag
lag time before observation of drug concentrations in 
sampled matrix
Tmax
time to first occurrence of Cmax
ULN
upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
GSKDrug
MedDRA
Phoenix WinNonlin
SAS
 
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12.2.
Appendix 2: Liver Chemistry Stopping Criteria
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow-Up Assessments section can be found in 
Appendix 3.
 
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12.3.
Appendix 3: Liver Safety Required Actions and Follow-Up 
Assessments
Phase I liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA guidance, “Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation,” [DHHS, 2009].
Phase I Liver Chemistry Stopping Criteria and Required Follow-up Assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubina,b 2 × ULN (>35% direct bilirubin) or INR >1.5, 
report as an SAE.
See additional actions and follow-up assessments listed below.
Required Actions and Follow-up Assessments Following Liver Stopping Event
Actions
Follow-Up Assessments

Report the event to GSK within 24 hours

Complete the Liver Event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb

Perform liver event follow-up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Viral hepatitis serologyc

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total bilirubin 
2 × ULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
 
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Liver Chemistry Stopping Criteria – Liver Stopping Event

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours

Monitor subjects weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline
globulins).

Serum acetaminophen adduct 
high-performance liquid chromatography 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic case 
report form; GSK = GlaxoSmithKline; IgM = Immunoglobulin M; INR = international normalized ratio; 
SAE = serious adverse event; ULN = upper limit of normal.
a
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3 × ULN and bilirubin 2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
c
Includes: hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (IgM); hepatitis C 
RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); hepatitis E IgM antibody.
 
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12.4.
Appendix 4: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to interindividual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration are reported 
to account for much of the risk for the condition [Gorin, 2012] with certain variants 
reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of 
medicines. Additionally, genetic variability may impact the pharmacokinetics 
(absorption, distribution, metabolism, and elimination), or pharmacodynamics 
(relationship between concentration and pharmacologic effects or the time course of 
pharmacologic effects) of a specific medicine, and/or clinical outcomes (efficacy and/or 
safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including gepotidacin or any concomitant medicines
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
 
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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6-mL blood sample will be taken for DNA extraction. A blood sample is collected 
at the baseline visit, after the subject has provided informed consent for genetic 
research. Instructions for collection and shipping of the genetic sample are described 
in the laboratory manual. The DNA from the blood sample may undergo quality 
control analyses to confirm the integrity of the sample. If there are concerns regarding 
the quality of the sample, then the sample may be destroyed. The blood sample is 
taken on a single occasion unless a duplicate sample is required due to an inability to 
utilize the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to the 
subject by the investigator or clinic staff. Coded samples do not carry personal identifiers 
(such as a name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers), will only use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal From Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research, in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the clinic study records.
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will continue to 
be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance a sample destruction form will not be available to 
include in the clinic files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately, and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that,
at any dose:
c.
Results in death
d.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient 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.
f.
Results in disability/incapacity
NOTE:

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 or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
 
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h.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3 × ULN and total bilirubin* 2 × ULN (>35% direct), or

ALT 3 × ULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3 × ULN 
and total bilirubin 2 × ULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.5.3.
Recording of Adverse Events and Serious Adverse Events
Adverse Events and Serious Adverse Event 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
 
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12.5.4.
Evaluating Adverse Events and Serious Adverse Events
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 
Diseases Division of Microbiology and Infectious Diseases (DMID) criteria for toxicity 
assessment (Appendix 6).
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE (Section 12.5.2).
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts, evidence, 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of Adverse Events and Serious Adverse Events

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
 
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
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any postmortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.5.
Reporting of Serious Adverse Events to GSK
Serious adverse event reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the clinic will use 
the paper SAE data collection tool and fax it to the medical monitor or the SAE 
coordinator.

The clinic will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given clinic, the electronic data collection tool 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data.

If a clinic receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the clinic can report this information on a paper SAE form or to the 
medical monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.6.
Appendix 6: Division of Microbiology and Infectious Disease 
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 AIDs and modified to better meet the needs of 
participants in DMID trials.

For parameters not included in the following Toxicity Tables, 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 mg/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
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated partial thromboplastin
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.
 
 
 
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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to 135 mEq/L
123 to 129 mEq/L
116 to 122 mEq/L
<116 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypernatremia
146 to 150 mEq/L
151 to 157 mEq/L
158 to 165 mEq/L
>165 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypokalemia
3.0 to 3.4 mEq/L
2.5 to 2.9 mEq/L
2.0 to 2.4 mEq/L or intensive 
replacement therapy of 
hospitalization required
<2.0 mEq/L or abnormal potassium with
paresis, ileus, or life-threatening arrhythmia
Hyperkalemia
5.6 to 6.0 mEq/L
6.1 to 6.5 mEq/L
6.6 to 7.0 mEq/L
>7.0 mEq/L or abnormal potassium with
life-threatening arrhythmia
Hypoglycemia
55 to 64 mg/dL
40 to 54 mg/dL
30 to 39 mg/dL
<30 mg/dL or abnormal glucose with mental 
status changes or coma
Hyperglycemia
(nonfasting and no prior 
diabetes)
116 to 160 mg/dL
161 to 250 mg/dL
251 to 500 mg/dL
>500 mg/dL or abnormal glucose with
ketoacidosis or seizures
Hypocalcemia
(corrected for albumin)
8.4 to 7.8 mg/dL
7.7 to 7.0 mg/dL
6.9 to 6.1 mg/dL
<6.1 mg/dL or abnormal calcium with
life-threatening arrhythmia or tetany
Hypercalcemia
(corrected for albumin)
10.6 to 11.5 mg/dL
11.6 to 12.5 mg/dL
12.6 to 13.5 mg/dL
>13.5 mg/dL or abnormal calcium with
life-threatening arrhythmia
Hypomagnesemia
1.4 to 1.2 mEq/L
1.1 to 0.9 mEq/L
0.8 to 0.6 mEq/L
<0.6 mEq/L or abnormal magnesium with
life-threatening arrhythmia
Hypophosphatemia
2.0 to 2.4 mg/dL
1.5 to 1.9 mg/dL or 
replacement Rx required
1.0 to 1.4 mg/dL
intensive therapy or hospitalization 
required
<1.0 mg/dL or abnormal phosphate with
life-threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any increase in 
other liver function test)
1.1 to <1.25 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.
 
 
 
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase 
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
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.
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or 
200 mg to 1 gm loss/day
2 to 3+ or
1 to 2 gm loss/day
4+ or
2 to 3.5 gm loss/day
Nephrotic syndrome or
>3.5 gm loss/day
Hematuria
Microscopic only
<10 RBC/HPF
Gross, no clots
>10 RBC/HPF
Gross, with or without clots,
or red blood cells casts
Obstructive or 
required transfusion
HPF = high-powered field; RBC = red blood cells.
 
 
 
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm
N/A
Asymptomatic, transient signs, no 
Rx required
Recurrent/persistent; symptomatic 
Rx required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension
Transient increase >20 mm Hg;
no treatment 
Recurrent, chronic increase 
>20 mm Hg;
treatment required 
Acute treatment required; 
outpatient treatment or 
hospitalization possible 
End organ damage or 
hospitalization required 
Hypotension
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mmHg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, blood loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
BP = blood pressure; EKG = electrocardiogram; IV = intravenous; mm Hg = millimeters of mercury; N/A = not applicable; Rx = therapy.
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment 
responsive
Paroxysmal cough; uncontrolled 
with treatment
N/A
Bronchospasm, acute
Transient; no treatment; FEV1 70 
to 80% of peak flow
Requires treatment; normalizes 
with bronchodilator; FEV1 50 to 
70% of peak flow
No normalization with 
bronchodilator; FEV1 25 to 50% of 
peak flow; or retractions present
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen 
therapy
N/A = not applicable; FEV1 = forced expiratory volume in 1 second.
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; maintains 
reasonable intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV 
fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or 
needing IV fluids
Physiologic consequences 
requiring hospitalization or 
requiring parenteral nutrition
Constipation
Requiring stool softener or dietary 
modification
Requiring laxatives
Obstipation requiring manual 
evacuation or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 4 loose 
stools/day or mild diarrhea lasting 
<1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week
>7 loose stools/day or bloody 
diarrhea; or orthostatic 
hypotension or electrolyte 
imbalance or >2L IV fluids 
required
Hypotensive shock or physiologic 
consequences requiring 
hospitalization
Oral discomfort/Dysphagia
Mild discomfort; no difficulty 
swallowing
Some limits on eating/drinking
Eating/talking very limited; unable 
to swallow solid foods
Unable to drink fluids; requires IV 
fluids
IV = intravenous.
 
 
 
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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
 
 
 
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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia 
(joint pain)
Mild pain not interfering with function
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL
Severe paid; pain and/or analgesics 
interfering with ADL
Disabling pain
Arthritis
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL
Severe pain with inflammation, erythema 
or joint swelling, and interfering with ADL
Permanent and/or 
disabling joint 
destruction
Myalgia
Myalgia with no limitation of activity
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity
Severe muscle tenderness with marked 
impairment of activity
Frank myonecrosis
ADL = activities of daily living.
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
Erythema; pruritus
Diffuse, maculo papular rash, dry 
desquamation
Vesiculation or moist 
desquamation or ulceration
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery
Induration
<15 mm
15 to 30 mm
>30 mm
N/A
Erythema
<15 mm
15 to 30 mm
>30 mm
N/A
Edema
<15 mm
15 to 30 mm
>30 mm
N/A
Rash at injection site
<15 mm
15 to 30 mm
>30 mm
N/A
Pruritus
Slight itching at injection site
Moderate itching at injection extremity
Itching over entire body
N/A
N/A = not applicable.
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 103 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25 to 50%; 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self
 
 
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
and Collection of Pregnancy Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential
The list does not apply to females of reproductive potential with same sex partners or for 
subjects who are and will continue to be abstinent from penile-vaginal intercourse on a 
long term and persistent basis, when this is their preferred and usual lifestyle. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the clinic 
personnel’s review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
The GSK definition is based on the definition provided by the ICH 
[ICH, M3 (R2), 2009].
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child-bearing potential must comply with the 
following contraception requirements from 30 days prior to the first dose until 
completion of the Follow-up visit.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant
 
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
Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject’s pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to 
GSK as described in Appendix 5. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating:

Will be withdrawn from the study.

The investigator will attempt to collect pregnancy information on any female 
partner of a male study subject who becomes pregnant while participating in this 
study. This applies only to subjects who are randomized to receive study 
medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy.
 
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
The partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
 
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12.8.
Appendix 8: Follow-Up for Gastrointestinal Findings
Subjects who experience diarrhea or enteritis should be evaluated with additional fecal 
occult blood tests and stool cultures as deemed appropriate by the investigator. Any 
subject with a positive fecal occult blood test should be referred to a gastroenterologist 
for further evaluation at the discretion of the investigator.
Subjects who experience an AE of diarrhea or enteritis should have additional fecal 
occult blood testing, as well as a routine stool culture performed, which may include the 
recovery of pathogenic bacteria such as Salmonella, Shigella, Campylobacter, Yersinia, 
Vibrio, Staphylococcus aureus, Escherichia coli 0157, and enterohemorrhagic 
Escherichia coli.
In addition, if the subject meets the clinical criteria outlined in Appendix 9, Clostridium 
difficile toxin detection should be conducted.
Note: Additional testing is at the discretion of the investigator if it is believed the 
GI signs/symptoms are due to cholinergic effects and/or if the GI signs/symptoms occur 
within 24 hours of the infusion.
 
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12.9.
Appendix 9: Clostridium Difficile Testing Procedure and 
Algorithm
 
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12.10.
Appendix 10: Country-Specific Requirements
No country-specific requirements exist.
 
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12.11.
Appendix 11: Protocol Changes
Protocol Amendment 1
Where the Amendment Applies
To the site participating in Part 2 of BTZ117351
Summary of Amendment Changes With Rationale
The Chinese cohort will be removed from Part 2 of this study since PK data obtained 
from Chinese subjects living abroad would not satisfy regulatory requirements in China. 
Japanese subjects in Part 2 will receive a single 1500 mg oral dose followed by a single 
3000 mg oral dose of gepotidacin selected from Part 1a in a fixed-sequence design. The 
inclusion of a 3000-mg dose will be to assess the PK, safety, and tolerability of a higher 
dose that is intended for future Phase III studies. Blood and urine samples (Part 2 only) 
will also be collected for PK analysis of gepotidacin concentrations in Japanese subjects.
Minor formatting and administrative changes are also made for clarity.
Protocol Amendment 2
Where the Amendment Applies
To the site participating in Part 3 of BTZ117351
Summary of Amendment Changes With Rationale
An additional part to the study (Part 3) was added, and an additional cohort of Japanese 
subjects will be enrolled in a fixed sequence design. This additional part was added based 
on tolerability results from 3000 mg in the fasted state during Part 2. Japanese subjects in 
the fed state will receive single escalating doses of gepotidacin (1500 mg, 2250 mg, and 
3000 mg) in Periods 1, 2, and 3, respectively, or placebo. This amendment also provides
additional guidelines for managing subjects in Part 3 who experience adverse events of 
diarrhea.
Formatting, grammatical, and administrative changes are also made for clarity.
 
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The GlaxoSmithKline group of companies
BTZ117351
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I, Multi-Center, Open-Label, Single-Dose, 2-Part Study 
to Evaluate the Relative Bioavailability of Three Formulations in 
Healthy Subjects, Food Effect on Tablet Formulation in Healthy 
Subjects, and Pharmacokinetics of Gepotidacin (GSK2140944) 
in Japanese Subjects
Compound Number:
GSK2140944
Development Phase:
I
Effective Date:
16-MARCH -2017
Protocol Amendment Number:  1
Author (s):
GSK Authors:
 (Clinical Pharmacology Modeling and Simulation), 
 (ID, Medicines Discovery and Development), 
 (Clinical 
Statistics), and 
 (Projects Clinical Platforms and Sciences)
PPD Authors: 
 (Pharmacokineticist), 
 (Biostatistician), and 
(Medical Writer)
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N281831_00
2016-JUL-12
Original
2016N281831_01
2017-MAR-16
Amendment No. 1
The purpose of this amendment is to remove the Chinese cohort and introduce a second 
oral dose for Japanese subjects in Part 2 in a fixed sequence design. Japanese subjects 
will receive a single 1500-mg dose in Period 1 followed by a single 3000-mg dose in 
Period 2. Blood and urine samples (Part 2 only) will also be collected for 
pharmacokinetic analysis of gepotidacin concentrations in Japanese subjects.
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone Number 
and E-mail 
Address
After-Hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor and 
SAE Contact 
Information
MD
Safety Hotline:
PPD
929 N Front St
Wilmington, NC 
28401
Secondary 
Medical 
Monitor
MD
Safety Hotline:
PPD
7551 Metro Center
Austin, TX 78744
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address: 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089
Collegeville, PA 19426-0989
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): IND 111885
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BTZ117351
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351 .................................................8
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVES AND ENDPOINTS...........................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................18
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................20
4.6.
Benefit:Risk Assessment ............................................................................21
4.6.1.
Risk Assessment .........................................................................22
4.6.2.
Benefit Assessment.....................................................................24
4.6.3.
Overall Benefit:Risk Conclusion...................................................24
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............24
5.1.
Inclusion Criteria.........................................................................................24
5.2.
Exclusion Criteria........................................................................................26
5.3.
Screening/Baseline/Run-In Failures............................................................28
5.4.
Withdrawal/Stopping Criteria.......................................................................28
5.4.1.
Liver Chemistry Stopping Criteria ................................................29
5.4.2.
QTc Stopping Criteria ..................................................................29
5.4.3.
Gastrointestinal Stopping Criteria ................................................29
5.4.4.
Rash/Hypersensitivity Stopping Criteria .......................................30
5.5.
Subject and Study Completion....................................................................30
6.
STUDY TREATMENT ............................................................................................30
6.1.
Investigational Product and Other Study Treatment....................................30
6.2.
Treatment Assignment................................................................................31
6.3.
Planned Dose Adjustments.........................................................................32
6.4.
Blinding.......................................................................................................32
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Compliance With Study Treatment Administration ......................................32
6.8.
Treatment of Study Treatment Overdose....................................................33
6.9.
Treatment After the End of the Study..........................................................33
6.10.
Lifestyle and/or Dietary Restrictions............................................................33
6.10.1.
Meals and Dietary Restrictions ....................................................33
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................34
6.10.3.
Activity .........................................................................................34
6.11.
Concomitant Medications and Non-Drug Therapies....................................34
6.11.1.
Permitted Medications and Non-Drug Therapies..........................34
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................34
 
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
7.1.
Time and Events Table...............................................................................36
7.2.
Screening and Critical Baseline Assessments ............................................38
7.3.
Safety .........................................................................................................38
7.3.1.
Adverse Events and Serious Adverse Events..............................38
7.3.1.1.
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
information .................................................................38
7.3.1.2.
Method of Detecting Adverse Events and 
Serious Adverse Events .............................................39
7.3.1.3.
Follow-Up of Adverse Events and Serious 
Adverse Events ..........................................................39
7.3.1.4.
Regulatory Reporting Requirements for 
Serious Adverse Events .............................................39
7.3.2.
Pregnancy ...................................................................................39
7.3.3.
Physical Exams ...........................................................................40
7.3.4.
Vital Signs....................................................................................40
7.3.5.
Electrocardiogram........................................................................40
7.3.6.
Clinical Safety Laboratory Assessments ......................................40
7.4.
Pharmacokinetics .......................................................................................41
7.4.1.
Blood Sample Collection..............................................................41
7.4.2.
Urine Sample Collection ..............................................................42
7.4.3.
Sample Analysis ..........................................................................42
7.5.
Genetics .....................................................................................................42
8.
DATA MANAGEMENT ...........................................................................................42
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................43
9.1.
Hypotheses.................................................................................................43
9.2.
Sample Size Considerations.......................................................................43
9.2.1.
Sample Size Assumptions ...........................................................43
9.2.2.
Sample Size Re-Estimation or Adjustment...................................44
9.3.
Data Analysis Considerations .....................................................................44
9.3.1.
Analysis Populations....................................................................44
9.3.2.
Interim Analysis ...........................................................................44
9.4.
Key Elements of Analysis Plan ...................................................................45
9.4.1.
Primary Analyses.........................................................................45
9.4.2.
Secondary Analyses ....................................................................46
10. STUDY GOVERNANCE CONSIDERATIONS........................................................47
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............47
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................49
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................50
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
11. REFERENCES.......................................................................................................51
 
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12. APPENDICES........................................................................................................53
12.1.
Appendix 1: Abbreviations and Trademarks................................................53
12.2.
Appendix 2: Liver Chemistry Stopping Criteria............................................55
12.3.
Appendix 3: Liver Safety Required Actions and Follow-Up 
Assessments ..............................................................................................56
12.4.
Appendix 4: Genetic Research ...................................................................58
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting of Adverse Events..............................................61
12.5.1.
Definition of Adverse Events........................................................61
12.5.2.
Definition of Serious Adverse Events...........................................62
12.5.3.
Recording of Adverse Events and Serious Adverse Events .........63
12.5.4.
Evaluating Adverse Events and Serious Adverse Events.............64
12.5.5.
Reporting of Serious Adverse Events to GSK..............................65
12.6.
Appendix 6: Division of Microbiology and Infectious Disease Adult 
Toxicity Tables for Adverse Event Assessment...........................................66
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential and Collection of 
Pregnancy Information................................................................................74
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential.........................74
12.7.2.
Collection of Pregnancy Information ............................................75
12.8.
Appendix 8: Follow-Up for Gastrointestinal Findings...................................77
12.9.
Appendix 9: Clostridium Difficile Testing Procedure and Algorithm .............78
12.10. Appendix 10: Country-Specific Requirements.............................................79
12.11. Appendix 11: Protocol Changes..................................................................80
 
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1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351
Rationale
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet
granulation [HSWG]) compared with the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK) and safety data in Part 1a, 
a decision will be made whether to proceed with Parts 1b and 2.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349 (see 
GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Part 2 will evaluate the pharmacokinetics, safety, and tolerability of 2 different doses of 
the tablet formulation selected in Part 1a in Japanese subjects. Testing gepotidacin in this
specific population will provide PK data and enable future pivotal Phase III studies in 
Japan.
 
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Objectives/Endpoints
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared 
with the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of
gepotidacin tablets (RC or HSWG) selected from 
Part 1a
Part 2

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects
Parts 1a and 2

Plasma gepotidacin AUC(0-), 
AUC(0-t), Frel (for Part 1a only), Cmax, 
Tmax, tlag and t1/2, as data permit

Urine endpoints include Ae total, 
Ae(t1-t2), AUC(0-12), AUC(0-24), 
AUC(0-48), fe%, and CLr of 
gepotidacin, as data permit
Part 1b

Plasma gepotidacin AUC(0-), 
AUC(0-t), Cmax, Tmax, tlag, and t1/2, 
as data permit
Secondary
Part 1a

To assess the safety and tolerability of a single 1500-mg 
dose of gepotidacin tablet formulations (RC and HSWG; 
2 × 750 mg) compared with the reference capsule 
formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a when administered with a 
moderate fat meal
Part 2

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose followed by a single 3000-
mg (4 × 750 mg) dose of gepotidacin tablets (RC or 
HSWG) selected from Part 1a in Japanese subjects
Parts 1 and 2

Clinical safety data from AEs, clinical 
laboratory tests, vital signs (systolic and 
diastolic blood pressure and heart rate), 
and 12-lead ECG readings

Plasma gepotidacin AUC(0-) and 
Cmax, as data permit (for Part 2 only)
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related compound.
Overall Design
This is a Phase I, multi-center, open-label, single-dose, 2-part study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared with the reference capsule formulation under fasted conditions. 
Based upon safety and PK data obtained from Part 1a, a decision will be made whether to 
use the free base RC or HSWG tablet formulation for Parts 1b and 2. Part 1b will 
evaluate the bioavailability of the selected tablet formulation under fasted and fed 
conditions. Part 2 will evaluate pharmacokinetics of 2 different doses of the formulation 
selected from Part 1a in Japanese subjects under fasted conditions.
 
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Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a 
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC 
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA).
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations. Blood and urine samples will be 
collected up to approximately 48 hours after dosing.
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
formulation (selected in Part 1a). If both formulations of the free base tablet exhibit 
similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349 
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations. Blood samples will be collected up to 
approximately 48 hours after dosing.
Part 2: Pharmacokinetics in Japanese Subjects
Part 2 is a 2-period, fixed-sequence study and will evaluate the pharmacokinetics of a 
single dose of 1500 mg followed by a single dose of 3000 mg gepotidacin tablet 
formulation (RC or HSWG tablet) in a cohort of Japanese subjects under fasted 
conditions. A decision will be made whether to use the RC tablet formulation or the 
HSWG tablet formulation based upon the safety and PK data obtained from Part 1a.
Subjects will participate in 2 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations. Blood and urine samples will be 
collected up to approximately 48 hours after dosing.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets
 
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
Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
Based on PK, safety, and tolerability data from Part 1a, subjects for Parts 1b (food effect) 
and 2 (Japanese subjects) may be enrolled.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Part 2: Pharmacokinetics in Japanese Subjects

Treatment B or C: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets, 
respectively

Treatment F: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets selected from 
Part 1a
On Day 1 of Period 1, subjects will receive a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablet (RC or HSWG) selected from Part 1a. On Day 1 of Period 2, subjects 
will receive a single 3000-mg (4 × 750 mg) dose of gepotidacin tablet (RC or HSWG) 
selected from Part 1a. There will be a washout period of at least 3 days between doses. 
Subjects will remain in the clinical research unit from Day –1 until Day 3 of Period 2
after all scheduled PK and safety assessments have been completed, and will return to the 
clinic for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. 
The duration of the study (from Screening to the Follow-up visit) will be approximately 
41 days.
 
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Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK 
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Part 2, approximately 10 Japanese subjects will be enrolled.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
Analysis
Plasma concentrations of gepotidacin will be analyzed (as data permit) by 
noncompartmental PK analysis to determine the following PK metrics: area under the 
plasma concentration-time curve (AUC) from time 0 extrapolated to infinite time 
[AUC(0-)], AUC from time 0 to time of last quantifiable concentration [AUC(0-t)], 
maximum observed concentration (Cmax), relative bioavailability of drug (Frel; Part 1a 
only), terminal phase half-life (t1/2), lag time before observation of drug concentrations 
in sampled matrix (tlag), and time to first occurrence of Cmax (Tmax). AUC(0-∞) and 
Cmax following single dose may be used for assessment of dose proportionality (Part 2 
only).
Urine (Parts 1a and 2 only) concentrations of gepotidacin will be analyzed (as data 
permit) by noncompartmental PK analysis to determine the following PK metrics: total 
unchanged drug (Ae total), amount of drug excreted in urine [Ae(t1-t2)], AUC from 
time 0 to 12 hours after dosing [AUC(0-12)], AUC from time 0 to 24 hours after dosing 
[AUC(0-24)], AUC from time 0 to 48 hours after dosing [AUC(0-48)], percentage of the 
given dose of drug excreted in urine (fe%), and renal clearance of drug (CLr). 
Plasma and urine (Parts 1a and 2 only) concentrations of gepotidacin and the associated 
PK parameters will be listed, and summary statistics (n, mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) will be presented by day 
and treatment. Mean and individual plasma concentration versus time profiles will be 
presented graphically on linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed-effect terms for sequence, period, and regimen, and treating subject within 
sequence as a random effect. Point estimates and 90% confidence intervals (CIs) for the 
differences of interest (RC tablets and HSWG tablets versus capsules) will be constructed 
using the residual variance. Point and interval estimates will then be exponentially 
back-transformed to construct point and 90% CI estimates for the ratios of interest (RC 
tablets and HSWG tablets versus capsules).
 
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Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
Dose proportionality of AUC(0-∞) and Cmax will be assessed in Part 2.
For the bioavailability assessment, Tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
Safety endpoints will include monitoring adverse events, clinical laboratory results, vital 
sign measurements, 12-lead electrocardiogram measurements, and physical examination 
findings.
 
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2.
INTRODUCTION
Gepotidacin is a novel type II triazaacenaphthylene bacterial topoisomerase inhibitor, 
which inhibits bacterial DNA replication and has in vitro activity against susceptible and 
drug resistant pathogens associated with a range of conventional and biothreat infections.
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 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 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
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet 
granulation [HSWG]) compared with the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK) and safety data in Part 1a, 
a decision will be made whether to proceed with Parts 1b and 2.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349 
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Part 2 will evaluate the pharmacokinetics, safety, and tolerability of 2 different doses of 
the tablet formulation selected in Part 1a in Japanese subjects. Testing gepotidacin in this
specific population will provide PK data and enable future pivotal Phase III studies in 
Japan.
2.2.
Brief Background
Gepotidacin has been administered to healthy subjects in 7 Phase I studies and 2 Phase II 
studies. Gepotidacin has demonstrated clinical efficacy in a Phase II study for acute 
bacterial skin and skin structure infections, and is currently being evaluated in a Phase II 
study for gonorrhea. Additional details can be found in the Investigator’s Brochure (IB; 
GlaxoSmithKline Document Number CM2010/00033/04).
 
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared 
with the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from 
Part 1a
Part 2

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose followed by a single 3000-mg 
(4 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1a in Japanese subjects
Parts 1a and 2

Plasma gepotidacin AUC(0-), 
AUC(0-t), Frel (for Part 1a only), 
Cmax, Tmax, tlag and t1/2, as 
data permit

Urine endpoints include Ae 
total, Ae(t1-t2), AUC(0-12), 
AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data 
permit
Part 1b

Plasma gepotidacin AUC(0-), 
AUC(0-t), Cmax, Tmax, tlag, 
and t1/2, as data permit
Secondary
Part 1a

To assess the safety and tolerability of a single 
1500-mg dose of gepotidacin tablet formulations (RC 
and HSWG; 2 × 750 mg) compared with the reference 
capsule formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a when administered 
with a moderate fat meal
Part 2

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose followed by a single 
3000-mg (4 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1a in Japanese subjects

To assess dose proportionality following a single 
1500-mg (2 × 750 mg) dose followed by a single 3000-
mg (4 × 750 mg) dose of gepotidacin tablets (RC or 
HSWG) selected from Part 1a in Japanese subjects
Parts 1 and 2

Clinical safety data from AEs, 
clinical laboratory tests, vital 
signs (systolic and diastolic 
blood pressure and heart rate), 
and 12-lead ECG readings

Plasma gepotidacin AUC(0-) 
and Cmax, as data permit (for 
Part 2 only)
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related 
compound.
 
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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I, multi-center, open-label, single-dose, 2-part study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared with the reference capsule formulation under fasted conditions. 
Based upon safety and PK data obtained from Part 1a, a decision will be made whether to 
use the free base RC or HSWG tablet formulation for Parts 1b and 2. Part 1b will 
evaluate the bioavailability of the selected tablet formulation under fasted and fed 
conditions. Part 2 will evaluate pharmacokinetics of 2 different doses of the formulation 
selected from Part 1a in Japanese subjects under fasted conditions.
Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a 
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC 
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA). See 
the study schematic in Table 1 for more details.
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Time and Events 
Table (Table 7). Blood and urine samples will be collected up to approximately 48 hours 
after dosing.
Table 1
Part 1a Relative Bioavailability Study Design Schematic
Treatment
Cross-over
Follow-up
Capsule 
(reference)a
Period 1
Wash-out
At least 
3 days
Period 2
Wash-out
At least 
3 days
Period 3
5 to 7 days 
after final 
dose
RC and HSWG 
tabletb
Sequence 1
A
B
C
Sequence 2
C
A
B
Sequence 3
B
C
A
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 3 × 500-mg capsules (Treatment A; reference formulation)
b
1500 mg single dose given as 2 × 750-mg RC (Treatment B) or HSWG (Treatment C) tablets
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
formulation (selected in Part 1a). If both formulations of the free base tablet exhibit 
 
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similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349 
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food. See the study schematic in Table 2 for 
more details.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations according to the Time and Events Table 
(Table 7). Blood samples will be collected up to approximately 48 hours after dosing.
Table 2
Part 1b Food Effect Study Design Schematic
Treatment
Cross-over
Follow-up
RC or HSWG tablet fasteda
Period 1
Wash-out
At least 3 days
Period 2
5 to 7 days after 
final dose
RC or HSWG tablet feda
Sequence 4
D
E
Sequence 5
E
D
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750 mg tablets fasted (Treatment D) and fed (Treatment E)
Part 2: Pharmacokinetics in Japanese Subjects
Part 2 is a 2-period, fixed-sequence study and will evaluate the pharmacokinetics of a 
single dose of 1500 mg followed by a single dose of 3000 mg gepotidacin tablet 
formulation (RC or HSWG tablet) in a cohort of Japanese subjects under fasted 
conditions. A decision will be made whether to use the RC tablet formulation or the 
HSWG tablet formulation based upon the safety and PK data obtained from Part 1a. See 
the study schematic in Table 3 for more details.
Subjects will participate in 2 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Time and Events 
Table (Table 7). Blood and urine samples will be collected up to approximately 48 hours 
after dosing.
Table 3
Part 2 Pharmacokinetic Study Design Schematic
Treatment
Fixed-sequence
Follow-up
RC and HSWG 
tableta
Period 1
Wash-out
At least 3 days
Period 2
Wash-out
At least 3 days
5 to 7 days after 
final dose
Sequence 6
B or C
F
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750-mg RC (Treatment B) or HSWG (Treatment C) tablets; 3000 mg single 
dose given as 4 × 750-mg RC or HSWG tablets (Treatment F)
 
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4.2.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets

Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.
Based on PK, safety, and tolerability data from Part 1a, subjects for Parts 1b (food effect) 
and 2 (Japanese subjects) may be enrolled.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Part 2: Pharmacokinetics in Japanese Subjects

Treatment B or C: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets, 
respectively

Treatment F: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets selected from 
Part 1a
 
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On Day 1 of Period 1, subjects will receive a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablet (RC or HSWG) selected from Part 1a. On Day 1 of Period 2, subjects 
will receive a single 3000-mg (4 × 750 mg) dose of gepotidacin tablet (RC or HSWG) 
selected from Part 1a. There will be a washout period of at least 3 days between doses. 
Subjects will remain in the clinical research unit from Day –1 until Day 3 of Period 2
after all scheduled PK and safety assessments have been completed, and will return to the 
clinic for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. 
The duration of the study (from Screening to the Follow-up visit) will be approximately 
41 days.
4.3.
Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Part 2, approximately 10 Japanese subjects will be enrolled.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
4.4.
Design Justification
The study design for Part 1a is commonly used when evaluating relative bioavailability 
of a drug entity in subjects. It is based on recommendations given in the US Food and 
Drug Administration (FDA) draft guidance for industry, Bioavailability and 
Bioequivalence Studies Submitted in NDAs or INDs — General Considerations 
[DHHS, 2014].
The study design for Part 1b is commonly used when evaluating the effect of food on a 
drug entity in subjects. It is based on recommendations given in the US FDA draft 
guidance for industry, Food-Effect Bioavailability and Fed Bioequivalence Studies 
[DHHS, 2002].
The study design for Part 2 is commonly used when evaluating pharmacokinetics of a 
drug entity in subjects from different ethnic groups. The fixed-sequence design allows for 
dosing of a lower dose followed by a higher dose within a subject and requires fewer
subjects for PK evaluation compared with a parallel cohort. Pharmacokinetic data 
obtained from this group would satisfy regulatory guidelines and provide dosing 
recommendations for future Phase III studies in Japanese subjects.
Gepotidacin exhibits linear and time-independent pharmacokinetics, which indicates a 
single-dose study is adequate to achieve study objectives. A multiple-dose study is not 
necessary since there are no safety concerns with metabolites of this study drug.
 
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4.5.
Dose Justification
The 1500-mg dose of gepotidacin is considered to be the likely dose used for future 
Phase III studies and will be evaluated in all parts of this study. The 3000-mg dose of 
gepotidacin will be evaluated in Part 2 of this study to evaluate PK, safety, and 
tolerability for planned use in future Phase III studies. Selection of dose and dosing 
frequency for this study is justified based on observed safety and PK data following oral 
single (100 to 3000 mg) and repeat twice daily (400 to 2300 mg) and 3 times daily 
(1500 to 2000 mg) capsule doses in healthy subjects in Studies BTZ114595 and 
BTZ116778, and single 1500-mg doses of the capsule and RC tablet formulations in 
Study BTZ117349. The 1500-mg dose (PK data for Study BTZ116778 [Table 4] and 
Study BTZ117349 [Table 5]) and 3000-mg dose (PK for Study BTZ114595 [Table 6]) 
achieve the projected therapeutic target plasma concentration and will be evaluated in all 
parts of the study. A moderate fat meal should only have a minimal effect on PK after 
administration of the tablet formulation since only a minimal food effect on PK was 
previously observed in Studies BTZ114595 and BTZ117349 [Table 5].
Table 4
Selected PK Parameters of Gepotidacin After Single and Repeat BID 
Dose of 1500 mg Orally (Study BTZ116778)
AUC(0-)a 
(µg.hr/mL)
Cmax (µg/mL)a
Tmax (hr)b
t1/2 (hr)a
Single Dose PK
[Day 1] (N=12)
20.1 (21.5%)
4.08 (40.3%)
2.0
[1.5 – 4.0]
12.0 (17.9%)
AUC(0-12)a
(µg.hr/mL)
Cmax1 (µg/mL)a
Tmax (hr)b
Roa
Repeat BID Dose PK
[Day 14] (N=12)
22.4 (29.6%)
5.41 (31.1%)
2.0
[1.5 – 4.0]
1.30 (34.9%)
BID = twice daily, CVb% = percent coefficient of variation, PK = pharmacokinetic, Ro = accumulation ratio.
a
Geometric mean (CVb%) [range]
b
Median [range]
Table 5
Selected Gepotidacin PK Parameters After Single Dose Oral Capsule 
and Tablet Administration Under Fasted and Fed Conditions 
(Study BTZ117349)
Gepotidacin 
1500-mg 
Capsule/Fasted
(N=15)
Gepotidacin 
1500 mg RC 
Tablet/Fasted
(N=14)
Gepotidacin 
1500 mg RC 
Tablet/Fed
(N=13)
AUC(0-)a (µg.hr/mL)
13.6 (28.8%)
15.8 (20.3%)
16.9 (16.2%)
Cmax (µg/mL)a
3.77 (58.1%)
4.37 (24.7%)
3.73 (29.1%)
Tmax (hr)b
1.5 (0.5 – 6.0)
1.75 (1.0 – 3.0)
3.0 (1.5 – 4.0)
t1/2 (hr)c
12.1 (27.3)
11.8 (19.2)
11.7 (18.6)
CVb% = percent coefficient of variation, PK = pharmacokinetic.
a
Geometric mean (CVb%)
b
Median [range]
c
Arithmetic mean (CVb%)
 
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Table 6
Selected Gepotidacin PK Parameters After Single Oral Capsule 
Administration of 3000 mg (Study BTZ114595)
AUC(0-)a 
(µg.hr/mL)
Cmax (µg/mL)a
Tmax (hr)b
t1/2 (hr)b
Single Dose PK
[Day 1] (N=6)
33.1 (31.5%)
9.03 (36.0%)
1.25
[1.00 – 2.00]
10.8
[8.66 – 13.90]
CVb% = percent coefficient of variation, PK = pharmacokinetic.
a
Geometric mean (CVb%)
b
Median [range]
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
gepotidacin can be found in the IB (GlaxoSmithKline Document 
Number CM2010/00033/04).
Section 4.6.1 outlines the risk assessment and mitigation strategy for this study 
(GlaxoSmithKline Document Number 2013N174977).
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product Gepotidacin
Gastrointestinal (GI) Effects
Lower GI effects (soft stools, flatulence, and diarrhea) are the most 
common GI-associated adverse events (AEs) reported in human 
subjects dosed with gepotidacin. Additional events of heme + stool 
have been observed.
In the Phase I studies, out of approximately 400 healthy subjects 
who have received gepotidacin, Clostridium difficile has been 
reported in 8 subjects.
In an acute bacterial skin and skin structure infection study of 
122 patients from 13 sites in the USA, the most frequently reported 
AEs were in the GI system including diarrhea, nausea, and 
abdominal cramping (see GlaxoSmithKline Document 
Number 2015N243789_00 Study ID BTZ116704). Events were 
usually mild in severity with fewer of moderate severity. No patients 
experienced severe GI AEs and none withdrew due to GI AEs.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Subjects with significant GI symptoms will obtain the 
appropriate work-up (Appendix 8).
Subject stopping criteria: Subjects experiencing Grade 3 or 
Grade 4 AEs will have permanent discontinuation of the 
investigational product and will be followed as appropriate 
until resolution of the AE.
Cardiovascular Effects
Reversible increase in QT prolongation and a 
mild increase in heart rate in human subjects.
In Study BTZ115775 [see GlaxoSmithKline Document Number 
2015N227098_00 Study ID BTZ115775], the infusion of gepotidacin 
at a dose of 1000 mg and 1800 mg over 2 hours caused a mild heart 
rate effect of approximately 6 beats per minute to 10 beats per 
minute and a QT prolongation, measured as ∆∆QTcF, of 12 msec to 
22 msec. 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.
The 1500 mg oral dose yields a Cmax of 4.8 µg/mL with predicted 
ΔΔQTcF (90% CI) of 7.5 msec (6.8 to 8.3 msec) compared with that 
observed after the therapeutic 1,000 mg intravenous (IV) dose 
(Cmax of 7.3 µg/mL) administered in the thorough QTc study.
Exclusion criteria, oral dosing of capsule and tablet 
formulations will have lower Cmax compared with IV doses 
in the thorough QTc study, close monitoring of clinical 
parameters, and AEs will be conducted and stopping 
criteria will be utilized to mitigate and assess 
cardiovascular effects.
Note: Subjects with a QRS duration <70 and >120 msec 
will be excluded. 
Subject stopping criteria: Subjects 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
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 total drug concentration).
At higher doses, some subjects have experienced effects consistent 
with increased cholinergic tone, including central nervous system 
and GI effects (including dizziness, abdominal pain, salivary 
hypersecretion, hot flush, diarrhea, fatigue, and nausea). These 
effects appear to be related to Cmax and are significantly attenuated 
when Cmax is below 14 g/mL.
Coadministration of anticholinergics and administration in 
subjects 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. The Cmax will be below 14 g/mL in this study.
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was seen in 3 of 
8 subjects following 10 days of dosing 1500 mg 3 times daily (see 
GlaxoSmithKline Document Number 2014N198291_00
Study ID BTZ115198)
Rash was reported as an AE for 4 of 122 subjects (3%) and 
consisted of mild, related urticaria; moderate, related rash 
maculopapular; mild, related rash; mild, related urticaria; and mild, 
not related arthropod bite (see GlaxoSmithKline Document Number 
2015N243789_00 Study ID BTZ116704).
There has been no other evidence of hypersensitivity in human 
subjects 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 GlaxoSmithKline medical 
monitor, contraindicates their participation.
Subject monitoring:
Patients will be monitored closely for cutaneous effects 
throughout the study, and specialist advice will be sought 
as needed to evaluate any clinically significant finding.
Subject stopping criteria:
Grade 3 or higher rash or Grade 2 rash with evidence of 
systemic involvement.
 
 
 
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4.6.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy subjects, there is no direct clinical 
benefit to study subjects. Participation in this study will contribute to the process of 
developing new antibiotic therapies in areas of growing unmet need.
4.6.3.
Overall Benefit:Risk Conclusion
The risk of adverse events (AEs) is minimized for the populations being investigated in 
the proposed study by careful selection of dose and subjects for the study; the relatively 
short duration of study drug exposure; and the extent of safety monitoring incorporated 
into the study.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB (GlaxoSmithKline Document 
Number CM2010/00033/04).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Male or female subjects between 18 and 64 years of age inclusive, at the time of 
signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator based on medical history, clinical 
laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign 
measurements, 12-lead electrocardiogram (ECG) results, and physical examination 
findings. A subject with a 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 subjects (Part 2):

The subject was a non-naturalized Japanese citizen and held a Japanese passport.

The subject had 2 Japanese parents and 4 Japanese grandparents who were all 
 
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non-naturalized Japanese citizens, as confirmed by interview.

The subject had been living outside of Japan for up to 10 years as confirmed by 
interview.
WEIGHT
4. Body weight:

Subjects in Part 1a and Part 1b: 50 kg and body mass index (BMI) within the 
range 19 and 32 kg/m2, inclusive.

Japanese subjects (Part 2): 50 kg and BMI within the range 18 and 32 kg/m2, 
inclusive.
SEX
5. Male or female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin test, not lactating, and at least one of the 
following conditions applies:
a.
Nonreproductive potential defined as:

Premenopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented bilateral oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea (in 
questionable cases a blood sample with simultaneous follicle-stimulating 
hormone [FSH] and estradiol levels consistent with menopause [refer to 
laboratory reference ranges for confirmatory levels]). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the 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 prior to study 
enrollment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (Appendix 7) from 30 days prior to the first dose of study 
medication and until completion of the Follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
 
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INFORMED CONSENT
6. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Subject has a clinically significant abnormality in past medical history or at the 
Screening physical examination that in the investigator’s opinion may place the 
subject at risk or interfere with outcome variables of the study. This includes, but is 
not limited to, history or current cardiac, hepatic, renal, neurologic, 
gastrointestinal (GI), respiratory, hematologic, or immunologic disease.
2. Subject has any surgical or medical condition (active or chronic) that may interfere 
with drug absorption, distribution, metabolism, or excretion of the study drug, or any 
other condition that may place the subject at risk, in the opinion of the investigator.
3. Corrected QT (QTc) >450 msec.
4. Use of a systemic antibiotic within 30 days of Screening.
5. Within 2 months before Screening, either a confirmed history of Clostridium difficile
diarrhea infection or a past positive Clostridium 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 sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
uses heparin to maintain intravenous cannula patency).
CONCOMITANT MEDICATIONS
8. Subjects cannot use any over-the-counter, or prescription medication (except for 
hormonal contraceptives and/or acetaminophen; see Section 6.11 for more details), 
vitamin supplement, or herbal medication within 7 days (or 5 half-lives, whichever is 
longer) before dosing and during the study.
RELEVANT HABITS
9. 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.
 
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10. Urinary cotinine level indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months before screening.
CONTRAINDICATIONS 
11. History of sensitivity to any of the study medications, or components thereof, or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
13. Female subject has a positive pregnancy test result or is lactating at Screening or upon 
admission to the clinic.
14. Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN)
15. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. Urinalysis positive for blood without other cause identified.
17. A positive pre-study drug/alcohol screen.
18. A positive test for human immunodeficiency virus (HIV) antibody.
19. Subject has clinically significant abnormal findings in serum chemistry, hematology, 
or urinalysis results obtained at Screening or Day –1.
20. Donation of 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.
21. Previous exposure to gepotidacin within 12 months prior to the first dosing day.
22. Exclusion criteria for screening and baseline 12-lead ECG (a single repeat is allowed 
for eligibility determination):
Males
Females
Heart rate
<40 and >100 beats per minute
<50 and >100 beats per minute
PR interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcB or QTcF interval
>450 msec
QTcB = corrected QT interval using Bazett’s formula, QTcF = corrected QT interval using 
Fridericia’s formula.

Evidence of previous myocardial infarction (does not include ST segment changes 
associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, atrioventricular block [second degree or higher], 
Wolf-Parkinson-White syndrome), sinus pauses >3 seconds, non-sustained or 
sustained ventricular tachycardia (≥3 consecutive ventricular ectopic beats) or any 
significant arrhythmia which, in the opinion of the principal investigator and GSK 
medical monitor, will interfere with the safety of the individual subject.
 
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23. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
24. Subject is unable to comply with all study procedures, in the opinion of the
investigator.
25. The subject should not participate in the study, in the opinion of the investigator or
sponsor.
5.3.
Screening/Baseline/Run-In Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials publishing requirements, 
and respond to queries from regulatory authorities, a minimal set of screen failure 
information is required including demographics, screen failure details, eligibility criteria, 
and serious AEs (SAEs).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The clinic must attempt to contact the subject and reschedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow-up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 
3 telephone calls and if necessary a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “lost to follow-up”.
A subject may withdraw from study treatment 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 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
 
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5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
guidance, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” 
[DHHS, 2009].
Study treatment will be stopped if the following liver chemistry stopping criterion is met:

ALT 3 × ULN
For details of the required assessments if a subject meets the above criteria, refer to 
Appendix 2, Liver Chemistry Stopping Criteria.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on the QTcF, then 
the QTcF must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, 
the same formula must continue to be used for that subject 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 triplicate 
ECGs obtained over a brief (e.g., 5 to 10 minute) recording period.
A subject who meets either bulleted criterion below will be withdrawn from the study:

QTc >500 msec

Increase from baseline of QTc >60 msec
For subjects with underlying bundle branch block, the following discontinuation criteria 
will be used instead:
Baseline QTc With Bundle Branch Block
Discontinuation QTc With Bundle Branch Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec
5.4.3.
Gastrointestinal Stopping Criteria
Subjects experiencing Grade 3 or Grade 4 AEs (confluent pseudomembranes or 
ulcerations OR mucosal bleeding with minor trauma; tissue necrosis OR diffuse 
spontaneous mucosal bleeding OR life-threatening consequences, e.g., aspiration, 
choking) will be followed as appropriate until resolution of the AE(s).
 
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Furthermore, subjects who experience diarrhea or enteritis should be evaluated with 
additional fecal occult blood tests and stool cultures as deemed appropriate by the 
investigator as outlined in Appendix 8 and Appendix 9.
5.4.4.
Rash/Hypersensitivity Stopping Criteria
A subject 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).
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
Gepotidacin 
(GSK2140944) capsule
Gepotidacin 
(GSK2140944B) 
RC tablet
Gepotidacin 
(GSK2140944B) 
HSWG tablet
Formulation 
description:
Immediate release 
capsules containing 
gepotidacin (mesylate 
salt) and inactive 
formulation excipients
Immediate release 
tablets containing 
gepotidacin (free 
base) and inactive 
formulation 
excipients
Immediate release 
tablets containing 
gepotidacin (free 
base) and inactive 
formulation 
excipients
Dosage form:
Capsule
Tablet
Tablet
Unit dose strength/
Dosage level:
500 mg/
1500 mg (3 × 500 mg)
750 mg/
1500 mg 
(2 × 750 mg)
750 mg/
1500 mg 
(2 × 750 mg)
Route of 
Administration:
Oral
Oral
Oral
 
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Study Treatment
Dosing instructions:
Dose with 240 mL of 
water. Up to an 
additional 100 mL of 
water may be given to 
assist in swallowing 
capsules.
Dose with 240 mL of 
water. Up to an 
additional 100 mL of 
water may be given 
to assist in 
swallowing tablets.
Dose with 240 mL 
of water. Up to an 
additional 100 mL of 
water may be given 
to assist in 
swallowing tablets.
Physical description:
Pink Gelatin size 00 
capsule with no 
identifying markings 
containing slightly 
agglomerated pale 
yellow to grayish 
yellow to yellowish 
gray powder.
A capsule-shape 
white film-coated 
tablet with no 
identifying markings.
An oval shape white 
film-coated tablet 
with no identifying 
markings.
Manufacturer/Source of 
procurement:
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
6.2.
Treatment Assignment
Subjects in Part 1a will be assigned to a treatment sequence to receive gepotidacin 
(GSK2140944) capsules, RC tablets, and HSWG tablets in accordance with the 
randomization schedule generated by PPD before the start of the study, using validated 
internal software. Subjects in Part 1b will be assigned to a treatment sequence to receive 
gepotidacin RC or HSWG tablets under fasted and fed conditions.
A description of each regimen for Parts 1 and 2 is provided in the table below:
Part 
Treatment 
Code
Treatment
1a
A
Treatment A: Gepotidacin 1500 mg (3 × 500 mg) capsules
1a
B
Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets
1a
C
Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
1b
D
Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets 
selected from Part 1a – fasted
1b
E
Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets 
selected from Part 1a – fed
2
B or C
Treatment B or C: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG 
tablets, respectively
2
F
Treatment F: Gepotidacin 3000 mg (4 × 750 mg) RC or HSWG tablets 
selected from Part 1a
Subjects in Part 2 will receive 2 different doses of the tablet formulation (RC or HSWG) 
selected based on PK, safety, and tolerability data from Part 1a.
 
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Subjects will be given a subject number that will be a unique identifier. Once a subject 
number has been assigned, the number will not be reused even if the subject withdraws 
from the study before receiving gepotidacin.
6.3.
Planned Dose Adjustments
Planned dose adjustments are not allowed during this study.
6.4.
Blinding
This will be an open-label study.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are to be reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized clinic staff may supply or administer study treatment. All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized clinic staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to clinic staff.

A Material Safety Data Sheet or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request 
from GSK.
6.7.
Compliance With Study Treatment Administration
When subjects are dosed at the clinic, they will receive study treatment directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
 
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administered in the clinic will be recorded in the source documents. The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the clinic staff other than the person administering the study treatment. Study 
site personnel will examine each subject’s mouth to ensure that the study treatment was 
ingested.
6.8.
Treatment of Study Treatment Overdose
Gepotidacin will be administered at the clinic, thus limiting the risk of overdose. In the 
unlikely event that an overdose with gepotidacin 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 subject’s clinical 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 subject for AEs/SAEs and laboratory abnormalities until 
gepotidacin can no longer be detected systemically (at least 3 days for gepotidacin).
3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment 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).
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on a clinical evaluation of the subject.
6.9.
Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Standard meals will be provided during the study dosing period at specified times.
Subjects will refrain from consumption of red wine, Seville oranges, grapefruit, or 
grapefruit juice (and/or pummelos, exotic citrus fruits, or grapefruit hybrids) from 7 days 
prior to the first dose of study medication until after the final dose.
 
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Subjects will fast from food and drink (except water) for at least 10 hours before dosing 
on Day 1 of each period. For the fed group of the food effect evaluation in Part 1b, study 
drug will be administered within 30 minutes after the completion of a moderate fat meal.
Fasting requirements may be modified, relaxed, or removed based on emerging safety, 
tolerability, and PK data from Part 1a. If fasting requirements are removed, then Part 1b 
may be conducted as a single-period study with drug administered only under fed 
conditions. In the event that the formulation tested for Part 1b is not tolerated in the 
fasting state, subjects may receive the formulation with a meal after consultation with the 
sponsor and investigator.
6.10.2.
Caffeine, Alcohol, and Tobacco
Subjects will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to the start of dosing until 
collection of the final PK sample. 
During each dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final PK sample.
Use of tobacco products is not allowed from 3 months before Screening until after the 
final Follow-up visit.
6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. Subjects may participate in light recreational activities during 
the study (e.g., watch television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Hormonal contraceptives and/or acetaminophen, at doses of ≤2 grams/day are permitted 
for use. Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor.
All concomitant medication use will be documented on the concomitant medication page 
in the eCRF.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Subjects 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) prior to the first dose of 
study medication until completion of the Follow-up visit, unless in the opinion of the 
investigator and sponsor the medication will not interfere with the study.
 
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Since gepotidacin is known to have some prolongation of QTc, any drugs known to 
increase QTc interval should be avoided when treating an AE.
Due to the potential for acetylcholinesterase inhibition with gepotidacin, the following 
medications are prohibited:

Succinylcholine or other depolarizing muscle relaxants

Acetylcholinesterase inhibitors as required for myasthenia gravis including 
edrophonium, pyridostigmine, neostigmine, etc
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 7), are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table (Table 7).
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety and PK 
assessments, may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which will be approved by the relevant 
GSK study team member and then archived in the study sponsor and clinic study 
files, but this will not constitute a protocol amendment. 

The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the informed consent form.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
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7.1.
Time and Events Table
Table 7
Time and Events Table: Parts 1a, 1b, and 2
Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Part 2 – Pharmacokinetics: Periods 1 and 2
Follow-up
(5 to 
7 days 
post last 
dose)
Day
–1a
Day 1
Day 2
Day 3
Predose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Admission to unit
X
Informed consent
X
Demographics including BMI
X
Full physical examination including 
height and weightb
X
Brief physical examinationb
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECGc
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
Drug/alcohol/cotinine screen
X
X
Serum pregnancy, FSH, and estradiol 
(women)
X
X
X
HIV antibody, HBsAg, and hepatitis C 
antibody screen
X
Safety laboratory testse
X
X
X
X
Study drug administrationf
X
Pharmacokinetic sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for pharmacokinetics 
(Parts 1a and 2 only)g
X
X
X
X
X
X
X
X
X
 
 
 
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Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Part 2 – Pharmacokinetics: Periods 1 and 2
Follow-up
(5 to 
7 days 
post last 
dose)
Day
–1a
Day 1
Day 2
Day 3
Predose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Pharmacogenetic sampleh
========================================================================
AE/SAE Review
X
==================================================================================
X
Concomitant medication review
X
========================================================================
X
Dischargei
X
Outpatient visit
X
X
AE = adverse event, BMI = body mass index, ECG = electrocardiogram, FSH = follicle-stimulating hormone, h = hour, HBsAg = hepatitis B surface antigen, HIV = human 
immunodeficiency virus, SAE = serious adverse event.
a
The Day –1 visit occurs in Period 1 only. Periods 2 (all parts) and 3 (Part 1a only) begin on Day 1.
b
A complete physical examination will include at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal, 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).
c
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured in 
semi-supine position after 5 minutes rest at all other time points during the study
d
Single vital signs will be measured in semi-supine position after 5 minutes rest and will include systolic and diastolic blood pressure, and heart rate. Body temperature and 
respiratory rate will be collected at Screening only.
e
Safety laboratory tests include serum chemistry, hematology, and urinalysis.
f
Subjects will fast from food and drink (except water) for at least 10 hours before study drug administration on Day 1 of each period. For the fed group of the food effect evaluation 
in Part 1b, study drug will be administered within 30 minutes after the completion of a moderate fat meal.
g
Urine collection intervals (Parts 1a and 2 only) for subjects include 0 (predose), 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.
h
For subjects who consent only: collect 1 pharmacogenetic sample after the start of dosing (preferably Day 1). Informed consent for optional pharmacogenetics research must be 
obtained before collecting a sample.
i
For Part 1a, subjects will be discharged from the clinical research unit on Day 3 of Period 3. For Parts 1b and 2, subjects will be discharged on Day 3 of Period 2.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Table 7). Additional time points for safety tests such as vital signs, physical exams, and 
laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.
7.3.1.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

AEs will be collected from the time informed consent is obtained until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Table 7).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
 
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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5.
7.3.1.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
Follow-Up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.3.1.4.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for noninterventional post marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met.
GlaxoSmithKline has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a product under clinical investigation. 
GlaxoSmithKline will comply with country specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC, and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of dosing and until the Follow-up visit.
 
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If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
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.
7.3.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
systolic and diastolic blood pressure, and heart rate. Body temperature and respiratory 
rate will be collected at Screening only.
7.3.5.
Electrocardiogram
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured 
in semi-supine position after 5 minutes rest at all other time points during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 5.4.2 for QTc stopping criteria and additional QTc 
readings that may be necessary.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 8, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Table (Table 7). 
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
 
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Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 8.
Table 8
Protocol-Required Safety Laboratory Assessments
Hematology
Platelet count 
RBC indices:
WBC count with differential:
RBC count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Eosinophils
Basophils
Serum Chemistrya
Blood urea nitrogen
Potassium 
Aspartate aminotransferase
Total and direct bilirubin
Creatinine
Sodium
Alanine aminotransferase
Total protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Creatine kinase
Bicarbonate
Chloride
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
Hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing potential only)
Serum test for human chorionic gonadotropin (as needed in women of childbearing potential)
Alcohol (via urine, blood alcohol, or breathalyzer test), cotinine, and drug screen (via serum, urine, or saliva) to include, 
at a minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines).
Fecal occult blood test and stool cultures as appropriate for gastrointestinal adverse events (Appendix 8)
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; RBC = red blood cell; WBC = white blood cell.
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 5.4.1 and Appendix 3.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation should be repeated until the values return to normal or baseline. If 
such values do not return to normal within a period judged reasonable by the investigator, 
the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for PK analysis of gepotidacin will be collected at the time points 
indicated in the Time and Events Table (Table 7). The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.
For each sample, 3 mL of blood will be drawn via an indwelling catheter and/or direct 
venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. Details of 
PK blood sample processing, storage, and shipping procedures are provided in the SRM.
 
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7.4.2.
Urine Sample Collection
Pharmacokinetic urine samples for the analysis of gepotidacin (Parts 1a and 2 only) will 
be collected at the time points listed in the Time and Events Table (Table 7). The actual 
date and time of each urine sample collection will be recorded. The timing of PK samples 
may be altered and/or PK samples may be obtained at additional time points to ensure 
thorough PK monitoring.
Details of PK urine sample processing, storage, and shipping procedures are provided in 
the SRM.
7.4.3.
Sample Analysis
Plasma and urine analysis will be performed under the control of PTS-DMPK/Scinovo, 
GSK, the details of which will be included in the SRM. Concentrations of gepotidacin 
will be determined in plasma and urine samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM). 
Since plasma protein binding of gepotidacin is low (33%), only total drug concentrations 
will be reported for the PK analysis.
Once the plasma and urine samples have been analyzed for gepotidacin, any remaining 
plasma and urine samples may be analyzed for other compound-related metabolites and 
the results reported under a separate PTS-DMPK/Scinovo, GSK protocol.
7.5.
Genetics
Depending on the clinical study results, exploratory pharmacogenomics analyses may be 
performed to examine the potential relationship between genetic variants and clinical 
endpoints.
The pharmacogenomics samples will be collected according to the Time and Events 
Table (Table 7). Information regarding genetic research is included in Appendix 4.
8.
DATA MANAGEMENT

For this study, subject data will be entered via an eCRF into Oracle Clinical Remote 
Data Capture System. Subject data will be available for viewing through access to the 
Oracle Clinical Remote Data Capture System. Data provided from other sources will 
be received, reconciled, combined, and transferred to GSK at predetermined time 
points.

Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity and quality of the data 
(e.g., removing errors and inconsistencies in the data). Adverse events and 
concomitant medications terms will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and a validated medication dictionary, GSKDrug.
 
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
The eCRFs (including queries and audit trails) will be sent at the end of the study in 
electronic format to GSK to be retained. Each investigator will receive a copy of their 
site specific data in the same format to maintain as the investigator copy. In all cases, 
subject initials will not be collected or transmitted.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
All statistical analyses will be performed by PPD using SAS (SAS Institute Inc., Cary, 
North Carolina, USA), version 9.2 or higher. Pharmacokinetic parameters will be 
calculated using Phoenix WinNonlin (Certara USA Inc., Princeton, New Jersey, USA), 
version 6.2.1 or higher.
Before database lock, a reporting and analysis plan (RAP) will be issued as a separate 
document, providing detailed methods for the analyses outlined below.
Any deviations from the planned analyses will be described in a RAP addendum and 
justified in the final integrated clinical study report.
9.1.
Hypotheses
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the relative bioavailability of the gepotidacin RC and HSWG tablet 
formulations relative to the reference gepotidacin capsule formulation in healthy subjects 
(Part 1a), estimate the effect of food on the tablet formulation selected in Part 1a 
(Part 1b), and to evaluate the pharmacokinetics of the tablet formulation selected in 
Part 1a in Japanese subjects (Part 2).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size is largely based on feasibility, however some justification is provided below.
Part 1a – Relative Bioavailability:
The sample size of 24 PK parameter population subjects will be used based on feasibility 
to address the objectives of Part 1a of the study.
There are no estimates for the coefficient of variation (CV) of HSWG for any PK 
parameters. An assumed CV of 27.5% for a PK parameter implies that the sample size of 
24 PK parameter evaluable subjects will provide at least 80% power to demonstrate 
equivalence of the PK parameter. Equivalence is demonstrated when 90% confidence 
interval (CI) for the ratio of Test:Reference of the PK parameter will be within 0.8 to 
1.25 following log transformation.
Two different test formulations are being used in this study. No adjustment for 
pre-planned multiple comparisons are made.
 
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The total sample size of 27 subjects (9 subjects in 3 sequences) will be randomized to 
ensure 24 PK parameter evaluable subjects with PK parameter estimates from the 
reference and at least one test formulation.
Part 1b – Food Effect:
A sample size of 16 subjects will be randomized (8 per sequence) based on feasibility to 
address the objectives of Part 1b of the study.
This sample size will ensure equivalence (as specified in sample size assumption in 
Part 1a) with 80% power with an assumed CV of 22%.
Part 2 – Pharmacokinetics:
A sample size of approximately 10 subjects will be used in Part 2 based on feasibility to 
address the objectives of Part 2 of the study.
9.2.2.
Sample Size Re-Estimation or Adjustment
Not applicable.
9.3.
Data Analysis Considerations
In general, descriptive summaries will include number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum for continuous variables; and percent 
for categorical variables. Summaries will present data by group, and where appropriate, 
by assessment time.
9.3.1.
Analysis Populations
The Safety Population will consist of all subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.
The PK Population will consist of all subjects who received at least 1 dose of 
gepotidacin and have evaluable PK data for gepotidacin. 
The PK Parameter Population will consist of all subjects in the PK Population, for 
whom valid and evaluable PK parameters were derived. This population will be used in 
the assessment and characterization of PK parameters.
9.3.2.
Interim Analysis
No formal interim analyses are planned for this study. However, all preliminary safety, 
tolerability, and available PK data will be reviewed by the study team after completing 
Part 1a of the study to select the formulation for Part 1b, and Part 2, and also to determine 
if the effect of food on the selected formulation needs to be studied (Part 1b). At the time 
of finalization of the amendment, Part 1b is no longer needed based on data from Part 1a. 
The team will review unblinded data from Part 1a of this open-label study to select the 
appropriate formulation.
 
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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Pharmacokinetic Analyses
Plasma and urine concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods. Based on the individual concentration time data the 
following parameters will be estimated:
Plasma:
AUC(0-)
Area under the concentration-time curve (AUC) from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
the last quantifiable concentration
Cmax
Maximum observed concentration
Frel
Relative bioavailability of drug, calculated as:
[AUC(0-)tablet]/[AUC(0-)capsule] (Part 1a only)
t1/2
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled matrix
Tmax
Time to first occurrence of Cmax
Urine (Parts 1a and 2 only):
Ae total
Total unchanged drug (total amount of drug excreted in urine), calculated 
by adding all the fractions of drug collected over all the allotted time 
intervals
Ae(t1-t2)
Amount of drug excreted in urine in time intervals of predose, 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 for subjects
AUC(0-12)
Area under the concentration-time curve from time 0 (predose) to 12 hours 
after dosing
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 24 hours 
after dosing
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 48 hours 
after dosing
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)
Plasma (all subjects) and urine (Parts 1a and 2 only) concentrations of gepotidacin and 
the associated PK parameters will be listed, and summary statistics (n, mean, median, SD, 
minimum, maximum, and CV) will be presented by day and treatment. Mean and 
 
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individual plasma concentration versus time profiles will be presented graphically on 
linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed-effect terms for sequence, period, and regimen, and treating subject within 
sequence as a random effect. Point estimates and 90% CIs for the differences of interest
(RC tablets and HSWG tablets versus capsules) will be constructed using the residual 
variance. Point and interval estimates will then be exponentially back-transformed to 
construct point and 90% CI estimates for the ratios of interest (RC tablets and HSWG
tablets versus capsules).
Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
For the bioavailability assessment, Tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
Detailed descriptions of the analyses in this study will be presented in the RAP.
Dose Proportionality (Part 2 only)
Dose proportionality of AUC(0-∞) and Cmax will be explored based on dose normalized 
parameters (log transformed parameters) using reference dose.  The lower dose group 
(1500 mg) would be chosen as the reference dose.  
The dose proportionality of AUC(0-∞) and Cmax will be summarized by descriptive 
statistics (including 90% confidence interval).
9.4.2.
Secondary Analyses
Safety Analyses
The following safety evaluations will be performed:

Monitoring for AEs
 
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
Changes in routine clinical laboratory parameters including serum chemistry, 
hematology, and urinalysis

Clinically significant changes in vital sign measurements or physical examination 
findings 

Changes in 12-lead ECG measurements
Safety endpoints will include AEs, clinical laboratory results (serum chemistry [including 
liver function parameters], hematology, and urinalysis), vital sign measurements (systolic 
and diastolic blood pressure and heart rate), 12-lead ECG measurements, and physical 
examination findings.
All safety data will be presented in the data listings. Subject demographics, medical 
history, and prior and concomitant medications will be summarized by group using 
descriptive statistics. For continuous variables, these summaries will include sample size, 
mean, median, SD, minimum, and maximum.
For categorical variables, the summaries will include frequencies and corresponding 
percentages. No inferential hypothesis testing will be performed on the safety variables.
Adverse events will be coded using the MedDRA classification system. 
Treatment-emergent AEs will be defined as any AEs, regardless of relationship to 
investigational product, that occur after the dose of investigational product. The 
treatment-emergent AEs will be summarized by group at AE onset for the overall number 
of AEs and the percentage of subjects who experience them. The total number of AEs 
will be summarized by group and overall. The AEs will be further summarized by 
severity and relationship to the study drug. If relationship information is missing, the AE 
will be considered treatment related. Listings for the subsets of SAEs and 
treatment-related SAEs will be provided. The number of SAEs will be summarized. The 
incidence of AEs will also be summarized by system organ class and preferred term.
Clinical laboratory results, vital sign measurements (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG results will be summarized by change from baseline. 
Clinical laboratory values that are outside of the reference ranges will be flagged and 
evaluated for clinical significance by the investigator. Any ECG abnormalities, including 
but not limited to a QTc >500 msec or increase in QTc from the baseline ECG of 
≥60 msec, will be summarized by group.
Detailed descriptions of the analyses in this study will be presented in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
 
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10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.

Obtaining signed informed consent.

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to the IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IRB/IEC, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP and GSK/PPD 
procedures, GSK/PPD monitors will contact the clinic prior to the start of the 
study to review the following with the clinic staff: the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK/PPD requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
 
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GSK/PPD will monitor the study and clinic activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees 
to allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the clinic records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit, or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct 
access to all relevant documents and to allocate their time and the time of their 
staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any 
findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK/PPD 
monitor will conduct clinic closure activities with the investigator or clinic staff, 
as appropriate, in accordance with applicable regulations including GCP, and 
GSK/PPD standard operating procedures.

GSK/PPD reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical 
issues or severe noncompliance. For multi-center studies, this can occur at 1 or 
more or at all clinics.

If GSK/PPD determines such action is needed, GSK/PPD will discuss the reasons 
for taking such action with the investigator or the head of the medical institution 
(where applicable). When feasible, GSK/PPD will provide advance notification to 
the investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, 
GSK/PPD will promptly inform all investigators, heads of the medical institutions 
(where applicable) and/or institution(s) conducting the study. GSK/PPD will also 
promptly inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
 
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10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all clinic study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.

The records must be maintained to allow easy and timely retrieval when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with an assessment of the facility, supporting systems, and relevant 
clinic staff.

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including regenerating a hard copy, if required. Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK/PPD will inform the investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to that clinic for the 
study, as dictated by any institutional requirements or local laws or regulations, 
GSK/PPD standards/procedures, and/or institutional requirements.

The investigator must notify GSK/PPD of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the clinic.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
 
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11.
REFERENCES
Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA 
topoisomerase inhibition by a new class of antibacterial agents. Nature. 
2010;466(7309):935-40.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in age-related macular 
degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a 
meta-analysis. PloS ONE. 2012; 7: e42464.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in 
NDAs or INDs — General Considerations. March 2014. [29 screens]. Available from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm389370.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. July 2009. [28 screens]. Available from: 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Drug Evaluation and Research 
(US). Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence 
Studies. December 2002. [12 screens.] Available from: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126833.pdf
GlaxoSmithKline Document Number 2013N176846_01 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. 
2014.
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 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.
 
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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 CM2010/00033/04. GSK2140944 Investigator’s 
Brochure. 2016.
GlaxoSmithKline Document Number 2013N174977. Benefit Risk Management Plan 
Version 3. 2015.
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th ed. Atlanta, Georgia: Ardent Media, Inc., 2011: 
50. Table 3-2.
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
M3 (R2); June 2009. [31 screens]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplina
ry/M3_R2/Step4/M3_R2__Guideline.pdf
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et. al. 
Pharmacokinetics of acetaminophen-adducts in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos 2009; 37(8):1779-84.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
adverse event
Ae total
total unchanged drug
Ae (t1-t2)
amount of drug excreted in urine in a time interval
ALT
alanine aminotransferase 
AUC
area under the plasma concentration-time curve
AUC(0-)
area under the concentration-time curve from time 0 
(predose) extrapolated to infinite time
AUC(0-t)
area under the concentration-time curve from time 0 
(predose) to time of the last quantifiable concentration
BMI
body mass index
CI
confidence interval
CLr
renal clearance of drug
Cmax
maximum observed concentration
CV
coefficient of variation
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fe%
percentage of the given dose of drug excreted in urine
Frel
relative bioavailability of drug
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HSWG
high shear wet granulation
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
independent ethics committee
IRB
institutional review board
MedDRA
Medical Dictionary for Regulatory Activities
mm Hg
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 Bazett’s formula
 
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QTcF
corrected QT interval using Fridericia’s formula
RAP
reporting and analysis plan
RC
related compound
SAE
serious adverse event
SD
standard deviation
SRM
Study Reference Manual
t1/2
terminal phase half-life
tlag
lag time before observation of drug concentrations in 
sampled matrix
Tmax
time to first occurrence of Cmax
ULN
upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
GSKDrug
MedDRA
Phoenix WinNonlin
SAS
 
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12.2.
Appendix 2: Liver Chemistry Stopping Criteria
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow-Up Assessments section can be found in 
Appendix 3.
 
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12.3.
Appendix 3: Liver Safety Required Actions and Follow-Up 
Assessments
Phase I liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA guidance, “Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation,” [DHHS, 2009].
Phase I Liver Chemistry Stopping Criteria and Required Follow-up Assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubina,b 2 × ULN (>35% direct bilirubin) or INR >1.5, 
report as an SAE.
See additional actions and follow-up assessments listed below.
Required Actions and Follow-up Assessments Following Liver Stopping Event
Actions
Follow-Up Assessments

Report the event to GSK within 24 hours

Complete the Liver Event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb

Perform liver event follow-up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Viral hepatitis serologyc

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total bilirubin 
2 × ULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
 
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Liver Chemistry Stopping Criteria – Liver Stopping Event

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours

Monitor subjects weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline
globulins).

Serum acetaminophen adduct 
high-performance liquid chromatography 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic case 
report form; GSK = GlaxoSmithKline; IgM = Immunoglobulin M; INR = international normalized ratio; 
SAE = serious adverse event; ULN = upper limit of normal.
a
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3 × ULN and bilirubin 2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
c
Includes: hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (IgM); hepatitis C 
RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); hepatitis E IgM antibody.
 
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12.4.
Appendix 4: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to interindividual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration are reported 
to account for much of the risk for the condition [Gorin, 2012] with certain variants 
reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of 
medicines. Additionally, genetic variability may impact the pharmacokinetics 
(absorption, distribution, metabolism, and elimination), or pharmacodynamics 
(relationship between concentration and pharmacologic effects or the time course of 
pharmacologic effects) of a specific medicine, and/or clinical outcomes (efficacy and/or 
safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including gepotidacin or any concomitant medicines
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
 
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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6-mL blood sample will be taken for DNA extraction. A blood sample is collected 
at the baseline visit, after the subject has provided informed consent for genetic 
research. Instructions for collection and shipping of the genetic sample are described 
in the laboratory manual. The DNA from the blood sample may undergo quality 
control analyses to confirm the integrity of the sample. If there are concerns regarding 
the quality of the sample, then the sample may be destroyed. The blood sample is 
taken on a single occasion unless a duplicate sample is required due to an inability to 
utilize the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to the 
subject by the investigator or clinic staff. Coded samples do not carry personal identifiers 
(such as a name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers), will only use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal From Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research, in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the clinic study records.
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will continue to 
be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance a sample destruction form will not be available to 
include in the clinic files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately, and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that,
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient 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 disability/incapacity
NOTE:

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 or prevent everyday 
life functions but do not constitute a substantial disruption
e.
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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3 × ULN and total bilirubin* 2 × ULN (>35% direct), or

ALT 3 × ULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3 × ULN 
and total bilirubin 2 × ULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.5.3.
Recording of Adverse Events and Serious Adverse Events
Adverse Events and Serious Adverse Event 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
 
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12.5.4.
Evaluating Adverse Events and Serious Adverse Events
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 
Diseases Division of Microbiology and Infectious Diseases (DMID) criteria for toxicity 
assessment (Appendix 6).
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE (Section 12.5.2).
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts, evidence, 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of Adverse Events and Serious Adverse Events

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
 
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
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any postmortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.5.
Reporting of Serious Adverse Events to GSK
Serious adverse event reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the clinic will use 
the paper SAE data collection tool and fax it to the medical monitor or the SAE 
coordinator.

The clinic will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given clinic, the electronic data collection tool 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data.

If a clinic receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the clinic can report this information on a paper SAE form or to the 
medical monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.6.
Appendix 6: Division of Microbiology and Infectious Disease 
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 AIDs and modified to better meet the needs of 
participants in DMID trials.

For parameters not included in the following Toxicity Tables, 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 mg/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
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated partial thromboplastin
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.
 
 
 
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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to 135 mEq/L
123 to 129 mEq/L
116 to 122 mEq/L
<116 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypernatremia
146 to 150 mEq/L
151 to 157 mEq/L
158 to 165 mEq/L
>165 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypokalemia
3.0 to 3.4 mEq/L
2.5 to 2.9 mEq/L
2.0 to 2.4 mEq/L or intensive 
replacement therapy of 
hospitalization required
<2.0 mEq/L or abnormal potassium with
paresis, ileus, or life-threatening arrhythmia
Hyperkalemia
5.6 to 6.0 mEq/L
6.1 to 6.5 mEq/L
6.6 to 7.0 mEq/L
>7.0 mEq/L or abnormal potassium with
life-threatening arrhythmia
Hypoglycemia
55 to 64 mg/dL
40 to 54 mg/dL
30 to 39 mg/dL
<30 mg/dL or abnormal glucose with mental 
status changes or coma
Hyperglycemia
(nonfasting and no prior 
diabetes)
116 to 160 mg/dL
161 to 250 mg/dL
251 to 500 mg/dL
>500 mg/dL or abnormal glucose with
ketoacidosis or seizures
Hypocalcemia
(corrected for albumin)
8.4 to 7.8 mg/dL
7.7 to 7.0 mg/dL
6.9 to 6.1 mg/dL
<6.1 mg/dL or abnormal calcium with
life-threatening arrhythmia or tetany
Hypercalcemia
(corrected for albumin)
10.6 to 11.5 mg/dL
11.6 to 12.5 mg/dL
12.6 to 13.5 mg/dL
>13.5 mg/dL or abnormal calcium with
life-threatening arrhythmia
Hypomagnesemia
1.4 to 1.2 mEq/L
1.1 to 0.9 mEq/L
0.8 to 0.6 mEq/L
<0.6 mEq/L or abnormal magnesium with
life-threatening arrhythmia
Hypophosphatemia
2.0 to 2.4 mg/dL
1.5 to 1.9 mg/dL or 
replacement Rx required
1.0 to 1.4 mg/dL
intensive therapy or hospitalization 
required
<1.0 mg/dL or abnormal phosphate with
life-threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any increase in 
other liver function test)
1.1 to <1.25 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.
 
 
 
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase 
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
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.
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or 
200 mg to 1 gm loss/day
2 to 3+ or
1 to 2 gm loss/day
4+ or
2 to 3.5 gm loss/day
Nephrotic syndrome or
>3.5 gm loss/day
Hematuria
Microscopic only
<10 RBC/HPF
Gross, no clots
>10 RBC/HPF
Gross, with or without clots,
or red blood cells casts
Obstructive or 
required transfusion
HPF = high-powered field; RBC = red blood cells.
 
 
 
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm
N/A
Asymptomatic, transient signs, no 
Rx required
Recurrent/persistent; symptomatic 
Rx required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension
Transient increase >20 mm Hg;
no treatment 
Recurrent, chronic increase 
>20 mm Hg;
treatment required 
Acute treatment required; 
outpatient treatment or 
hospitalization possible 
End organ damage or 
hospitalization required 
Hypotension
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mmHg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, blood loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
BP = blood pressure; EKG = electrocardiogram; IV = intravenous; mm Hg = millimeters of mercury; N/A = not applicable; Rx = therapy.
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment 
responsive
Paroxysmal cough; uncontrolled 
with treatment
N/A
Bronchospasm, acute
Transient; no treatment; FEV1 70 
to 80% of peak flow
Requires treatment; normalizes 
with bronchodilator; FEV1 50 to 
70% of peak flow
No normalization with 
bronchodilator; FEV1 25 to 50% of 
peak flow; or retractions present
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen 
therapy
N/A = not applicable; FEV1 = forced expiratory volume in 1 second.
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; maintains 
reasonable intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV 
fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or 
needing IV fluids
Physiologic consequences 
requiring hospitalization or 
requiring parenteral nutrition
Constipation
Requiring stool softener or dietary 
modification
Requiring laxatives
Obstipation requiring manual 
evacuation or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 4 loose 
stools/day or mild diarrhea lasting 
<1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week
>7 loose stools/day or bloody 
diarrhea; or orthostatic 
hypotension or electrolyte 
imbalance or >2L IV fluids 
required
Hypotensive shock or physiologic 
consequences requiring 
hospitalization
Oral discomfort/Dysphagia
Mild discomfort; no difficulty 
swallowing
Some limits on eating/drinking
Eating/talking very limited; unable 
to swallow solid foods
Unable to drink fluids; requires IV 
fluids
IV = intravenous.
 
 
 
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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
 
 
 
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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia 
(joint pain)
Mild pain not interfering with function
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL
Severe paid; pain and/or analgesics 
interfering with ADL
Disabling pain
Arthritis
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL
Severe pain with inflammation, erythema 
or joint swelling, and interfering with ADL
Permanent and/or 
disabling joint 
destruction
Myalgia
Myalgia with no limitation of activity
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity
Severe muscle tenderness with marked 
impairment of activity
Frank myonecrosis
ADL = activities of daily living.
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
Erythema; pruritus
Diffuse, maculo papular rash, dry 
desquamation
Vesiculation or moist 
desquamation or ulceration
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery
Induration
<15 mm
15 to 30 mm
>30 mm
N/A
Erythema
<15 mm
15 to 30 mm
>30 mm
N/A
Edema
<15 mm
15 to 30 mm
>30 mm
N/A
Rash at injection site
<15 mm
15 to 30 mm
>30 mm
N/A
Pruritus
Slight itching at injection site
Moderate itching at injection extremity
Itching over entire body
N/A
N/A = not applicable.
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 103 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25 to 50%; 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self
 
 
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
and Collection of Pregnancy Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential
The list does not apply to females of reproductive potential with same sex partners or for 
subjects who are and will continue to be abstinent from penile-vaginal intercourse on a 
long term and persistent basis, when this is their preferred and usual lifestyle. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the clinic 
personnel’s review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
The GSK definition is based on the definition provided by the ICH 
[ICH, M3 (R2), 2009].
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child-bearing potential must comply with the 
following contraception requirements from 30 days prior to the first dose until 
completion of the Follow-up visit.
8.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
9.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant
 
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
Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject’s pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to 
GSK as described in Appendix 5. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating:

Will be withdrawn from the study.

The investigator will attempt to collect pregnancy information on any female 
partner of a male study subject who becomes pregnant while participating in this 
study. This applies only to subjects who are randomized to receive study 
medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy.
 
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
The partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
 
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12.8.
Appendix 8: Follow-Up for Gastrointestinal Findings
Subjects who experience diarrhea or enteritis should be evaluated with additional fecal 
occult blood tests and stool cultures as deemed appropriate by the investigator. Any 
subject with a positive fecal occult blood test should be referred to a gastroenterologist 
for further evaluation at the discretion of the investigator.
Subjects who experience an AE of diarrhea or enteritis should have additional fecal 
occult blood testing, as well as a routine stool culture performed, which may include the 
recovery of pathogenic bacteria such as Salmonella, Shigella, Campylobacter, Yersinia, 
Vibrio, Staphylococcus aureus, Escherichia coli 0157, and enterohemorrhagic 
Escherichia coli.
In addition, if the subject meets the clinical criteria outlined in Appendix 9, Clostridium 
difficile toxin detection should be conducted.
Note: Additional testing is at the discretion of the investigator if it is believed the 
GI signs/symptoms are due to cholinergic effects and/or if the GI signs/symptoms occur 
within 24 hours of the infusion.
 
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12.9.
Appendix 9: Clostridium Difficile Testing Procedure and 
Algorithm
 
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12.10.
Appendix 10: Country-Specific Requirements
No country-specific requirements exist.
 
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12.11.
Appendix 11: Protocol Changes
Protocol Amendment 1
Where the Amendment Applies
To the site participating in Part 2 of BTZ117351
Summary of Amendment Changes With Rationale
The Chinese cohort will be removed from Part 2 of this study since PK data obtained 
from Chinese subjects living abroad would not satisfy regulatory requirements in China. 
Japanese subjects in Part 2 will receive a single 1500 mg oral dose followed by a single 
3000 mg oral dose of gepotidacin selected from Part 1a in a fixed-sequence design. The 
inclusion of a 3000-mg dose will be to assess the PK, safety, and tolerability of a higher 
dose that is intended for future Phase III studies. Blood and urine samples (Part 2 only) 
will also be collected for PK analysis of gepotidacin concentrations in Japanese subjects.
Minor formatting and administrative changes are also made for clarity.
 
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GlaxoSmithKline group of companies
BTZ117351
1
TITLE PAGE
Division: Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase I, Multi-Center, Open-Label, Single-Dose, 2-Part Study 
to Evaluate the Relative Bioavailability of Three Formulations in 
Healthy Subjects, Food Effect on Tablet Formulation in Healthy 
Subjects, and Pharmacokinetics of Gepotidacin (GSK2140944)
in Japanese and Chinese Subjects
Compound Number:
GSK2140944
Development Phase
I
Effective Date:
12-JUL-2016
Authors:
GSK Authors:
 (Clinical Pharmacology Modeling and Simulation), 
 (ID, Medicines Discovery and Development), 
 (Clinical 
Statistics), and 
 (Projects Clinical Platforms and Sciences).
PPD Authors: 
 (Pharmacokineticist), 
 (Biostatistician), and 
(Medical Writer)
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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PPD

 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone Number
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary Medical 
Monitor and 
SAE Contact 
Information
 MD
Safety Hotline:
PPD
929 N Front St
Wilmington, NC 
28401
Secondary 
Medical Monitor
MD
Safety Hotline:
PPD
7551 Metro 
Center
Austin, Texas 
78744
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address: 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089
Collegeville, PA 19426-0989
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): IND 111885
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study.
Investigator Name: 
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351 .................................................8
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVES AND ENDPOINTS...........................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................17
4.3.
Type and Number of Subjects.....................................................................18
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................19
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................23
4.6.3.
Overall Benefit:Risk Conclusion...................................................23
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............23
5.1.
Inclusion Criteria.........................................................................................23
5.2.
Exclusion Criteria........................................................................................25
5.3.
Screening/Baseline/Run-in Failures............................................................27
5.4.
Withdrawal/Stopping Criteria.......................................................................27
5.4.1.
Liver Chemistry Stopping Criteria ................................................27
5.4.2.
QTc Stopping Criteria ..................................................................28
5.4.3.
Gastrointestinal Stopping Criteria ................................................28
5.4.4.
Rash/Hypersensitivity Stopping Criteria .......................................29
5.5.
Subject and Study Completion....................................................................29
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................30
6.3.
Planned Dose Adjustments.........................................................................30
6.4.
Blinding.......................................................................................................30
6.5.
Packaging and Labeling..............................................................................31
6.6.
Preparation/Handling/Storage/Accountability..............................................31
6.7.
Compliance with Study Treatment Administration.......................................31
6.8.
Treatment of Study Treatment Overdose....................................................31
6.9.
Treatment after the End of the Study ..........................................................32
6.10.
Lifestyle and/or Dietary Restrictions............................................................32
6.10.1.
Meals and Dietary Restrictions ....................................................32
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................33
6.10.3.
Activity .........................................................................................33
6.11.
Concomitant Medications and Non-Drug Therapies....................................33
6.11.1.
Permitted Medications and Non-Drug Therapies..........................33
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
 
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7.1.
Time and Events Table...............................................................................35
7.2.
Screening and Critical Baseline Assessments ............................................37
7.3.
Safety .........................................................................................................37
7.3.1.
Adverse Events and Serious Adverse Events..............................37
7.3.1.1.
Time Period and Frequency for collecting 
Adverse Event and Serious Adverse Event 
information .................................................................37
7.3.1.2.
Method of Detecting Adverse Events and 
Serious Adverse Events .............................................38
7.3.1.3.
Follow-up of Adverse Events and Serious 
Adverse Events ..........................................................38
7.3.1.4.
Regulatory Reporting Requirements for 
Serious Adverse Events .............................................38
7.3.2.
Pregnancy ...................................................................................38
7.3.3.
Physical Exams ...........................................................................39
7.3.4.
Vital Signs....................................................................................39
7.3.5.
Electrocardiogram........................................................................39
7.3.6.
Clinical Safety Laboratory Assessments ......................................39
7.4.
Pharmacokinetics .......................................................................................40
7.4.1.
Blood Sample Collection..............................................................40
7.4.2.
Urine Sample Collection ..............................................................41
7.4.3.
Sample Analysis ..........................................................................41
7.5.
Genetics .....................................................................................................41
8.
DATA MANAGEMENT ...........................................................................................41
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................42
9.1.
Hypotheses.................................................................................................42
9.2.
Sample Size Considerations.......................................................................42
9.2.1.
Sample Size Assumptions ...........................................................42
9.2.2.
Sample Size Re-estimation or Adjustment...................................43
9.3.
Data Analysis Considerations .....................................................................43
9.3.1.
Analysis Populations....................................................................43
9.3.2.
Interim Analysis ...........................................................................43
9.4.
Key Elements of Analysis Plan ...................................................................44
9.4.1.
Primary Analyses.........................................................................44
9.4.2.
Secondary Analyses ....................................................................45
10. STUDY GOVERNANCE CONSIDERATIONS........................................................46
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............46
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................46
10.3.
Quality Control (Study Monitoring) ..............................................................47
10.4.
Quality Assurance.......................................................................................48
10.5.
Study and Site Closure ...............................................................................48
10.6.
Records Retention......................................................................................48
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................52
 
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12.1.
Appendix 1 – Abbreviations and Trademarks..............................................52
12.2.
Appendix 2: Liver Chemistry Stopping Criteria............................................54
12.3.
Appendix 3: Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................55
12.4.
Appendix 4 - Genetic Research ..................................................................57
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................60
12.5.1.
Definition of Adverse Events........................................................60
12.5.2.
Definition of Serious Adverse Events...........................................61
12.5.3.
Recording of Adverse Events and Serious Adverse Events .........62
12.5.4.
Evaluating Adverse Events and Serious Adverse Events.............63
12.5.5.
Reporting of Serious Adverse Events to GSK..............................64
12.6.
Appendix 6: Division of Microbiology and Infectious Disease Adult 
Toxicity Tables for Adverse Event Assessment...........................................65
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential and Collection of 
Pregnancy Information................................................................................73
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential.........................73
12.7.2.
Collection of Pregnancy Information ............................................74
12.8.
Appendix 8 – Follow-up for Gastrointestinal Findings .................................76
12.9.
Appendix 9: Clostridium Difficile Testing Procedure and Algorithm .............77
12.10. Appendix 10 - Country Specific Requirements............................................78
 
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1.
PROTOCOL SYNOPSIS FOR STUDY BTZ117351
Rationale
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet 
granulation [HSWG]) compared to the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK) and safety data in Part 1a, 
a decision will be made whether to proceed with Parts 1b and 2.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349 (see 
GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Part 2a will evaluate the pharmacokinetics of the tablet formulation selected in Part 1a in 
Japanese subjects. Part 2b will evaluate the pharmacokinetics of the tablet formulation 
selected in Part 1a in Chinese subjects. Testing gepotidacin in these specific populations 
will provide PK data and enable future pivotal Phase III studies in the respective 
countries.
 
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Objectives/Endpoints
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared to 
the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from Part 1
Part 2a

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Japanese subjects
Part 2b

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Chinese subjects
Part 1a

Plasma gepotidacin AUC(0-), 
AUC(0-t), Frel, Cmax, tmax, tlag and 
t1/2, as data permit.

Urine endpoints include Ae total, 
Ae(t1-t2), AUC(0-12), AUC(0-24), 
AUC(0-48), fe%, and CLr of 
gepotidacin, as data permit.
Parts 1b, 2a, and 2b

Plasma gepotidacin AUC(0-), 
AUC(0-t), Cmax, tmax, tlag, and t1/2, 
as data permit.
Secondary
Part 1a

To assess the safety and tolerability of a single 1500-mg 
dose of gepotidacin tablet formulations (RC and HSWG; 
2 × 750 mg) compared to the reference capsule 
formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 when administered with a moderate 
fat meal
Part 2a

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Japanese subjects
Part 2b

To assess the safety and tolerability of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Chinese subjects
Parts 1 and 2

Clinical safety data from adverse 
events (AEs), clinical laboratory tests, 
vital signs (systolic and diastolic blood 
pressure and heart rate), and 12-lead 
electrocardiogram (ECG) readings.
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related compound.
Overall Design
This is a Phase I, multi-center, open-label, single-dose, 2-part study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared to the reference capsule formulation under fasted conditions. 
Based upon safety and PK data obtained from Part 1a, a decision will be made whether to 
use the free base RC or HSWG tablet formulation for Parts 1b and 2. Part 1b will 
evaluate the bioavailability of the selected tablet formulation under fasted and fed 
conditions. Part 2 will evaluate pharmacokinetics in Japanese subjects (Part 2a) under 
 
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fasted conditions, and pharmacokinetics in Chinese subjects (Part 2b) under fasted 
conditions.
Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a 
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC 
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA).
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations. Blood and urine samples will be 
collected up to approximately 48 hours after dosing.
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
formulation (selected in Part 1a). If both formulations of the free base tablet exhibit 
similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349 will be 
used to guide dosing recommendations with food.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations. Blood samples will be collected up to 
approximately 48 hours after dosing.
Parts 2a and 2b: Pharmacokinetics in Japanese and Chinese Subjects
Parts 2a and 2b will evaluate the pharmacokinetics of a single dose of 1500 mg 
gepotidacin tablet formulation (RC or HSWG tablet) in a cohort of Japanese (Part 2a) and 
Chinese subjects (Part 2b) under fasted conditions. A decision will be made whether to 
use the RC tablet formulation or the HSWG tablet formulation based upon the safety and 
PK data obtained from Part 1a.
Subjects will receive study drug on Day 1 and blood samples will be collected for PK 
analysis of gepotidacin concentrations. Blood samples will be collected up to 
approximately 48 hours after dosing.
 
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Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets

Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately 
44 days.

Based on PK, safety, and tolerability data from Part 1a, subjects for Parts 1b (food 
effect), 2a (Japanese subjects), and 2b (Chinese subjects) may be enrolled.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Parts 2a and 2b: Pharmacokinetics in Japanese and Chinese Subjects
On Day 1, subjects will receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet 
(RC or HSWG) selected from Part 1a. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 after all scheduled PK and safety assessments have been 
completed, and will return to the clinic for a Follow-up visit approximately 5 to 7 days 
after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 38 days.
 
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Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK 
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Parts 2a and 2b, 12 Japanese and 12 Chinese subjects will be 
enrolled, respectively.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
Analysis
Plasma concentrations of gepotidacin will be analyzed (as data permit) by 
noncompartmental PK analysis to determine the following PK metrics: area under the 
plasma concentration-time curve (AUC) from time 0 extrapolated to infinite time
[AUC(0-)], AUC from time 0 to time of last quantifiable concentration [AUC(0-t)], 
maximum observed concentration (Cmax), relative bioavailability of drug (Frel; Part 1a
only), terminal phase half-life (t1/2), lag time before observation of drug concentrations 
in sampled matrix (tlag), and time to first occurrence of Cmax (Tmax).
Urine (Part 1a only) concentrations of gepotidacin will be analyzed (as data permit) by 
noncompartmental PK analysis to determine the following PK metrics: total unchanged 
drug (Ae total), amount of drug excreted in urine [Ae(t1-t2)], AUC from time 0 to 
12 hours after dosing [AUC(0-12)], AUC from time 0 to 24 hours after dosing 
[AUC(0-24)], AUC from time 0 to 48 hours after dosing [AUC(0-48)], percentage of the 
given dose of drug excreted in urine (fe%), and renal clearance (CLr). 
Plasma and urine (Part 1a only) concentrations of gepotidacin and the associated PK 
parameters will be listed, and summary statistics (n, mean, median, standard deviation, 
minimum, maximum, and coefficient of variation) will be presented by day and 
treatment. Mean and individual plasma concentration versus time profiles will be 
presented graphically on linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed effect terms for sequence, period, and regimen, and treating subject within sequence 
as a random effect. Point estimates and 90% confidence intervals (CIs) for the differences 
of interest (RC tablets and HSWG tablets versus capsules) will be constructed using the 
residual variance. Point and interval estimates will then be exponentially 
back-transformed to construct point and 90% CI estimates for the ratios of interest (RC 
tablets and HSWG tablets versus capsules).
 
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Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
For the bioavailability assessment, tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
Safety endpoints will include monitoring adverse events, clinical laboratory results, vital 
sign measurements, 12-lead electrocardiogram measurements, and physical examination 
findings.
 
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2.
INTRODUCTION
Gepotidacin is a novel type II triazaacenaphthylene bacterial topoisomerase inhibitor, 
which inhibits bacterial DNA replication and has in vitro activity against susceptible and 
drug resistant pathogens associated with a range of conventional and biothreat infections.
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 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 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
Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability 
of the 2 free base tablet formulations (related compound [RC] and high shear wet 
granulation [HSWG]) compared to the reference capsule formulation. This will guide 
which gepotidacin formulation will be used for future pivotal studies and 
commercialization. Following review of pharmacokinetic (PK) and safety data in Part 1a, 
a decision will be made whether to proceed with Parts 1b and 2.
Part 1b will assess the effect of food on the pharmacokinetics of the tablet formulation 
selected from Part 1a. If the relative bioavailability of the tablet formulations are similar 
to the reference capsule formulation, Part 1b may not be needed, and the results of 
moderate fat meal evaluated in the RC mesylate tablet from Study BTZ117349
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349) will be 
used to guide dosing recommendations with food.
Parts 2a will evaluate the pharmacokinetics of the tablet formulation selected in Part 1a in 
Japanese subjects. Part 2b will evaluate the pharmacokinetics of the tablet formulation 
selected in Part 1a in Chinese subjects. Testing gepotidacin in these specific populations 
will provide PK data and enable future pivotal Phase III studies in the respective 
countries.
2.2.
Brief Background
Gepotidacin has been administered to healthy subjects in 7 Phase I studies and 2 Phase II 
studies. Gepotidacin has demonstrated clinical efficacy in a Phase II study for acute 
bacterial skin and skin structure infections, and is currently being evaluated in a Phase II 
study for gonorrhea. Additional details can be found in the Investigator’s Brochure (IB; 
GlaxoSmithKline Document Number CM2010/00033/03) and supplement to the IB 
(GlaxoSmithKline Document Number 2016N275883_00).
 
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Part 1a

To evaluate the relative bioavailability of a single 
1500-mg dose of gepotidacin free base tablet 
formulations (RC and HSWG; 2 × 750 mg) compared to 
the reference capsule formulation (3 × 500 mg)
Part 1b

To evaluate the effect of a moderate fat meal on the 
bioavailability of a single 1500-mg (2 × 750 mg) dose of 
gepotidacin tablets (RC or HSWG) selected from Part 1
Part 2a

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Japanese subjects
Part 2b

To evaluate the pharmacokinetics of a single 1500-mg 
(2 × 750 mg) dose of gepotidacin tablets (RC or HSWG) 
selected from Part 1 in Chinese subjects
Part 1a

Plasma gepotidacin AUC(0-), 
AUC(0-t), Frel, Cmax, tmax, 
tlag and t1/2, as data permit.

Urine endpoints include Ae 
total, Ae(t1-t2), AUC(0-12), 
AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data 
permit.
Parts 1b, 2a, and 2b

Plasma gepotidacin AUC(0-), 
AUC(0-t), Cmax, tmax, tlag, and 
t1/2, as data permit.
Secondary
Part 1a

To assess the safety and tolerability of a single 
1500-mg dose of gepotidacin tablet formulations (RC 
and HSWG; 2 × 750 mg) compared to the reference
capsule formulation (3 × 500 mg)
Part 1b

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1 when administered with 
a moderate fat meal
Part 2a

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1 in Japanese subjects
Part 2b

To assess the safety and tolerability of a single 
1500-mg (2 × 750 mg) dose of gepotidacin tablets (RC 
or HSWG) selected from Part 1 in Chinese subjects
Parts 1 and 2

Clinical safety data from 
adverse events (AEs), clinical 
laboratory tests, vital signs 
(systolic and diastolic blood 
pressure and heart rate), and 
12-lead electrocardiogram 
(ECG) readings.
AE = adverse event; ECG = electrocardiogram; HSWG = high shear wet granulation; RC = related 
compound.
 
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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I, multi-center, open-label, single-dose, 2-part study. Part 1a is being 
conducted to evaluate the relative bioavailability of 2 free base tablet formulations of 
gepotidacin compared to the reference capsule formulation under fasted conditions.
Based upon safety and PK data obtained from Part 1a, a decision will be made whether to 
use the free base RC or HSWG tablet formulation for Parts 1b and 2. Part 1b will 
evaluate the bioavailability of the selected tablet formulation under fasted and fed 
conditions. Part 2 will evaluate pharmacokinetics in Japanese subjects (Part 2a) under 
fasted conditions, and pharmacokinetics in Chinese subjects (Part 2b) under fasted 
conditions.
Part 1a: Relative Bioavailability
Part 1a is a 3-period, cross-over study that will assess the relative bioavailability of a
single 1500-mg dose of gepotidacin in 2 free base tablet formulations (2 × 750 mg RC 
and HSWG tablets) compared with the reference capsule formulation of gepotidacin 
(3 × 500-mg capsules). Each subject will receive all 3 treatments according to their 
assigned treatment sequence based on a Latin square design (ABC, CAB, or BCA). See 
the study schematic in Table 1 for more details.
Subjects will participate in 3 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Time and Events 
Table (Table 5). Blood and urine samples will be collected up to approximately 48 hours 
after dosing.
Table 1
Part 1a Relative Bioavailability Study Design Schematic
Treatment
Cross-over
Follow-up
Capsule 
(reference)a
Period 1
Wash-out
At least 3 
days
Period 2
Wash-out
At least 3 
days
Period 3
5 to 7 days 
after final 
dose
RC and HSWG 
tabletb
Sequence 1
A
B
C
Sequence 2
C
A
B
Sequence 3
B
C
A
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 3 × 500-mg capsules (Treatment A; reference formulation)
b
1500 mg single dose given as 2 × 750-mg RC (Treatment B) or HSWG (Treatment C) tablets
Part 1b (Optional): Food Effect
Part 1b is a 2-period, cross-over study and will evaluate the effect of food on the safety, 
tolerability, and pharmacokinetics of a single dose of 1500 mg gepotidacin tablet 
 
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formulation (selected in Part 1a). If both formulations of the free base tablet exhibit 
similar bioavailability to the capsule formulation, then the results of the moderate fat 
meal evaluated in the RC mesylate tablet formulation from Study BTZ117349
(GlaxoSmithKline Document Number 2013N176846_01 Study ID BTZ117349 will be 
used to guide dosing recommendations with food. See the study schematic in Table 2 for 
more details.
Subjects will participate in 2 treatment periods and blood samples will be collected for 
PK analysis of gepotidacin concentrations according to the Time and Events Table 
(Table 5). Blood samples will be collected up to approximately 48 hours after dosing.
Table 2
Part 1b Food Effect Study Design Schematic
Treatment
Cross-over
Follow-up
RC or HSWG tablet fasteda
Period 1
Wash-out
At least 3 days
Period 2
5 to 7 days after 
final dose
RC or HSWG tablet feda
Sequence 4
D
E
Sequence 5
E
D
HSWG = high shear wet granulation; RC = related compound.
a
1500 mg single dose given as 2 × 750 mg tablets fasted (Treatment D) and fed (Treatment E)
Parts 2a and 2b: Pharmacokinetics in Japanese and Chinese Subjects
Parts 2a and 2b will evaluate the pharmacokinetics of a single dose of 1500 mg 
gepotidacin tablet formulation (RC or HSWG tablet) in a cohort of Japanese (Part 2a) and 
Chinese subjects (Part 2b) under fasted conditions. A decision will be made whether to 
use the RC tablet formulation or the HSWG tablet formulation based upon the safety and 
PK data obtained from Part 1a.
Subjects will receive study drug on Day 1 and blood samples will be collected for PK 
analysis of gepotidacin concentrations according to the Time and Events Table (Table 5). 
Blood samples will be collected up to approximately 48 hours after dosing.
4.2.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will enter 
the clinic at Check-in (Day –1) before study drug administration (Day 1) and will be 
enrolled as follows:
Part 1a – Relative Bioavailability:

Treatment A: Gepotidacin 1500 mg (3 × 500 mg) reference capsules

Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets

Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (ABC, 
CAB, or BCA) to receive a single dose of gepotidacin 1500 mg (2 × 750 mg) RC tablet, 
 
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1500 mg (2 × 750 mg) HSWG tablet, or 1500 mg (3 × 500 mg) reference capsule in each 
period. There will be a washout period of at least 3 days between doses. Subjects will 
remain in the clinical research unit from Day –1 until Day 3 of Period 3 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up visit approximately 5 to 7 days after the final dose of study drug. The 
duration of the study (from Screening to the Follow-up visit) will be approximately
44 days.
Based on PK, safety, and tolerability data from Part 1a, subjects for Parts 1b (food 
effect), 2a (Japanese subjects), and 2b (Chinese subjects) may be enrolled.
Part 1b (Optional) – Food Effect:

Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fasted

Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets selected from 
Part 1a – fed
On Day 1 (Period 1), subjects will be randomly assigned to a treatment sequence (DE or 
ED) and receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet (RC or 
HSWG) selected from Part 1a under fasted and fed conditions. There will be a washout 
period of at least 3 days between doses. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 of Period 2 after all scheduled PK and safety assessments have 
been completed, and will return to the clinic for a Follow-up visit approximately 5 to 
7 days after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 41 days.
Parts 2a and 2b: Pharmacokinetics in Japanese and Chinese Subjects
On Day 1, subjects will receive a single 1500-mg (2 × 750 mg) dose of gepotidacin tablet 
(RC or HSWG) selected from Part 1a. Subjects will remain in the clinical research unit 
from Day –1 until Day 3 after all scheduled PK and safety assessments have been 
completed, and will return to the clinic for a Follow-up visit approximately 5 to 7 days 
after the final dose of study drug. The duration of the study (from Screening to the 
Follow-up visit) will be approximately 38 days.
4.3.
Type and Number of Subjects
For Part 1a, approximately 27 subjects will be enrolled with approximately 9 subjects in 
each of the 3 treatment sequences to ensure 24 PK parameter evaluable subjects with PK 
parameter estimates from the reference and at least one test formulation. For Part 1b, 
approximately 16 subjects will be enrolled with approximately 8 subjects in each of the 
2 treatment sequences. For Parts 2a and 2b, 12 Japanese and 12 Chinese subjects will be 
enrolled, respectively.
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment sequence at the discretion of the 
sponsor in consultation with the investigator.
 
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4.4.
Design Justification
The study design for Part 1a is commonly used when evaluating relative bioavailability 
of a drug entity in subjects. It is based on recommendations given in the US Food and 
Drug Administration (FDA) draft guidance for industry, Bioavailability and 
Bioequivalence Studies Submitted in NDAs or INDs — General Considerations 
[DHHS, 2014].
The study design for Part 1b is commonly used when evaluating the effect of food on a 
drug entity in subjects. It is based on recommendations given in the US FDA draft 
guidance for industry, Food-Effect Bioavailability and Fed Bioequivalence Studies 
[DHHS, 2002].
The study designs for Parts 2a and 2b are commonly used when evaluating 
pharmacokinetics of a drug entity in subjects from different ethnic groups.
Pharmacokinetic data obtained from these groups would satisfy regulatory guidelines and 
provide dosing recommendations for future Phase III studies in specific ethnic groups.
Gepotidacin exhibits linear and time-independent pharmacokinetics, which indicates a 
single-dose study is adequate to achieve study objectives. A multiple-dose study is not 
necessary since there are no safety concerns with metabolites of this study drug.
4.5.
Dose Justification
The 1500-mg dose of gepotidacin is considered to be the likely dose used for future 
Phase 3 studies and will be evaluated in all parts of this study. Selection of dose and 
dosing frequency for this study is justified based on observed safety and PK data 
following oral single (100 to 3000 mg) and repeat twice daily (400 to 2300 mg) and 
3 times daily (1500 to 2000 mg) capsule doses in healthy subjects in Studies BTZ114595 
and BTZ116778, and single 1500-mg doses of the capsule and RC tablet formulations in 
Study BTZ117349. The 1500-mg dose (PK data for Study BTZ116778 [Table 3] and 
Study BTZ117349 [Table 4]) achieves the projected therapeutic target plasma 
concentration and will be evaluated in all parts of the study. A moderate fat meal should 
only have a minimal effect on PK after administration of the tablet formulation since only 
a minimal food effect on PK was previously observed in Studies BTZ114595 and 
BTZ117349 [Table 4].
 
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Table 3
Preliminary PK Parameters of Gepotidacin after Single and Repeat 
BID Dose of 1500 mg Orally (Study BTZ116778)
AUC(0-)a
(µg.hr/mL)
Cmax (µg/mL)a
tmax (hr)b
t1/2 (hr)a
Single Dose PK
[Day 1] (N=12)
20.0 (21.5%)
[15.6 – 31.0]
4.08 (40.3%)
[2.0 – 6.62]
2.0
[1.5 – 4.0]
11.7 (19.2%)
[9.09 – 16.4]
AUC(0-12)a
(µg.hr/mL)
Cmax1 (µg/mL)a
tmax (hr)b
Roa
Repeat BID Dose PK
[Day 14] (N=12)
22.4 (29.5%)
[15.8 – 39.9]
5.41 (31.1%)
[3.61 – 8.09]
2.0
[1.5 – 4.0]
1.30 (34.9%)
[0.59 – 1.89]
BID = twice daily, CVb% = percent coefficient of variation, PK = pharmacokinetic, Ro = accumulation ratio.
a
Geometric mean (CVb%) [range]
b
Median [range]
Table 4
Selected Gepotidacin PK Parameters After Single Dose Oral Capsule 
and Tablet Administration Under Fasted and Fed Conditions 
(Study BTZ117349)
Gepotidacin 1500-
mg Capsule/Fasted
(N=15)
Gepotidacin 
1500 mg RC 
Tablet/Fasted
(N=15)
Gepotidacin 
1500 mg RC 
Tablet/Fed
(N=15)
AUC(0-)a(µg.hr/mL)
13.6 (28.8%)
15.8 (20.3%)
16.9 (16.2%)
Cmax (µg/mL)a
3.77 (58.1%)
4.37 (24.7%)
3.73 (29.1%)
tmax (hr)b
1.5 (0.5 – 6.0)
1.75 (1.0 – 3.0)
3.0 (1.5 – 4.0)
t1/2 (hr)c
12.1 (27.3)
11.8 (19.2)
11.7 (18.6)
CVb% = percent coefficient of variation, PK = pharmacokinetic.
a
Geometric mean (CVb%)
b
Median [range]
c
Arithmetic mean (CVb%)
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
gepotidacin can be found in the IB(GlaxoSmithKline Document 
Number CM2010/00033/03) and supplement to the IB (GlaxoSmithKline Document 
Number 2016N275883_00).
Section 4.6.1 outlines the risk assessment and mitigation strategy for this study
(GlaxoSmithKline Document Number 2013N174977).
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product Gepotidacin
Gastrointestinal (GI) Effects
Lower GI effects (soft stools, flatulence, and diarrhea) are the most 
common GI-associated adverse events (AEs) reported in human 
subjects dosed with gepotidacin. Additional events of heme + stool 
have been observed.
In the Phase I studies, out of approximately 400 healthy subjects 
who have received gepotidacin, C. difficile has been reported in 8 
subjects.
In an acute bacterial skin and skin structure infection study of 
122 patients from 13 sites in the USA, the most frequently reported 
AEs were in the GI system including diarrhea, nausea, and 
abdominal cramping (see GlaxoSmithKline Document 
Number 2015N243789_00 Study ID BTZ116704). Events were 
usually mild in severity with fewer of moderate severity. No patients 
experienced severe GI AEs and none withdrew due to GI AEs.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Subjects with significant GI symptoms will obtain the 
appropriate work-up (Appendix 8).
Subject stopping criteria: Subjects experiencing Grade 3 or 
Grade 4 AEs will have permanent discontinuation of the 
investigational product and will be followed as appropriate 
until resolution of the AE.
Cardiovascular Effects
Reversible increase in QT prolongation and a 
mild increase in heart rate in human subjects.
In Study BTZ115775 [see GlaxoSmithKline Document Number 
2015N227098_00 Study ID BTZ115775], the infusion of 
gepotidacin at a dose of 1000 mg and 1800 mg over 2 hours 
caused a mild heart rate effect of approximately 6 beats per minute
to 10 beats per minute and a QT prolongation, measured as 
∆∆QTcF, of 12 msec to 22 msec. 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. 
The 1500 mg oral dose yields a Cmax of 4.8 µg/mL with predicted 
ΔΔQTcF (90% CI) of 7.5 msec (6.8 to 8.3 msec) compared to that 
observed after the therapeutic 1,000 mg intravenous dose 
Exclusion criteria, oral dosing of capsule and tablet 
formulations will have lower Cmax compared to IV doses in 
the thorough QTc study, close monitoring of clinical 
parameters, and AEs will be conducted and stopping criteria 
will be utilized to mitigate and assess cardiovascular effects.
Note: Subjects with a QRS duration <70 and >120 msec will 
be excluded. 
Subject stopping criteria: Subjects 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
(Cmax of 7.3 µg/mL) administered in the thorough QTc study.
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 total drug concentration).
At higher doses, some subjects have experienced effects 
consistent with increased cholinergic tone, including central 
nervous system and GI effects (including dizziness, abdominal 
pain, salivary hypersecretion, hot flush, diarrhea, fatigue and 
nausea). These effects appear to be related to Cmax and are 
significantly attenuated when Cmax is below 14 g/mL.
Coadministration of anticholinergics and administration in 
subjects 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. The Cmax will be below 14 g/mL in this study.
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was seen in 3 of 
8 subjects following 10 days of dosing 1500 mg 3 times daily (see 
GlaxoSmithKline Document Number 2014N198291_00
Study ID BTZ115198)
Rash was reported as an AE for 4 of 122 subjects (3%) and 
consisted of mild, related urticaria; moderate, related rash 
maculopapular; mild, related rash; mild, related urticaria; and mild, 
not related arthropod bite (see GlaxoSmithKline Document Number 
2015N243789_00 Study ID BTZ116704).
There has been no other evidence of hypersensitivity in human 
subjects 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 GlaxoSmithKline medical 
monitor, contraindicates their participation.
Subject monitoring:
Patients will be monitored closely for cutaneous effects 
throughout the study, and specialist advice will be sought as 
needed to evaluate any clinically significant finding.
Subject stopping criteria:
Grade 3 or higher rash or Grade 2 rash with evidence of 
systemic involvement.
 
 
 
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4.6.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy subjects, there is no direct clinical 
benefit to study subjects. Participation in this study will contribute to the process of 
developing new antibiotic therapies in areas of growing unmet need.
4.6.3.
Overall Benefit:Risk Conclusion
The risk of adverse events (AEs) is minimized for the populations being investigated in 
the proposed study by careful selection of dose and subjects for the study; the relatively 
short duration of study drug exposure; and the extent of safety monitoring incorporated 
into the study.
5.
SELECTION OF STUDY POPULATION AND
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB (GlaxoSmithKline Document 
Number CM2010/00033/03) and supplement to the IB (GlaxoSmithKline Document 
Number 2016N275883_00).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Male or female subjects between 18 and 64 years of age inclusive, at the time of 
signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator based on medical history, clinical 
laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign 
measurements, 12-lead ECG results, and physical examination findings. A subject 
with a 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 subjects (Part 2a only):

The subject was a non-naturalized Japanese citizen and held a Japanese passport.

The subject had 2 Japanese parents and 4 Japanese grandparents who were all 
non-naturalized Japanese citizens, as confirmed by interview.
 
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
The subject had been living outside of Japan for up to 10 years as confirmed by 
interview. 
4. Additional inclusion criteria for Chinese subjects (Part 2b only):

The subject was a non-naturalized Chinese citizen and held a Chinese passport.

The subject had 2 Chinese parents and 4 Chinese grandparents who were all 
non-naturalized Chinese citizens, as confirmed by interview.

The subject had been living outside of China for up to 10 years as confirmed by 
interview.
WEIGHT
5. Body weight:

Subjects in Part 1a and Part 1b:  50 kg and body mass index (BMI) within the 
range 19 and 32 kg/m2, inclusive.

Japanese and Chinese subjects (Part 2a and Part 2b):  50 kg and BMI within the 
range 18 and 32 kg/m2, inclusive.
SEX
6. Male or female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin test, not lactating, and at least one of the 
following conditions applies:
a.
Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented bilateral oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea (in 
questionable cases a blood sample with simultaneous follicle-stimulating 
hormone (FSH) and estradiol levels consistent with menopause [refer to 
laboratory reference ranges for confirmatory levels]). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status prior to study 
enrollment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (Appendix 7) from 30 days prior to the first dose of study 
 
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medication and until completion of the Follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Subject has a clinically significant abnormality in past medical history or at the 
Screening physical examination that in the investigator’s opinion may place the 
subject at risk or interfere with outcome variables of the study. This includes, but is 
not limited to, history or current cardiac, hepatic, renal, neurologic, 
gastrointestinal (GI), respiratory, hematologic, or immunologic disease.
2. Subject has any surgical or medical condition (active or chronic) that may interfere 
with drug absorption, distribution, metabolism, or excretion of the study drug, or any 
other condition that may place the subject at risk, in the opinion of the investigator.
3. Corrected QT (QTc) >450 msec.
4. Use of a systemic antibiotic within 30 days of Screening.
5. Within 2 months before Screening, either a confirmed history of Clostridium difficile
diarrhea infection or a past positive Clostridium 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 sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
uses heparin to maintain intravenous cannula patency).
CONCOMITANT MEDICATIONS
8. Subjects cannot use any over-the-counter, or prescription medication (except for 
hormonal contraceptives and/or acetaminophen; see Section 6.11 for more details), 
vitamin supplement, or herbal medication within 7 days (or 5 half-lives, whichever is 
longer) before dosing and during the study.
RELEVANT HABITS
9. 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, 
 
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30 mL of spirits, or 100 mL of wine.
10. Urinary cotinine level indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months before screening.
CONTRAINDICATIONS 
11. History of sensitivity to any of the study medications, or components thereof, or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
13. Female subject has a positive pregnancy test result or is lactating at Screening or upon 
admission to the clinic.
14. Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN)
15. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. Urinalysis positive for blood without other cause identified.
17. A positive pre-study drug/alcohol screen.
18. A positive test for human immunodeficiency virus antibody.
19. Subject has clinically significant abnormal findings in serum chemistry, hematology, 
or urinalysis results obtained at Screening or Day –1.
20. Donation of 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.
21. Previous exposure to gepotidacin within 12 months prior to the first dosing day.
22. Exclusion criteria for screening and baseline 12-lead ECG (a single repeat is allowed 
for eligibility determination):
Males
Females
Heart rate
<40 and >100 beats per minute
<50 and >100 beats per minute
PR interval
<120 and >220 msec
QRS duration
<70 and >120 msec
QTcB or QTcF interval
>450 msec
QTcB = corrected QT interval using Bazett’s formula, QTcF = corrected QT interval using 
Fridericia’s formula.

Evidence of previous myocardial infarction (does not include ST segment changes 
associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, atrioventricular block [second degree or higher], 
Wolf-Parkinson-White syndrome), sinus pauses >3 seconds, non-sustained or 
sustained ventricular tachycardia (≥3 consecutive ventricular ectopic beats) or any 
significant arrhythmia which, in the opinion of the principal investigator and GSK 
medical monitor, will interfere with the safety of the individual subject.
 
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23. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
24. Subject is unable to comply with all study procedures, in the opinion of the
investigator.
25. The subject should not participate in the study, in the opinion of the investigator or
sponsor.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials publishing requirements, 
and respond to queries from regulatory authorities, a minimal set of screen failure 
information is required including demographics, screen failure details, eligibility criteria, 
and serious AEs (SAEs).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The clinic must attempt to contact the subject and reschedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow-up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 
3 telephone calls and if necessary a certified letter to the subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “lost to follow-up”.
A subject may withdraw from study treatment 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 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
 
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guidance, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” 
[DHHS, 2009].
Study treatment will be stopped if the following liver chemistry stopping criterion is met:

ALT 3 × ULN
For details of the required assessments if a subject meets the above criteria, refer to 
Appendix 2, Liver Chemistry Follow-up Procedures.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on the QTcF, then 
the QTcF must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, 
the same formula must continue to be used for that subject 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 triplicate 
ECGs obtained over a brief (e.g., 5 to 10 minute) recording period.
A subject who meets either bulleted criterion below will be withdrawn from the study:

QTc >500 msec

Increase from baseline of QTc >60 msec
For subjects with underlying bundle branch block, the following discontinuation criteria 
will be used instead:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec
5.4.3.
Gastrointestinal Stopping Criteria
Subjects experiencing Grade 3 or Grade 4 AEs (confluent pseudomembranes or 
ulcerations OR mucosal bleeding with minor trauma; tissue necrosis OR diffuse 
spontaneous mucosal bleeding OR life-threatening consequences, e.g., aspiration, 
choking) will be followed as appropriate until resolution of the AE(s).
Furthermore, subjects who experience diarrhea or enteritis should be evaluated with 
additional fecal occult blood tests and stool cultures as deemed appropriate by the 
investigator as outlined in Appendix 8 and Appendix 9.
 
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5.4.4.
Rash/Hypersensitivity Stopping Criteria
A subject 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).
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
Gepotidacin 
(GSK2140944) capsule
Gepotidacin 
(GSK2140944B) 
RC tablet
Gepotidacin 
(GSK2140944B) 
HSWG tablet
Formulation 
description:
Immediate release 
capsules containing 
gepotidacin (mesylate 
salt) and inactive 
formulation excipients
Immediate release 
tablets containing 
gepotidacin (free 
base) and inactive 
formulation 
excipients
Immediate release 
tablets containing 
gepotidacin (free 
base) and inactive 
formulation 
excipients
Dosage form:
Capsule
Tablet
Tablet
Unit dose strength/
Dosage level:
500 mg/
1500 mg (3 × 500 mg)
750 mg/
1500 mg
(2 × 750 mg)
750 mg/
1500 mg 
(2 × 750 mg)
Route of 
Administration:
Oral
Oral
Oral
Dosing instructions:
Dose with 240 mL of
water. Up to an 
additional 100 mL of 
water may be given to 
assist in swallowing 
capsules.
Dose with 240 mL of
water. Up to an 
additional 100 mL of 
water may be given 
to assist in 
swallowing tablets.
Dose with 240 mL 
of water. Up to an 
additional 100 mL of 
water may be given 
to assist in 
swallowing tablets.
 
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Physical description:
Pink Gelatin size 00 
capsule with no 
identifying markings 
containing slightly 
agglomerated pale 
yellow to grayish 
yellow to yellowish 
gray powder.
A capsule-shape 
white film-coated 
tablet with no 
identifying markings.
An oval shape white 
film-coated tablet 
with no identifying 
markings.
Manufacturer/Source of 
procurement:
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
6.2.
Treatment Assignment
Subjects in Part 1a will be assigned to a treatment sequence to receive gepotidacin 
(GSK2140944) capsules, RC tablets, and HSWG tablets in accordance with the 
randomization schedule generated by PPD before the start of the study, using validated 
internal software. Subjects in Part 1b will be assigned to a treatment sequence to receive 
gepotidacin RC or HSWG tablets under fasted and fed conditions.
A description of each regimen for Parts 1a and 1b is provided in the table below:
Part 
Treatment 
Code
Treatment
1a
A
Treatment A: Gepotidacin 1500 mg (3 × 500 mg) capsules
1a
B
Treatment B: Gepotidacin 1500 mg (2 × 750 mg) RC tablets
1a
C
Treatment C: Gepotidacin 1500 mg (2 × 750 mg) HSWG tablets
1b
D
Treatment D: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets
selected from Part 1 – fasted
1b
E
Treatment E: Gepotidacin 1500 mg (2 × 750 mg) RC or HSWG tablets 
selected from Part 1 – fed
Subjects in Parts 2a, and 2b will receive the tablet formulation (RC or HSWG) selected 
based on PK, safety, and tolerability data from Part 1a.
Subjects will be given a subject number that will be a unique identifier. Once a subject 
number has been assigned, the number will not be reused even if the subject withdraws 
from the study before receiving gepotidacin.
6.3.
Planned Dose Adjustments
Planned dose adjustments are not allowed during this study.
6.4.
Blinding
This will be an open-label study.
 
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6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are to be reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized clinic staff may supply or administer study treatment. All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized clinic staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to clinic staff.

A Material Safety Data Sheet or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request 
from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the clinic, they will receive study treatment 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 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the clinic staff other than the person administering the study treatment. Study 
site personnel will examine each subject’s mouth to ensure that the study treatment was 
ingested.
6.8.
Treatment of Study Treatment Overdose
Gepotidacin will be administered at the clinic, thus limiting the risk of overdose. In the 
unlikely event that an overdose with gepotidacin 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 
 
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recommended that the appropriate supportive clinical care should be instituted, as 
dictated by the subject’s clinical status.
GSK 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 subject for AEs/SAEs and laboratory abnormalities until 
gepotidacin can no longer be detected systemically (at least 3 days for gepotidacin)
3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment 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)
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on a clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Standard meals will be provided during the study dosing period at specified times.
Subjects will refrain from consumption of red wine, Seville oranges, grapefruit, or 
grapefruit juice (and/or pummelos, exotic citrus fruits, or grapefruit hybrids) from 7 days 
prior to the first dose of study medication until after the final dose.
Subjects will fast from food and drink (except water) for at least 10 hours before dosing 
on Day 1 of each period. For the fed group of the food effect evaluation in Part 1b, study
drug will be administered within 30 minutes after the completion of a moderate fat meal.
Fasting requirements may be modified, relaxed, or removed based on emerging safety, 
tolerability, and PK data from Part 1a. If fasting requirements are removed, then Part 1b
may be conducted as a single-period study with drug administered only under fed 
conditions. In the event that the formulation tested for Part 1b is not tolerated in the 
fasting state, subjects may receive the formulation with a meal after consultation with the 
sponsor and investigator.
 
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6.10.2.
Caffeine, Alcohol, and Tobacco
Subjects will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to the start of dosing until 
collection of the final PK sample. 
During each dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final PK sample.
Use of tobacco products is not allowed from 3 months before Screening until after the
final Follow-up visit.
6.10.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. Subjects may participate in light recreational activities during 
the study (e.g., watch television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Hormonal contraceptives and/or acetaminophen, at doses of ≤2 grams/day is permitted 
for use. Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the medical monitor.
All concomitant medication use will be documented on the concomitant medication page 
in the eCRF.
6.11.2.
Prohibited Medications and Non-Drug Therapies
Subjects 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) prior to the first dose of 
study medication until completion of the Follow-up visit, unless in the opinion of the 
investigator and sponsor the medication will not interfere with the study.
Since gepotidacin is known to have some prolongation of QTc, any drugs known to 
increase QTc interval should be avoided when treating an AE.
Due to the potential for acetylcholinesterase inhibition with gepotidacin, the following 
medications are prohibited:

Succinylcholine or other depolarizing muscle relaxants.

Acetylcholinesterase inhibitors as required for myasthenia gravis including 
edrophonium, pyridostigmine, neostigmine, etc.
 
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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety and PK 
assessments, may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which will be approved by the relevant 
GSK study team member and then archived in the study sponsor and clinic study 
files, but this will not constitute a protocol amendment. 

The institutional review board (IRB)/independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the informed consent form.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
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7.1.
Time and Events Table
Table 5
Time and Events Table: Parts 1a, 1b, 2a, and 2b
Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Parts 2a and 2b – Pharmacokinetics: Study Day
Follow-up
(5 to 7 
days post-
last dose)
Day
–1a
Day 1
Day 2
Day 3
Pre-dose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Admission to unit
X
Informed consent
X
Demographics including BMI
X
Full physical examination including 
height and weightb
X
Brief physical examinationb
X
X
Medical/medication/
drug/alcohol history
X
12-lead ECGc
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
Drug/alcohol/cotinine screen
X
X
Serum pregnancy, FSH, and estradiol 
(women)
X
X
X
HIV antibody, HBsAg, and hepatitis C 
antibody screen
X
Safety laboratory testse
X
X
X
X
Study drug administrationf
X
Pharmacokinetic sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for pharmacokinetics 
(Part 1a only)g
X
X
X
X
X
X
X
X
X
 
 
 
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Procedure
Screening 
(up to 
30 days 
prior to 
Day 1)
Part 1a – Relative Bioavailability: Periods 1, 2, and 3
Part 1b – Food Effect: Periods 1 and 2
Parts 2a and 2b – Pharmacokinetics: Study Day
Follow-up
(5 to 7 
days post-
last dose)
Day
–1a
Day 1
Day 2
Day 3
Pre-dose
0 h
0.5 h
1 h
1.5 h
2 h
2.5 h
3 h
4 h
6 h
8 h
12 h
24 h
36 h
48 h
Pharmacogenetic sampleh
========================================================================
AE/SAE Review
X
==================================================================================
X
Concomitant medication review
X
========================================================================
X
Dischargei
X
Outpatient visit
X
X
AE = adverse event, BMI = body mass index, ECG = electrocardiogram, FSH = follicle-stimulating hormone, HBsAg = hepatitis B surface antigen, HIV = human immunodeficiency 
virus, SAE = serious adverse event.
a
The Day –1 visit occurs in Period 1 only. Periods 2 and 3 (Part 1a only) begin on Day 1.
b
A complete physical examination will include at a minimum, assessment of the 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).
c
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured in 
semi-supine position after 5 minutes rest at all other time points during the study
d
Single vital signs will be measured in semi-supine position after 5 minutes rest and will include systolic and diastolic blood pressure, and heart rate. Body temperature and 
respiratory rate will be collected at Screening only.
e
Safety laboratory tests include serum chemistry, hematology, and urinalysis.
f
Subjects will fast from food and drink (except water) for at least 10 hours before study drug administration on Day 1 of each period. For the fed group of the food effect evaluation 
in Part 1b, study drug will be administered within 30 minutes after the completion of a moderate fat meal
g
Urine collection intervals (Part 1a only) for subjects 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.
h
For subjects who consent only: collect 1 pharmacogenetic sample after the start of dosing (preferably Day 1). Informed consent for optional pharmacogenetics research must be 
obtained before collecting a sample.
i
For Part 1a, subjects will be discharged from the clinical research unit on Day 3 of Period 3. For Part 1b, subjects will be discharged on Day 3 of Period 2. For Parts 2a and 2b, 
subjects will be discharged on Day 3.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Additional time points for safety tests such as vital signs, physical exams,
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.
7.3.1.1.
Time Period and Frequency for collecting Adverse Event and Serious 
Adverse Event information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

AEs will be collected from the time informed consent is obtained until the follow-up 
contact (see Section 7.3.1.3), at the time points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
 
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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5.
7.3.1.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.3.1.4.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non-interventional post marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects and, if indicated, female partners of male 
subjects will be collected after the start of dosing and until the Follow-up visit.
 
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If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
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.
7.3.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
systolic and diastolic blood pressure, and heart rate. Body temperature and respiratory 
rate will be collected at Screening only.
7.3.5.
Electrocardiogram
Triplicate 12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
and obtained at least 5 minutes apart on Day –1. Single 12-lead ECGs will be measured 
in semi-supine position after 5 minutes rest at all other time points during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 5.4.2 for QTc stopping criteria and additional QTc
readings that may be necessary.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 6, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Table
(Section 7.1). Laboratory requisition forms must be completed and samples must be 
clearly labelled with the subject number, protocol number, site/center number, and visit 
date. Details for the preparation and shipment of samples will be provided by the 
laboratory and are detailed in the SRM. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
 
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Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 6.
Table 6
Protocol Required Safety Laboratory Assessments
Hematology
Platelet Count 
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Eosinophils
Basophils
Serum Chemistrya
Blood urea nitrogen
Potassium 
Aspartate aminotransferase
Total and direct bilirubin
Creatinine
Sodium
Alanine aminotransferase
Total protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Creatine kinase
Bicarbonate
Chloride
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
Hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing potential only)
Serum test for human chorionic gonadotropin (as needed in women of childbearing potential)
Alcohol (via urine, blood alcohol, or breathalyzer test), cotinine, and drug screen (via serum, urine, or saliva) to include, 
at a minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines).
Fecal occult blood test and stool cultures as appropriate for gastrointestinal adverse events (Appendix 8)
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; RBC = red blood cell; WBC = white blood cell.
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 5.4.1 and Appendix 3.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation should be repeated until the values return to normal or baseline. If 
such values do not return to normal within a period judged reasonable by the investigator, 
the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for PK analysis of gepotidacin will be collected at the time points 
indicated in the Time and Events Table (Section 7.1). The actual date and time of each 
blood sample collection will be recorded. The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.
For each sample, 3 mL of blood will be drawn via an indwelling catheter and/or direct 
venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. Details of 
PK blood sample processing, storage, and shipping procedures are provided in the SRM.
 
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7.4.2.
Urine Sample Collection
Pharmacokinetic urine samples for the analysis of gepotidacin (Part 1a only) will be 
collected at the time points listed in the Time and Events Table (Section 7.1). The actual 
date and time of each urine sample collection will be recorded. The timing of PK samples 
may be altered and/or PK samples may be obtained at additional time points to ensure 
thorough PK monitoring.
Details of PK urine sample processing, storage, and shipping procedures are provided in 
the SRM.
7.4.3.
Sample Analysis
Plasma and urine analysis will be performed under the control of PTS-DMPK/Scinovo, 
GSK, the details of which will be included in the SRM. Concentrations of gepotidacin 
will be determined in plasma and urine samples using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM). 
Since plasma protein binding of gepotidacin is low (33%), only total drug concentrations 
will be reported for the PK analysis.
Once the plasma and urine samples have been analyzed for gepotidacin, any remaining 
plasma and urine samples may be analyzed for other compound-related metabolites and 
the results reported under a separate PTS-DMPK/Scinovo, GSK protocol.
7.5.
Genetics
Depending on the clinical study results, exploratory pharmacogenomics analyses may be 
performed to examine the potential relationship between genetic variants and clinical 
endpoints.
The pharmacogenomics samples will be collected according to the Time and Events 
Table (Table 5). Information regarding genetic research is included in Appendix 4.
8.
DATA MANAGEMENT

For this study, subject data will be entered via an eCRF into Oracle Clinical Remote 
Data Capture System. Subject data will be available for viewing through access to the 
Oracle Clinical Remote Data Capture System. Data provided from other sources will 
be received, reconciled, combined, and transferred to GSK at predetermined time 
points.

Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity and quality of the data 
(e.g., removing errors and inconsistencies in the data). Adverse events and 
concomitant medications terms will be coded using Medical Dictionary for
Regulatory Activities (MedDRA) and a validated medication dictionary, GSKDrug.
 
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
The eCRFs (including queries and audit trails) will be sent at the end of the study in 
electronic format to GSK to be retained. Each investigator will receive a copy of their 
site specific data in the same format to maintain as the investigator copy. In all cases, 
subject initials will not be collected or transmitted.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
All statistical analyses will be performed by PPD using SAS (SAS Institute Inc., Cary, 
North Carolina, USA), version 9.2 or higher. Pharmacokinetic parameters will be 
calculated using Phoenix WinNonlin (Certara USA Inc., Princeton, New Jersey, USA), 
version 6.2.1 or higher.
Before database lock, a reporting and analysis plan (RAP) will be issued as a separate 
document, providing detailed methods for the analyses outlined below.
Any deviations from the planned analyses will be described in a RAP addendum and 
justified in the final integrated clinical study report.
9.1.
Hypotheses
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the relative bioavailability of the gepotidacin RC and HSWG tablet 
formulations relative to the reference gepotidacin capsule formulation in healthy subjects
(Part 1a), estimate the effect of food on the tablet formulation selected in Part 1a
(Part 1b), and to evaluate the pharmacokinetics of the tablet formulation selected in 
Part 1a in Japanese (Part 2a) and Chinese (Part 2b) subjects.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size is largely based on feasibility, however some justification is provided below.
Part 1a – Relative Bioavailability:
The sample size of 24 PK parameter population subjects will be used based on feasibility 
to address the objectives of Part 1a of the study.
There are no estimates for the coefficient of variation (CV) of HSWG for any PK 
parameters. An assumed CV of 27.5% for a PK parameter implies that the sample size of 
24 PK parameter evaluable subjects will provide at least 80% power to demonstrate 
equivalence of the PK parameter. Equivalence is demonstrated when 90% confidence 
interval (CI) for the ratio of Test:Reference of the PK parameter will be within 0.8 to 
1.25 following log transformation.
Two different test formulations are being used in this study. No adjustment for 
pre-planned multiple comparisons are made.
 
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The total sample size of 27 subjects (9 subjects in 3 sequences) will be randomized to 
ensure 24 PK parameter evaluable subjects with PK parameter estimates from the 
reference and at least one test formulation.
Part 1b – Food Effect:
A sample size of 16 subjects will be randomized (8 per sequence) based on feasibility to 
address the objectives of Part 1b of the study.
This sample size will ensure equivalence (as specified in sample size assumption in 
Part 1a) with 80% power with an assumed CV of 22%.
Parts 2a and 2b – Pharmacokinetics:
A sample size of approximately 12 subjects will be used in each Part 2a and Part 2b 
based on feasibility to address the objectives of Part 2a and 2b of the study.
9.2.2.
Sample Size Re-estimation or Adjustment
Not applicable.
9.3.
Data Analysis Considerations
In general, descriptive summaries will include number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum for continuous variables; and percent 
for categorical variables. Summaries will present data by group, and where appropriate, 
by assessment time.
9.3.1.
Analysis Populations
The Safety Population will consist of all subjects who receive at least 1 dose of study 
drug and have at least 1 postdose safety assessment.
The PK Population will consist of all subjects who received at least 1 dose of 
gepotidacin and have evaluable PK data for gepotidacin. 
The PK Parameter Population will consist of all subjects in the PK Population, for 
whom valid and evaluable PK parameters were derived. This population will be used in 
the assessment and characterization of PK parameters.
9.3.2.
Interim Analysis
No formal interim analyses are planned for this study. However, all preliminary safety, 
tolerability, and available PK data will be reviewed by the study team after completing
Part 1a of the study to select the formulation for Part 1b, Part 2a, and Part 2b, and also to 
determine if the effect of food on the selected formulation needs to be studied (Part 1b). 
The team will review unblinded data from Part 1a of this open-label study to select the 
appropriate formulation.
 
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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Pharmacokinetic Analyses
Plasma and urine concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods. Based on the individual concentration time data the 
following parameters will be estimated:
Plasma:
AUC(0-)
Area under the concentration-time curve (AUC) from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
the last quantifiable concentration
Cmax
Maximum observed concentration
Frel
Relative bioavailability of drug, calculated as:
[AUC(0-)tablet]/[AUC(0-)capsule] (Part 1a only)
t1/2
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled matrix
Tmax
Time to first occurrence of Cmax
Urine (Part 1a only):
Ae total
Total unchanged drug (total amount of drug excreted in urine), calculated 
by adding all the fractions of drug collected over all the allotted time 
intervals
Ae(t1-t2)
Amount of drug excreted in urine in time intervals of predose, 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 for subjects
AUC(0-12)
Area under the concentration-time curve from time 0 (predose) to 12 hours 
after dosing
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 24 hours 
after dosing
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 48 hours 
after dosing
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)
Plasma (all subjects) and urine (Part 1a only) concentrations of gepotidacin and the 
associated PK parameters will be listed, and summary statistics (n, mean, median, SD, 
minimum, maximum, and CV) will be presented by day and treatment. Mean and 
 
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individual plasma concentration versus time profiles will be presented graphically on 
linear and semilogarithmic scales.
The log-transformed AUC(0-∞), AUC(0-t), and Cmax values for gepotidacin will be 
analyzed separately using a mixed effects model as appropriate to the study design, fitting 
fixed effect terms for sequence, period, and regimen, and treating subject within sequence 
as a random effect. Point estimates and 90% CIs for the differences of interest (RC tablets 
and HSWG tablets versus capsules) will be constructed using the residual variance. Point 
and interval estimates will then be exponentially back-transformed to construct point and 
90% CI estimates for the ratios of interest (RC tablets and HSWG tablets versus 
capsules).
Estimates of within-subject variability for AUC(0-∞), AUC(0-t), and Cmax of 
gepotidacin will be provided, where:
CVw (%) = sqrt(exp[MSE] − 1) × 100
and MSE is the residual mean squared error from the model. CVw(%) represents a 
pooled measure of within-subject variability across regimens.
Distributional assumptions will be assessed by residual plots. Homogeneity of variance 
will be assessed by plotting the residuals against the predicted values from the model, 
whilst normality will be examined by normal probability plots. If assumptions are grossly 
violated, alternative analyses will be considered.
For the bioavailability assessment, tmax will be analyzed nonparametrically using the 
Wilcoxon signed-rank test to compute the point estimate and 90% CI for the median 
difference for each comparison of interest.
Detailed descriptions of the analyses in this study will be presented in the RAP.
9.4.2.
Secondary Analyses
Safety Analyses
The following safety evaluations will be performed:

Monitoring for AEs

Changes in routine clinical laboratory parameters including serum chemistry, 
hematology, and urinalysis

Clinically significant changes in vital sign measurements or physical examination 
findings 

Changes in 12-lead ECG measurements
Safety endpoints will include AEs, clinical laboratory results (serum chemistry [including 
liver function parameters], hematology, and urinalysis), vital sign measurements (systolic 
 
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and diastolic blood pressure and heart rate), 12-lead ECG measurements, and physical 
examination findings.
All safety data will be presented in the data listings. Subject demographics, medical 
history, and prior and concomitant medications will be summarized by group using 
descriptive statistics. For continuous variables, these summaries will include sample size, 
mean, median, SD, minimum, and maximum.
For categorical variables, the summaries will include frequencies and corresponding 
percentages. No inferential hypothesis testing will be performed on the safety variables.
Adverse events will be coded using the MedDRA classification system. 
Treatment-emergent AEs will be defined as any AEs, regardless of relationship to 
investigational product, that occur after the dose of investigational product. The 
treatment-emergent AEs will be summarized by group at AE onset for the overall number 
of AEs and the percentage of subjects who experience them. The total number of AEs 
will be summarized by group and overall. The AEs will be further summarized by 
severity and relationship to the study drug. If relationship information is missing, the AE 
will be considered treatment related. Listings for the subsets of SAEs and 
treatment-related SAEs will be provided. The number of SAEs will be summarized. The 
incidence of AEs will also be summarized by system organ class and preferred term.
Clinical laboratory results, vital sign measurements (systolic and diastolic blood pressure 
and heart rate), and 12-lead ECG results will be summarized by change from baseline. 
Clinical laboratory values that are outside of the reference ranges will be flagged and 
evaluated for clinical significance by the investigator. Any ECG abnormalities, including 
but not limited to a QTc >500 msec or increase in QTc from the baseline ECG of 
≥60 msec, will be summarized by group.
Detailed descriptions of the analyses in this study will be presented in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
 
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The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.

Obtaining signed informed consent.

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to the IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study.

The IRB/IEC, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP and GSK/PPD 
procedures, GSK/PPD monitors will contact the clinic prior to the start of the 
study to review the following with the clinic staff: the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK/PPD requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
GSK/PPD will monitor the study and clinic activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees 
to allow the monitor direct access to all relevant documents.
 
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10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the clinic records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit, or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct 
access to all relevant documents and to allocate their time and the time of their 
staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any 
findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK/PPD 
monitor will conduct clinic closure activities with the investigator or clinic staff, 
as appropriate, in accordance with applicable regulations including GCP, and 
GSK/PPD standard operating procedures.

GSK/PPD reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical 
issues or severe noncompliance. For multi-center studies, this can occur at 1 or 
more or at all clinics.

If GSK/PPD determines such action is needed, GSK/PPD will discuss the reasons 
for taking such action with the investigator or the head of the medical institution 
(where applicable). When feasible, GSK/PPD will provide advance notification to 
the investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, 
GSK/PPD will promptly inform all investigators, heads of the medical institutions 
(where applicable) and/or institution(s) conducting the study. GSK/PPD will also 
promptly inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all clinic study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.

The records must be maintained to allow easy and timely retrieval when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
 
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in conjunction with an assessment of the facility, supporting systems, and relevant 
clinic staff.

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including regenerating a hard copy, if required. Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK/PPD will inform the investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to that clinic for the 
study, as dictated by any institutional requirements or local laws or regulations, 
GSK/PPD standards/procedures, and/or institutional requirements.

The investigator must notify GSK/PPD of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the clinic.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
 
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11.
REFERENCES
Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA 
topoisomerase inhibition by a new class of antibacterial agents. Nature. 
2010;466(7309):935-40.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in age-related macular 
degeneration (AMD) susceptibility gene CFH and treatment response of AMD: a 
meta-analysis. PloS ONE. 2012; 7: e42464.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in 
NDAs or INDs — General Considerations. March 2014. [29 screens]. Available from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm389370.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. July 2009. [28 screens]. Available from: 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Drug Evaluation and Research 
(US). Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence 
Studies. December 2002. [12 screens.] Available from: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126833.pdf
GlaxoSmithKline Document Number 2013N176846_01 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. 
2014.
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 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 
 
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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 CM2010/00033/03. GSK2140944 Investigator’s 
Brochure. 2015.
GlaxoSmithKline Document Number 2013N174977. Benefit Risk Management Plan 
Version 3. 2015.
GlaxoSmithKline Document Number 2016N275883_00. Supplement to Gepotidacin 
Investigator’s Brochure. 2016. 
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th ed. New York: Ardent Media, 2007(a): 24. Table 3-2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th ed. New York: Ardent Media, 2007(b): 28.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th ed. Atlanta, Georgia: Ardent Media, Inc., 2011: 
50. Table 3-2.
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). Guidance on Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
M3 (R2); June 2009. [31 screens]. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplina
ry/M3_R2/Step4/M3_R2__Guideline.pdf
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et. al. 
Pharmacokinetics of acetaminophen-adducts in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos 2009; 37(8):1779-84.
 
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
adverse event
Ae total
total unchanged drug
Ae (t1-t2)
amount of drug excreted in urine in a time interval
ALT
alanine aminotransferase 
AUC
area under the plasma concentration-time curve
AUC(0-)
area under the concentration-time curve from time 0 
(predose) extrapolated to infinite time
AUC(0-t)
area under the concentration-time curve from time 0
(predose) to time of the last quantifiable concentration
BMI
body mass index
CI
confidence interval
CLr
renal clearance of drug
Cmax
maximum observed concentration
CV
coefficient of variation
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fe%
percentage of the given dose of drug excreted in urine
Frel
Relative bioavailability of drug
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
HSWG
high shear wet granulation
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
mm Hg
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 Bazett’s formula
 
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QTcF
corrected QT interval using the Fridericia formula
RAP
reporting and analysis plan
RC
related compound
SAE
serious adverse event
SD
standard deviation
SRM
Study Reference Manual
t1/2
terminal phase half-life
tlag
lag time before observation of drug concentrations in 
sampled matrix
Tmax
time to first occurrence of Cmax
ULN
upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
GSKDrug
MedDRA
Phoenix WinNonlin
SAS
 
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12.2.
Appendix 2: Liver Chemistry Stopping Criteria
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 3.
 
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12.3.
Appendix 3: Liver Safety Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA guidance, “Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation,” [DHHS, 2009].
Phase I Liver Chemistry Stopping Criteria and Required Follow-up Assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubina,b 2 × ULN (>35% direct bilirubin) or INR >1.5, 
report as an SAE.
See additional actions and follow-up assessments listed below.
Required Actions and Follow-up Assessments Following Liver Stopping Event
Actions
Follow-Up Assessments

Report the event to GSK within 24 hours

Complete the Liver Event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb

Perform liver event follow-up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Viral hepatitis serologyc

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total bilirubin 
2 × ULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
 
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Liver Chemistry Stopping Criteria – Liver Stopping Event

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours

Monitor subjects weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline
globulins).

Serum acetaminophen adduct 
high-performance liquid chromatography 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eCRF = electronic case 
report form; GSK = GlaxoSmithKline; IgM = Immunoglobulin M; INR = international normalized ratio; 
SAE = serious adverse event; ULN = upper limit of normal.
a
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3 × ULN and bilirubin 2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
c
Includes: hepatitis A IgM antibody; hepatitis B surface antigen and hepatitis B Core Antibody (IgM); hepatitis C 
RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); hepatitis E IgM antibody.
 
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12.4.
Appendix 4 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to interindividual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration are reported 
to account for much of the risk for the condition [Gorin, 2012] with certain variants 
reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of 
medicines. Additionally, genetic variability may impact the pharmacokinetics 
(absorption, distribution, metabolism, and elimination), or pharmacodynamics 
(relationship between concentration and pharmacologic effects or the time course of 
pharmacologic effects) of a specific medicine, and/or clinical outcomes (efficacy and/or 
safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including gepotidacin or any concomitant medicines
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
 
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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6-mL blood sample will be taken for DNA extraction. A blood sample is collected 
at the baseline visit, after the subject has provided informed consent for genetic 
research. Instructions for collection and shipping of the genetic sample are described 
in the laboratory manual. The DNA from the blood sample may undergo quality
control analyses to confirm the integrity of the sample. If there are concerns regarding 
the quality of the sample, then the sample may be destroyed. The blood sample is 
taken on a single occasion unless a duplicate sample is required due to an inability to 
utilize the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to the 
subject by the investigator or clinic staff. Coded samples do not carry personal identifiers 
(such as a name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers), will only use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research, in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the clinic study records.
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will continue to 
be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance a sample destruction form will not be available to 
include in the clinic files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately, and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
 
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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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient 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 disability/incapacity
NOTE:

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 or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
 
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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3 × ULN and total bilirubin* 2 × ULN (>35% direct), or

ALT 3 × ULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3 × ULN 
and total bilirubin 2 × ULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.5.3.
Recording of Adverse Events and Serious Adverse Events
Adverse Events and Serious Adverse Event 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
 
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12.5.4.
Evaluating Adverse Events and Serious Adverse Events
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 
Diseases Division of Microbiology and Infectious Diseases (DMID) criteria for toxicity 
assessment (Appendix 6).
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE (Section 12.5.2).
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts, evidence, 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of Adverse Events and Serious Adverse Events

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
 
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
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any postmortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.5.
Reporting of Serious Adverse Events to GSK
Serious adverse event reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the clinic will use 
the paper SAE data collection tool and fax it to the medical monitor or the SAE 
coordinator.

The clinic will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given clinic, the electronic data collection tool 
(e.g., InForm system) will be taken off-line to prevent the entry of new data or 
changes to existing data.

If a clinic receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the clinic can report this information on a paper SAE form or to the 
medical monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.6.
Appendix 6: Division of Microbiology and Infectious Disease 
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 AIDs and modified to better meet the needs of 
participants in DMID trials.

For parameters not included in the following Toxicity Tables, 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 mg/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
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated Partial Thromboplastin
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.
 
 
 
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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to 135 mEq/L
123 to 129 mEq/L
116 to 122 mEq/L
<116 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypernatremia
146 to 150 mEq/L
151 to 157 mEq/L
158 to 165 mEq/L
>165 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypokalemia
3.0 to 3.4 mEq/L
2.5 to 2.9 mEq/L
2.0 to 2.4 mEq/L or intensive 
replacement therapy of 
hospitalization required
<2.0 mEq/L or abnormal potassium with
paresis, ileus, or life-threatening arrhythmia
Hyperkalemia
5.6 to 6.0 mEq/L
6.1 to 6.5 mEq/L
6.6 to 7.0 mEq/L
>7.0 mEq/L or abnormal potassium with
life-threatening arrhythmia
Hypoglycemia
55 to 64 mg/dL
40 to 54 mg/dL
30 to 39 mg/dL
<30 mg/dL or abnormal glucose with mental 
status changes or coma
Hyperglycemia
(nonfasting and no prior 
diabetes)
116 to 160 mg/dL
161 to 250 mg/dL
251 to 500 mg/dL
>500 mg/dL or abnormal glucose with
ketoacidosis or seizures
Hypocalcemia
(corrected for albumin)
8.4 to 7.8 mg/dL
7.7 to 7.0 mg/dL
6.9 to 6.1 mg/dL
<6.1 mg/dL or abnormal calcium with
life-threatening arrhythmia or tetany
Hypercalcemia
(corrected for albumin)
10.6 to 11.5 mg/dL
11.6 to 12.5 mg/dL
12.6 to 13.5 mg/dL
>13.5 mg/dL or abnormal calcium with
life-threatening arrhythmia
Hypomagnesemia
1.4 to 1.2 mEq/L
1.1 to 0.9 mEq/L
0.8 to 0.6 mEq/L
<0.6 mEq/L or abnormal magnesium with
life-threatening arrhythmia
Hypophosphatemia
2.0 to 2.4 mg/dL
1.5 to 1.9 mg/dL or 
replacement Rx required
1.0 to 1.4 mg/dL
intensive therapy or hospitalization 
required
<1.0 mg/dL or abnormal phosphate with
life-threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any increase in 
other liver function test)
1.1 to <1.25 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.
 
 
 
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase 
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
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.
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or 
200 mg to 1 gm loss/day
2 to 3+ or
1 to 2 gm loss/day
4+ or
2 to 3.5 gm loss/day
Nephrotic syndrome or
>3.5 gm loss/day
Hematuria
Microscopic only
<10 RBC/HPF
Gross, no clots
>10 RBC/HPF
Gross, with or without clots,
or red blood cells casts
Obstructive or 
required transfusion
HPF = high-powered field; RBC = red blood cells.
 
 
 
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm
N/A
Asymptomatic, transient signs, no 
Rx required
Recurrent/persistent; symptomatic 
Rx required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension
Transient increase >20 mm Hg;
no treatment 
Recurrent, chronic increase
>20 mm Hg;
treatment required 
Acute treatment required; 
outpatient treatment or 
hospitalization possible 
End organ damage or 
hospitalization required 
Hypotension
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mmHg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
BP = blood pressure; EKG = electrocardiogram; IV = intravenous; mm Hg = millimeters of mercury; N/A = not applicable; Rx = therapy
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment 
responsive
Paroxysmal cough; uncontrolled 
with treatment
N/A
Bronchospasm, Acute
Transient; no treatment; FEV1 70 
to 80% of peak flow
Requires treatment; normalizes 
with bronchodilator; FEV1 50 to 
70% of peak flow
No normalization with 
bronchodilator; FEV1 25 to 50% of 
peak flow; or retractions present
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen 
therapy
N/A = not applicable; FEV1 = forced expiratory volume in 1 second
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; maintains 
reasonable intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV 
fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or 
needing IV fluids
Physiologic consequences 
requiring hospitalization or 
requiring parenteral nutrition
Constipation
Requiring stool softener or dietary 
modification
Requiring laxatives
Obstipation requiring manual 
evacuation or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 4 loose 
stools/day or mild diarrhea lasting 
<1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea
lasting >1 week
>7 loose stools/day or bloody 
diarrhea; or orthostatic 
hypotension or electrolyte 
imbalance or >2L IV fluids 
required
Hypotensive shock or physiologic 
consequences requiring 
hospitalization
Oral discomfort/
Dysphagia
Mild discomfort; no difficulty 
swallowing
Some limits on eating/drinking
Eating/talking very limited; unable 
to swallow solid foods
Unable to drink fluids; requires IV 
fluids
IV = intravenous.
 
 
 
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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
 
 
 
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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia 
(joint pain)
Mild pain not interfering with function
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL
Severe paid; pain and/or analgesics 
interfering with ADL
Disabling pain
Arthritis
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL
Severe pain with inflammation, erythema 
or joint swelling, and interfering with ADL
Permanent and/or 
disabling joint 
destruction
Myalgia
Myalgia with no limitation of activity
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity
Severe muscle tenderness with marked 
impairment of activity
Frank myonecrosis
ADL = activities of daily living.
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
Erythema; pruritus
Diffuse, maculo papular rash, dry 
desquamation
Vesiculation or moist 
desquamation or ulceration
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery
Induration
<15 mm
15 to 30 mm
>30 mm
N/A
Erythema
<15 mm
15 to 30 mm
>30 mm
N/A
Edema
<15 mm
15 to 30 mm
>30 mm
N/A
Rash at injection site
<15 mm
15 to 30 mm
>30 mm
N/A
Pruritus
Slight itching at injection site
Moderate itching at injection extremity
Itching over entire body
N/A
N/A = not applicable.
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 103 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25 to 50%; 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self
 
 
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
and Collection of Pregnancy Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential
The list does not apply to females of reproductive potential with same sex partners or for 
subjects who are and will continue to be abstinent from penile-vaginal intercourse on a 
long term and persistent basis, when this is their preferred and usual lifestyle. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the clinic 
personnel’s review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child-bearing potential must comply with the 
following contraception requirements from 30 days prior to the first dose until 
completion of the Follow-up Visit.
8.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
9.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system
 
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
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject’s pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to 
GSK as described in Appendix 5. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating:

Will be withdrawn from the study.

The investigator will attempt to collect pregnancy information on any female 
partner of a male study subject who becomes pregnant while participating in this 
study. This applies only to subjects who are randomized to receive study 
medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy.
 
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
The partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
 
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12.8.
Appendix 8 – Follow-up for Gastrointestinal Findings
Subjects who experience diarrhea or enteritis should be evaluated with additional fecal 
occult blood tests and stool cultures as deemed appropriate by the investigator. Any 
subject with a positive fecal occult blood test should be referred to a gastroenterologist 
for further evaluation at the discretion of the investigator.
Subjects who experience an AE of diarrhea or enteritis should have additional fecal 
occult blood testing, as well as a routine stool culture performed, which may include the 
recovery of pathogenic bacteria such as Salmonella, Shigella, Campylobacter, Yersinia, 
Vibrio, Staphylococcus aureus, Escherichia coli 0157, and enterohemorrhagic 
Escherichia coli.
In addition, if the subject meets the clinical criteria outlined in Appendix 9, Clostridium 
difficile toxin detection should be conducted.
Note: Additional testing is at the discretion of the investigator if it is believed the 
GI signs/symptoms are due to cholinergic effects and/or if the GI signs/symptoms occur 
within 24 hours of the infusion.
 
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12.9.
Appendix 9: Clostridium Difficile Testing Procedure and 
Algorithm
 
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12.10.
Appendix 10 - Country Specific Requirements
No country-specific requirements exist.
 
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