A Phase I, Open-Label, Single-Dose, Multi-Part Study to Assess the Pharmacokinetics of Gepotidacin (GSK2140944) in Male and Female Adult Subjects With Varying Degrees of Renal Impairment and in Matched Control Subjects With Normal Renal Function
Phase: PHASE1
Conditions: Infections, Bacterial
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase I, Open-Label, Single-Dose, Multi-Part Study to Assess 
the Pharmacokinetics of Gepotidacin (GSK2140944) in Male 
and Female Adult Subjects with Varying Degrees of Renal 
Impairment and in Matched Control Subjects with Normal Renal 
Function
Compound Number:
GSK2140944
Development Phase
I
Effective Date:
01-MAR-2016
Authors:
GSK Authors: 
 (Clinical Pharmacology Modeling and Simulation), 
 (Investigative Safety and Drug Disposition), 
 (ID, Medicines 
Discovery and Development), 
 (Clinical Statistics), and 
 (Clinical 
Pharmacology).
PPD Authors: 
 (Pharmacokineticist), 
 (Biostatistician), 
 
(Global Product Development), 
 (Global Product Development), and 
 (Medical Writer)
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Clinic Address
Primary 
Medical 
Monitor and 
SAE contact 
Information
 
 MD 
Safety Hotline: 
Safety fax 
number:
PPD
7551 Metro Center
Austin, Texas 78744
Secondary 
Medical 
Monitor
 
 MD
GlaxoSmithKline
1250 South Collegeville 
Road
Collegeville, PA 19426, 
USA
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: 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 BTZ116849 .................................................8
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVES AND ENDPOINTS...........................................................................13
4.
STUDY DESIGN ....................................................................................................13
4.1.
Overall Design ............................................................................................13
4.2.
Treatment Arms and Duration.....................................................................15
4.3.
Type and Number of Subjects.....................................................................16
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................17
4.6.
Benefit:Risk Assessment ............................................................................18
4.6.1.
Risk Assessment .........................................................................19
4.6.2.
Benefit Assessment.....................................................................21
4.6.3.
Overall Benefit:Risk Conclusion...................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................23
5.3.
Screening/Baseline/Run-in Failures............................................................25
5.4.
Withdrawal/Stopping Criteria.......................................................................25
5.4.1.
Liver Chemistry Stopping Criteria ................................................25
5.4.2.
QTc Stopping Criteria ..................................................................26
5.4.3.
Gastrointestinal Stopping Criteria ................................................26
5.4.4.
Rash/Hypersensitivity Stopping Criteria .......................................27
5.5.
Subject and Study Completion....................................................................27
6.
STUDY TREATMENT ............................................................................................27
6.1.
Investigational Product and Other Study Treatment....................................27
6.2.
Treatment Assignment................................................................................27
6.3.
Planned Dose Adjustments.........................................................................28
6.4.
Blinding.......................................................................................................28
6.5.
Packaging and Labeling..............................................................................28
6.6.
Preparation/Handling/Storage/Accountability..............................................28
6.7.
Compliance with Study Treatment Administration.......................................29
6.8.
Treatment of Study Treatment Overdose....................................................29
6.9.
Treatment after the End of the Study ..........................................................30
6.10.
Lifestyle and/or Dietary Restrictions............................................................30
6.10.1.
Meals and Dietary Restrictions ....................................................30
6.10.2.
Caffeine and Alcohol....................................................................30
6.10.3.
Activity .........................................................................................30
6.11.
Concomitant Medications and Non-Drug Therapies....................................30
6.11.1.
Permitted Medications and Non-Drug Therapies..........................30
6.11.2.
Prohibited Medications and Nondrug Therapies...........................31
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................31
 
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7.1.
Time and Events Tables .............................................................................33
7.2.
Screening and Critical Baseline Assessments ............................................41
7.3.
Safety .........................................................................................................41
7.3.1.
Adverse Events and Serious Adverse Events..............................41
7.3.1.1.
Time period and Frequency for collecting
Adverse Event and Serious Adverse Event 
information .................................................................41
7.3.1.2.
Method of Detecting Adverse Events and 
Serious Adverse Events .............................................42
7.3.1.3.
Follow-up of Adverse Events and Serious 
Adverse Events ..........................................................42
7.3.1.4.
Regulatory Reporting Requirements for 
Serious Adverse Events .............................................42
7.3.2.
Pregnancy ...................................................................................42
7.3.3.
Physical Exams ...........................................................................43
7.3.4.
Vital Signs....................................................................................43
7.3.5.
Electrocardiogram........................................................................43
7.3.6.
Clinical Safety Laboratory Assessments ......................................43
7.4.
Pharmacokinetics .......................................................................................44
7.4.1.
Blood Sample Collection..............................................................44
7.4.2.
Urine Sample Collection ..............................................................45
7.4.3.
Saliva Sample Collection .............................................................45
7.4.4.
Dialysate Sample Collection ........................................................45
7.4.5.
Sample Analysis ..........................................................................45
7.5.
Optional Pharmacokinetic Markers .............................................................46
7.6.
Genetics .....................................................................................................46
8.
DATA MANAGEMENT ...........................................................................................46
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................46
9.1.
Hypotheses.................................................................................................46
9.2.
Sample Size Considerations.......................................................................47
9.2.1.
Sample Size Assumptions ...........................................................47
9.2.2.
Sample Size Re-estimation or Adjustment...................................47
9.3.
Data Analysis Considerations .....................................................................47
9.3.1.
Analysis Populations....................................................................47
9.3.2.
Interim Analysis ...........................................................................47
9.4.
Key Elements of Analysis Plan ...................................................................48
9.4.1.
Primary Analyses.........................................................................48
9.4.2.
Secondary Analyses ....................................................................50
9.4.2.1.
Safety Analyses..........................................................50
9.4.3.
Other Analyses ............................................................................51
9.4.3.1.
Exploratory Analyses..................................................51
10. STUDY GOVERNANCE CONSIDERATIONS........................................................51
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............51
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................51
10.3.
Quality Control (Study Monitoring) ..............................................................52
10.4.
Quality Assurance.......................................................................................53
10.5.
Study and Clinic Closure.............................................................................53
10.6.
Records Retention......................................................................................53
 
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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................54
11. REFERENCES.......................................................................................................55
12. APPENDICES........................................................................................................57
12.1.
Appendix 1: Abbreviations and Trademarks................................................57
12.2.
Appendix 2: Liver Chemistry Stopping Criteria............................................59
12.3.
Appendix 3: Liver Safety Required Actions and Follow-up 
Assessments ..............................................................................................60
12.4.
Appendix 4: Genetic Research ...................................................................62
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................65
12.5.1.
Definition of Adverse Events........................................................65
12.5.2.
Definition of Serious Adverse Events...........................................66
12.5.3.
Definition of Cardiovascular Events .............................................67
12.5.4.
Recording of Adverse Events and Serious Adverse Events .........68
12.5.5.
Evaluating Adverse Events and Serious Adverse Events.............68
12.5.6.
Reporting of Serious Adverse Events to GSK..............................69
12.6.
Appendix 6: Division of Microbiology and Infectious Disease Adult 
Toxicity Tables for Adverse Event Assessment...........................................71
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential and Collection of 
Pregnancy Information................................................................................79
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential.........................79
12.7.2.
Collection of Pregnancy Information ............................................80
12.8.
Appendix 8: Follow-up for Gastrointestinal Findings ...................................82
12.9.
Appendix 9: Clostridium Difficile Testing Procedure and Algorithm .............83
12.10. Appendix 10: Country-Specific Requirements.............................................84
12.11. Appendix 11: Physiologically Based Pharmacokinetic Model Input 
Parameters.................................................................................................85
 
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1.
PROTOCOL SYNOPSIS FOR STUDY BTZ116849
Rationale
This study will be conducted to determine if altered renal function affects the plasma 
pharmacokinetics of gepotidacin, which will inform if dosing recommendations based 
upon renal impairment are required. The proposed single IV infusion dose of gepotidacin 
750 mg administered over 2 hours will provide an approximate 2.5-fold margin for area 
under the plasma concentration-time curve (AUC) and maximum observed concentration 
(Cmax) based on the highest single IV dose of gepotidacin (1800 mg) evaluated in adult 
healthy subjects.
Objectives/Endpoints
Objectives
Endpoints
Primary

To compare the pharmacokinetics of 
gepotidacin administered as a 750-mg IV dose 
in normal healthy subjects compared with
subjects with mild, moderate, and severe renal 
impairment, and with subjects with end-stage 
renal disease (ESRD)

Plasma primary pharmacokinetic (PK) endpoints include 
AUC(0-∞) and Cmax of gepotidacin, as data permit

Urine primary PK end points include Ae total, fe%, and 
CLr of gepotidacin, as data permit

Dialysate primary PK end points include AUC(t0-t1), CLD, 
and Frem%(0-4), of gepotidacin, as data permit
Secondary

To assess the safety and tolerability of 
gepotidacin administered as a 750-mg IV dose 
in normal healthy subjects compared with 
subjects with mild, moderate, severe renal 
impairment, and with subjects with ESRD

12-lead safety electrocardiogram readings, change from 
baseline in vital sign measurements (blood pressure and 
heart rate), monitoring of adverse events, toxicity grading 
of clinical laboratory test results, and physical 
examinations

To evaluate the secondary PK parameters of 
gepotidacin administered as a 750-mg IV dose 
in normal healthy subjects compared with 
subjects with mild, moderate, and severe renal 
impairment, and with subjects with ESRD

Plasma PK endpoints include AUC(0-t), CL, z, t1/2, 
Tmax, Vss, and Vz, as data permit

Urine PK endpoint includes Ae(t1-t2), as data permit

Dialysate PK endpoints include Arem(0-1), Arem(1-2), 
Arem(2-3), Arem(3-4), and Arem(0-4), as data permit
Exploratory

To evaluate the saliva pharmacokinetics of 
gepotidacin (subjects in Part 1 only)

Primary PK endpoints include AUC(0-∞) and Cmax of 
gepotidacin, as data permit

Secondary PK endpoints include AUC(0-t), CL, λz, t1/2, 
Tmax, Vss, and Vz, as data permit
ESRD = end-stage renal disease; PK = pharmacokinetic
Overall Design
This is a Phase I, nonrandomized, open-label, parallel-group, multi-center, multi-part 
study that will evaluate the pharmacokinetics, safety, and tolerability of a single IV dose 
of gepotidacin 750 mg over 2 hours in subjects with normal renal function, subjects with 
mild, moderate, and severe renal impairment, and subjects with end-stage renal disease 
(ESRD; on dialysis and not on dialysis).
Subjects will be enrolled into groups based on the classification as defined in the United 
States Food and Drug Administration draft guidance for industry, “Pharmacokinetics in 
Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on 
 
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Dosing and Labeling” [DHHS, 2010]. Subjects with normal renal function and subjects 
with renal impairment will be classified based on the estimated glomerular filtration rate 
(eGFR; based on the Modification of Diet in Renal Disease Study). Subjects with normal 
renal function will also be classified based on estimated creatinine clearance (Clcr).
This will be a multi-part study, in which pharmacokinetic (PK) requirements must be met 
(observed mean values: AUC <48 ghr/mL and Cmax <14 g/mL); and safety and 
tolerability will be reviewed before enrolling subjects into the next part of the study. In 
Part 1, subjects with normal renal function; subjects with moderate renal impairment; and
subjects with severe renal impairment and subjects with ESRD not on hemodialysis will 
be enrolled. In Part 2 (optional), subjects with normal renal function, subjects with mild 
renal impairment, and subjects with ESRD on hemodialysis will be enrolled based on the 
PK, safety, tolerability, and data results of Part 1.
Subjects with renal impairment will be matched to subjects with normal renal function in 
terms of gender distribution, age (approximately ±10 years), and body mass index 
(approximately ±20%).
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic and will be enrolled 
as follows:
Part 1:

Group A: subjects with normal renal function (eGFR ≥90 mL/min/1.73m2)

Group B: subjects with moderate renal impairment (eGFR 30 to 59 mL/min/1.73m2)

Group C: subjects with severe renal impairment and subjects with ESRD not on 
hemodialysis (eGFR <30 mL/min/1.73m2)
If PK, safety, and tolerability requirements are not met in Part 1, and based on the 
emerging data, and/or data that are not expected to exceed the requirements in the 
subjects with ESRD on hemodialysis or may require dose adjustment, subjects for Part 2 
will be enrolled. In addition, based on emerging data from Part 1, Group E may not be 
enrolled in Part 2 (optional).
Part 2 (Optional):

Group D: subjects with normal renal function (eGFR ≥90 mL/min/1.73m2)*

Group E: subjects with mild renal impairment (eGFR 60 to 89 mL/min/1.73m2)

Group F: subjects with ESRD on hemodialysis 
* If there are a sufficient number of subjects with normal renal function enrolled in Part 1 
(Group A) that match subjects with renal impairment in other groups, a determination 
will be made regarding the enrollment of matching subjects with normal renal function in 
Part 2 (Group D).
Subjects in Groups A, B, C, D, and E will enter the clinic at Check-in (Day - 1, Period 1) 
before study drug administration (Day 1, Period 1). In Parts 1 and 2, on Day 1 (Period 1), 
 
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subjects in Group A, B, C, D, and E will receive a single dose of study drug as follows: 
gepotidacin 750 mg administered as a 2-hour IV infusion. All subjects will be discharged 
from the clinic on Day 3 after all scheduled PK and safety assessments have been 
completed, and will return to the clinic for a Follow-up Visit approximately 10 days 
(±5 days) after dose administration. The duration of the study (from Screening to the 
Follow-up Visit) will be approximately 44 days. 
In Part 2 (optional) of the study, subjects in Group F will participate in 2 treatment 
periods, with dosing in these periods separated by a washout period of at least 7 days. 
Subjects in Group F will enter the clinic at Check-in (Day –1, Period 1 and Day 7, 
Period 2) before each study drug administration (Day 1, Period 1 and Day 8, Period 2). 
On Day 1 (Period 1) and Day 8 (Period 2), subjects in Group F will receive a single dose 
of study drug as follows: gepotidacin 750 mg administered as a 2-hour IV infusion 
starting approximately 2 hours before the initiation of the last hemodialysis session of the 
week (Period 1) and gepotidacin 750 mg administered as a 2-hour IV infusion starting 
within 2 hours after completion of the last hemodialysis session of the week (Period 2). 
Subjects in Group F will be discharged from the clinic on Day 10, Period 2 after all 
scheduled PK and safety assessments have been completed, and will return to the clinic 
for a Follow-up Visit approximately 10 days (±5 days) after the last dose administration 
in Period 2. The duration of the study (from Screening to the Follow-up Visit) will be 
approximately 50 days.
Type and Number of Subjects
In Part 1, up to 16 subjects with normal renal function will be matched to approximately
8 subjects with moderate renal impairment, and approximately 8 subjects with severe 
renal impairment and/or subjects with ESRD not on hemodialysis for a total of 
approximately 32 subjects. In Part 2 (optional), approximately 4 to 8 subjects with 
normal renal function (if enrolled), approximately 4 to 8 subjects with mild renal 
impairment, and approximately 4 to 8 subjects with ESRD on hemodialysis will be 
enrolled for a total of approximately 12 to 24 subjects.
If there are a sufficient number of subjects with normal renal function enrolled in Part 1 
(Group A) that match subjects with renal impairment in other groups, a determination 
will be made regarding enrollment of matching subjects with normal renal function in 
Part 2 (Group D). In addition, if subjects prematurely discontinue the study, additional 
replacement subjects may be enrolled at the discretion of the Sponsor in consultation with 
the investigator.
Analysis
Plasma and saliva concentrations of gepotidacin will be analyzed (as data permit) by 
noncompartmental PK analysis to determine the following PK metrics: AUC from 
hour 0 to the last measurable plasma concentration (AUC(0-t)), AUC extrapolated to 
infinity (AUC(0-)), Cmax, time to maximum concentration (Tmax), apparent terminal 
phase half-life (t1/2), systemic clearance (CL), volume of distribution at steady-state of 
parent drug (Vss; plasma only), and volume of distribution of the terminal phase (Vz).
 
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Urine 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)), percentage of the given 
dose excreted in urine (fe%), and renal clearance (Clr). 
Plasma, urine, and saliva (subjects in Part 1 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.
Dialysate concentration of gepotidacin will be analyzed for all subjects with ESRD on 
dialysis (Group F subjects in Part 2 [optional]) to determine the following PK metrics: 
total amount of unchanged amount of drug removed by hemodialysis (Arem) from time 0 
to 1 hour after the start of hemodialysis (Arem(0-1)), Arem from time 1 to 2 hours after 
the start of hemodialysis (Arem(1-2)), Arem from time 2 to 3 hours after the start of 
hemodialysis (Arem(2-3)), Arem from time 3 to 4 hours after the start of hemodialysis 
(Arem(3-4)), cumulative amount of drug removed by hemodialysis from time 0 to 4 
hours (or to the end of dialysis if less than 4 hours; Arem(0-4)), partial area under the 
curve estimated from predialyzer samples collected from start of dialysis (t0) to end of 
dialysis (t1; AUC(t0-t1)), dialysis clearance (CLD), and fraction (%) of the dose removed 
by hemodialysis from 0 to 4 hours after the start of hemodialysis (or to the end of dialysis 
if less than 4 hours; Frem%(0-4)). Dialysate concentrations (Group F) 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.
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 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
In a previous absorption, distribution, metabolism, and excretion study for gepotidacin 
(See GSK Document Number 2014N189951_00 Study ID Study BTZ115774), the mean 
recovery of radioactivity in urine accounted for approximately 60% of [14C]-gepotidacin 
administered as a single IV dose. In addition, renal clearance of gepotidacin has been 
estimated to be approximately 40% of total systemic drug clearance. Therefore, renal 
impairment has the potential to adversely affect the elimination of gepotidacin.
It is expected that potential patients in future gepotidacin Phase III studies may have at 
least some degree of renal impairment. The results from this study will enable the 
development of appropriate dosing recommendations in patients with impaired renal 
function.
2.2.
Brief Background
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.
 
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the pharmacokinetics of 
gepotidacin administered as a 750-mg 
IV dose in normal healthy subjects 
compared with subjects with mild, 
moderate, and severe renal 
impairment, and with subjects with 
end-stage renal disease (ESRD)

Plasma primary pharmacokinetic (PK) endpoints 
include AUC(0-∞) and Cmax of gepotidacin, as 
data permit

Urine primary PK end points include Ae total, 
fe%, and CLr of gepotidacin, as data permit

Dialysate primary PK end points include 
AUC(t0-t1), CLD, and Frem%(0-4), of 
gepotidacin, as data permit
Secondary

To assess the safety and tolerability of 
gepotidacin administered as a 750-mg 
IV dose in normal healthy subjects 
compared with subjects with mild, 
moderate, severe renal impairment, 
and with subjects with ESRD

12-lead safety electrocardiogram readings, 
change from baseline in vital sign 
measurements (blood pressure and heart rate), 
monitoring of adverse events, toxicity grading of 
clinical laboratory test results, and physical 
examinations

To evaluate the secondary PK 
parameters of gepotidacin
administered as a 750-mg IV dose in 
normal healthy subjects compared with 
subjects with mild, moderate, and 
severe renal impairment, and with 
subjects with ESRD

Plasma PK endpoints include AUC(0-t), CL, z, 
t1/2, Tmax, Vss, and Vz, as data permit

Urine PK endpoint includes Ae(t1-t2), as data 
permit

Dialysate PK endpoints include Arem(0-1), 
Arem(1-2), Arem(2-3), Arem(3-4), and 
Arem(0-4), as data permit
Exploratory

To evaluate the saliva 
pharmacokinetics of gepotidacin 
(subjects in Part 1 only)

Primary PK endpoints include AUC(0-∞) and 
Cmax of gepotidacin, as data permit

Secondary PK endpoints include AUC(0-t), CL, 
λz, t1/2, Tmax, Vss, and Vz, as data permit
ESRD = end-stage renal disease; PK = pharmacokinetic
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I, nonrandomized, open-label, parallel-group, multi-center, multi-part 
study that will evaluate the pharmacokinetics, safety, and tolerability of a single IV dose 
of gepotidacin 750 mg over 2 hours in subjects with normal renal function; subjects with 
mild, moderate, and severe renal impairment; and subjects with end-stage renal disease 
(ESRD; on dialysis and not on dialysis). Subjects with renal impairment will be matched 
to subjects with normal renal function in terms of gender distribution, age (approximately 
±10 years), and body mass index (BMI; approximately ±20%).
At Screening, subjects will be enrolled to the appropriate groups based on the 
classification as defined in the Food and Drug Administration (FDA) draft guidance for 
 
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industry, “Pharmacokinetics in Patients with Impaired Renal Function – Study Design, 
Data Analysis, and Impact on Dosing and Labeling” [DHHS, 2010]. Subjects with 
normal renal function and subjects with renal impairment will be classified based on the 
estimated glomerular filtration rate (eGFR; based on the Modification of Diet in Renal 
Disease Study). Subjects with normal renal function will also be classified based on 
estimated creatinine clearance (Clcr). For more details see Section 6.2.
This will be a multi-part study, in which pharmacokinetic (PK) requirements must be met 
(observed mean values: area under the curve [AUC] <48 ghr/mL and maximum 
observed concentration [Cmax] <14 g/mL); and safety and tolerability will be reviewed 
before enrolling subjects into the next part of the study. In Part 1, subjects with normal 
renal function; subjects with moderate renal impairment; and subjects with severe renal 
impairment and subjects with ESRD not on hemodialysis will be enrolled. In Part 2 
(optional), subjects with normal renal function, subjects with mild renal impairment, and 
subjects with ESRD on hemodialysis will be enrolled based on the PK, safety, and 
tolerability data of Part 1.  Subjects with mild renal impairment may be studied if there is 
a significant difference in PK between subjects with moderate and severe renal 
impairment compared to subjects with normal renal function and modelling cannot 
accurately predict PK in subjects with mild renal impairment.  Subjects with ESRD on 
hemodialysis will be studied provided that the PK requirements are met (observed mean 
values in subjects with severe impairment do not exceed the threshold: area under the 
curve [AUC] <48 ghr/mL and maximum observed concentration [Cmax] <14 g/mL).  
The dose may be adjusted for subjects with ESRD on hemodialysis if either PK 
parameter is predicted to exceed the threshold.  See the study schematic in Figure 1 for 
more details.
For subjects with normal renal function, subjects with mild, moderate, and severe renal 
impairment, and subjects with ESRD not on dialysis: subjects will participate in 
1 treatment period and blood and urine samples will be collected for PK analysis of 
gepotidacin concentrations according to the Time and Events Tables (Table 2 and Table 
3). In addition, saliva samples (subjects in Part 1 only) will be collected for the 
PK analysis of gepotidacin concentrations according to the Time and Events Tables 
(Table 2 and Table 3). Blood, urine, and saliva samples will be collected up to 
approximately 48 hours after dosing.
For subjects with ESRD on hemodialysis: subjects will participate in 2 treatment periods 
and blood and urine (if applicable) samples in Period 1 will be collected for PK analysis 
of gepotidacin concentrations according to the Time and Events Tables (Table 4 and 
Table 5). Blood and urine (if applicable) samples will be collected up to approximately 
48 hours after dosing (i.e., the last sample will be collected before the next hemodialysis 
session). In addition, dialysate samples will be collected for the determination of 
gepotidacin concentrations according to the Time and Events Tables (Table 4 and Table 
5).
Optional PK Assessment: with the subject’s consent, if a kidney or bladder tissue sample 
is collected for a nonstudy purpose during this study, excess tissue may be collected and 
used for the purposes of measuring tissue gepotidacin concentrations.
 
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Figure 1
BTZ116849 Study Schematic
ESRD = end-stage renal disease; PK = pharmacokinetic
a
If there are a sufficient number of subjects with normal renal function enrolled in Part 1 (Group A), a determination 
will be made regarding enrollment of matching subjects with normal renal function in Part 2 (Group D).
b
Based on emerging data from Part 1, Group E (subjects with mild renal impairment) may not be enrolled in Part 2 
if there is not a significant difference between subjects with moderate and severe impairment compared to 
subjects with normal renal function or if the PK can be accurately predicted.    
c
If AUC and/or Cmax is predicted to exceed the threshold, the dose may be adjusted in Group F (optional). 
4.2.
Treatment Arms and Duration
Subjects will be screened within 30 days prior to entry to the clinic and will be enrolled 
as follows:
Part 1:

Group A: subjects with normal renal function (eGFR ≥90 mL/min/1.73m2)

Group B: subjects with moderate renal impairment (eGFR 30 to 59 mL/min/1.73m2)

Group C: subjects with severe renal impairment and subjects with ESRD not on 
hemodialysis (eGFR <30 mL/min/1.73m2)
If PK, safety, and tolerability requirements are not met in Part 1, and based on the 
emerging data, and/or data that are not expected to exceed the requirements in the 
subjects with ESRD on hemodialysis or may require dose adjustment, subjects for Part 2 
will be enrolled. In addition, based on emerging data from Part 1, Group E may not be 
enrolled in Part 2 (optional).
Part 1
Group A: Subjects with normal renal function
Group B: Subjects with moderate renal impairment
Group C: Subjects with severe renal impairment and subjects 
with ESRD not on hemodialysis
PK requirements to continue to Part 2
Observed Mean Values:
AUC <48 ghr/mL
Cmax <14 g/mL
(Based on emerging data, and/or data that are not expected to 
exceed these requirements in subjects with ESRD on 
hemodialysis or may require dose adjustment, subjects in Part 
2 will be enrolled.)
Part 2 (Optional)
Group D: Subjects with normal renal functiona
Group E: Subjects with mild renal impairmentb
Group F: Subjects with ESRD on hemodialysisc
 
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Part 2 (Optional):

Group D: subjects with normal renal function (eGFR ≥90 mL/min/1.73m2)*

Group E: subjects with mild renal impairment (eGFR 60 to 89 mL/min/1.73m2)

Group F: subjects with ESRD on hemodialysis 
* If there are a sufficient number of subjects with normal renal function enrolled in Part 1 
(Group A) that match subjects with renal impairment in other groups, a determination 
will be made regarding the enrollment of matching subjects with normal renal function in 
Part 2 (Group D).
Subjects with renal impairment will be matched to subjects with normal renal function in 
terms of gender distribution, age (approximately ±10 years), and BMI (approximately 
±20%).
Subjects in Groups A, B, C, D (if enrolled; see Section 4.3 for more details), and E will 
enter the clinic at Check-in (Day –1, Period 1) before study drug administration (Day 1,
Period 1). On Day 1 (Period 1), subjects in Group A, B, C, D, and E will receive a single 
dose of study drug as follows: gepotidacin 750 mg administered as a 2-hour IV infusion. 
All subjects will be discharged from the clinic on Day 3 after all scheduled PK and safety 
assessments have been completed, and will return to the clinic for a Follow-up Visit 
approximately 10 days (±5 days) after dose administration. The duration of the study 
(from Screening to the Follow-up Visit) will be approximately 44 days. 
In Part 2 (optional) of the study, subjects in Group F will participate in 2 treatment 
periods, with dosing in these periods separated by a washout period of at least 7 days. 
Subjects in Group F will enter the clinic at Check-in (Day –1, Period 1 and Day 7, 
Period 2) before each study drug administration (Day 1, Period 1 and Day 8, Period 2). 
On Day 1 (Period 1) and Day 8 (Period 2), subjects in Group F will receive a single dose 
of study drug as follows: gepotidacin 750 mg administered as a 2-hour IV infusion 
starting approximately 2 hours before the initiation of the last hemodialysis session of the 
week (Period 1) and gepotidacin 750 mg administered as a 2-hour IV infusion starting 
within 2 hours after completion of the last hemodialysis session of the week (Period 2). 
Subjects in Group F will be discharged from the clinic on Day 10 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 10 days (±5 days) after the last dose administration 
in Period 2. The duration of the study (from Screening to the Follow-up Visit) will be 
approximately 50 days.
4.3.
Type and Number of Subjects
In Part 1, up to 16 subjects with normal renal function will be matched to approximately 
8 subjects with moderate renal impairment, and approximately 8 subjects with severe 
renal impairment and/or subjects with ESRD not on hemodialysis for a total of 
approximately 32 subjects. In Part 2 (optional), approximately 4 to 8 subjects with 
normal renal function (if enrolled), approximately 4 to 8 subjects with mild renal 
impairment, and approximately 4 to 8 subjects with ESRD on hemodialysis will be 
enrolled for a total of approximately 12 to 24 subjects.
 
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If there are a sufficient number of subjects with normal renal function enrolled in Part 1 
(Group A) that match subjects with renal impairment in other groups, a determination 
will be made regarding enrollment of matching subjects with normal renal function in 
Part 2 (Group D). In addition, if subjects prematurely discontinue the study, additional 
replacement subjects may be enrolled at the discretion of the Sponsor in consultation with 
the investigator.
4.4.
Design Justification
This study design is commonly used when evaluating the pharmacokinetics of a drug 
entity in subjects with impaired renal function. It is based on recommendations given in 
the FDA draft guidance for industry, Pharmacokinetics in Patients with Impaired Renal 
Function — Study Design, Data Analysis, and Impact on Dosing and Labeling 
[DHHS, 2010]. 
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 proposed single IV infusion dose of gepotidacin 750 mg administered over 2 hours 
will provide an approximate 2.5-fold margin for mean Cmax and AUC based on the 
highest single IV dose of gepotidacin (1800 mg) evaluated in adult healthy subjects.
A physiologically-based pharmacokinetic (PBPK) model was developed for gepotidacin 
using the SimCYP population based absorption, distribution, metabolism, and excretion 
(ADME) simulator Version 15 (Certara USA, Inc, Princeton, NJ). Pharmacokinetic data 
from healthy Caucasian subjects following single 2-hour IV infusion doses of 400 mg, 
1000 mg, and 1800 mg (see GSK Document Number 2014N198291_00 Study ID 
BTZ115198) was used to predict the intrinsic hepatic clearance. The predictive 
performance of the PBPK model was verified by comparing the observed AUC from time 
0 to the time of the last quantifiable concentration (AUC(0-t)) and Cmax of gepotidacin 
to the predicted values at the 3 doses of 400 mg, 1000 mg, and 1800 mg. This model was 
further validated using a 750-mg IV 2-hour infusion dosing regimen in Japanese subjects 
from the same clinical study [see report of Study BTZ115198]. The model predictions 
agreed well with the observed data for the Caucasian population for all 3 dosing 
regimens, with predicted and observed values of a 5% to 12% difference in AUC(0-t) and 
a 1% to 5% difference, respectively, in Cmax. Simulations were also in good agreement 
with PK data in Japanese subjects. The model input parameters are listed in Appendix 11.
The PBPK model was then utilized to predict exposure for the proposed dosing regimen 
(750-mg IV 2-hour infusion) in healthy Caucasian subjects with normal renal function 
and subjects with various levels of impaired renal function as implemented in SimCYP 
with a female to male ratio of 0.5. The simulations were performed with the assumption 
of only GFR changes in subjects with renal impairment (software “RenalGFR30-60” and 
“RenalGFR_less_30”) and no active renal secretion due to the limited understanding of 
renal uptake mechanism for gepotidacin. The predicted geometric mean in gepotidacin 
exposure (AUC(0-t)) for subjects with moderate and severe renal impairment was 
 
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increased up to 2.0-fold compared with healthy subjects with normal renal function 
(Table 1).
Table 1
Simulated Gepotidacin Pharmacokinetic Parameters in Healthy 
(Normal) and Renally Impaired Populations
Pharmacokinetic
Parameters
Predicted Geomean (CV%) [N = 100]
Healthy 
(Normal Renal Function)
(GFR ≥90 mL/min)
Moderate Renal 
Impairment
(GFR 30 to 60 mL/min)
Severe Renal Impairment
(GFR 15 to <30 mL/min)
Cmax (g/mL)
5.65 (18)
7.29 (19)
7.93 (20)
AUC(0-t) (gh/mL)
17.5 (23)
25.8 (24)
28.9 (26)
CV = coefficient of variation; GFR = glomular filtration rate; N = number of subjects included in the simulation
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
gepotidacin can be found in the Investigator’s Brochure (IB). The following section 
outlines the risk assessment and mitigation strategy for this protocol.
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Gepotidacin
Gastrointestinal (GI) Effects
Lower GI effects (soft stools, flatulence, and diarrhoea) are 
the most common GI-associated adverse events (AEs)
reported in human subjects dosed with gepotidacin.
In the Phase I studies, out of approximately 400 healthy 
subjects who have received gepotidacin, C. difficile has 
been reported in 8 subjects.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Patients 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 medication 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 bpm to 10 bpm 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. 
Exclusion criteria, close monitoring of clinical parameters, 
and AEs will be conducted and stopping criteria will be 
utilized to mitigate and assess cardiovascular effects.
Note: 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.
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 (increased 
salivation, slurred speech, blurred vision, dizziness, 
light-headedness, and GI upset). 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Infusion-Site Reactions
Infusion-site reactions (mild to moderate), including 
phlebothrombosis, have been observed more frequently 
following repeat dosing at higher doses (750 mg BID).
Infusion-site reaction events were reported as AEs for 2 of 
122 subjects (2%) and consisted of mild, related 
infusion-site pain (see GSK Document Number 
2015N243789_00 Study ID BTZ116704). 
Intravenous administration of gepotidacin is given by a 
slow infusion following carefully defined procedures to 
minimize risk of infusion site reactions.
Infusion-site reactions will be evaluated in an ongoing 
fashion throughout the study with interventions 
implemented as appropriate.
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 the report of Study 
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 report of
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 with normal renal 
function; in subjects with mild, moderate, and severe renal impairment; and in subjects 
with ESRD (on and not on hemodialysis), 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.
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 subject between 18 and 80 years of age, inclusive.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy subject must be in clinically stable health 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. Subject with renal impairment must have 
clinical laboratory values consistent with their disease and are approved by the 
investigator.
3. Subject with renal impairment (mild, moderate, severe, or subjects with ESRD) may 
be taking medications, which in the opinion of the investigator, are believed to be 
therapeutic but do not affect study drug absorption, distribution, metabolism, or 
excretion. These medications must be stable doses taken for at least 7 days before the 
first dose of study drug. Any exceptions will be discussed with the sponsor or medical 
 
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monitor on a case-by-case basis and the reasons documented.
4. Subject with normal renal function or renal impairment (estimated eGFR 
corresponding to the calculated eGFR [the estimated eGFR may be rounded to the 
nearest integer]) at Screening (Section 6.2).
5. Subjects with ESRD on hemodialysis should be on hemodialysis for at least 3 months 
before Screening and is able to tolerate a hemodialysis treatment lasting 3 to 4 hours 
with blood flow rates of >200 mL/min.
6. Alanine aminotransferase (ALT) and bilirubin <1.5 × upper limit of normal (ULN; 
isolated bilirubin >1.5 × ULN is acceptable, if bilirubin is fractionated and direct 
bilirubin <35%).
WEIGHT
7. Body weight 50 kg and BMI within the range 18.5 and 40 kg/m2, inclusive.
SEX
8.
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 continuous spontaneous amenorrhea (in 
questionable cases a blood sample will be obtained to test for simultaneous 
follicle-stimulating hormone 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 1 of the options listed below in the GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (Appendix 7) requirements from 30 days prior to the first dose
until completion of the Follow-up Visit.
c
For subjects with indeterminate pregnancy test results or a persistently low human 
chorionic gonadotropin results, nonpregnancy status must be documented by other 
means (subjects with ESRD only).
The investigator is responsible for ensuring that subjects understand how to properly use 
 
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methods of contraception. 
INFORMED CONSENT
9.
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 (excluding renal insufficiency and other related 
stable medical conditions within the renally impaired population of subjects 
[e.g., hypertension, diabetes, or anemia, which should be stable for at least 3 months 
before the first dose of study drug]) 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, 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. Subject has a functioning renal transplant.
4. Subject with renal impairment has a systolic blood pressure outside the range of 90 to 
200 mm Hg, a diastolic blood pressure outside the range of 45 to 110 mm Hg, or a 
heart rate outside the range of 40 to 120 bpm.
5. Subject with renal impairment has a hemoglobin value <9 g/dL.
6. Female subject has a positive pregnancy test result or is lactating at Screening or upon 
admission to the clinic.
7. Use of a systemic antibiotic within 30 days of Screening
8. Within 2 months before Screening, either a confirmed history of Clostridium difficile
diarrhoea infection or a past positive Clostridium difficile toxin test.
9. Subject has a history of drug and/or alcohol abuse within 6 months before Screening, 
as determined by the investigator, or subject has a positive drug screen at Screening 
or upon admission to the clinic. For subjects with renal impairment, a positive drug 
screen result related to the use of prescription medications is allowed per investigator 
review and approval, and tetrahydrocannabinol use is allowed per investigator review 
and approval.
10. History of sensitivity to any of the study drugs, components thereof, or a history of 
drug or other allergy that, in the opinion of the investigator or GSK medical monitor, 
contraindicates their participation.
11. History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
 
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uses heparin to maintain IV cannula patency).
CONCOMITANT MEDICATIONS
12. Subject has used medications known to affect the elimination of serum creatinine 
(e.g., trimethoprim or cimetidine) or competitors of renal tubular secretion 
(e.g., probenecid) within 30 days before dosing.
13. 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 within 7 days before dosing and during the 
study. Any exceptions (including subjects with renal impairment that will be on 
medications during the study) will be discussed with the sponsor or medical monitor 
on a case-by-case basis and the reasons will be documented.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
14. Subjects with normal renal function have a presence of hepatitis B surface antigen or
positive hepatitis C antibody test result at Screening or within 3 months prior to first 
dose of study treatment. A subject with renal impairment with stable hepatitis C who 
has normal liver function test results is allowed with investigator approval.
15. A positive test for human immunodeficiency virus antibody.
16. Subject has clinically significant abnormal findings in serum chemistry, hematology, 
or urinalysis results obtained at Screening or Day –1 (and Day 7 for Group F only), 
other than those associated with underlying renal conditions or other stable medical 
conditions consistent with the disease process.
17. Subject with normal renal function has a baseline corrected QT interval using the 
Fridericia formula (QTcF) of >450 milliseconds (msec) and subject with renal 
impairment has a baseline QTcF of >480 msec. 
OTHER EXCLUSION CRITERIA
18. 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.
19. Previous exposure to gepotidacin within 12 months prior to the first dosing day.
20. 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).
21. Subject is unable to comply with all study procedures, in the opinion of the 
investigator.
22. The subject should not participate in the study, in the opinion of the investigator or 
Sponsor.
 
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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 demography, screen failure details, eligibility criteria, 
and serious adverse events (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 clinic 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, emails, or text messages; 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 clinic 
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
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
Although stopping criteria for continued dosing of investigational product due to liver 
chemistry parameters are not applicable for single-dose studies, and, in this case, for 
subjects that will receive the gepotidacin dose twice (Group F), if subjects are found to 
have values consistent with usual stopping parameters, it is appropriate to institute 
evaluation and monitoring criteria according to standard GSK criteria. Therefore, liver 
 
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function tests should be evaluated according to stopping criteria and work-up instituted if 
defined parameters are reached.
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 corrected QT 
interval using the Fridericia formula, then the corrected QT interval using the 
Fridericia formula 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 nonprotocol 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 of the bulleted criterion below will be withdrawn from the 
study:

QTcF >500 msec

Change from baseline of QTc >60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch Block
<450 msec
>500 msec
450 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 diarrhoea 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)
Dosage form:
IV
Unit dose strength/Dosage level:
750 mg
Route of Administration/Duration
Single IV dose over 2 hours
Dosing instructions:
Instructions for the preparation of the IV drug are 
included in the Study Procedures Manual.
Physical description:
Gepotidacin lyophile is a pale yellow to greyish 
yellow cake.
Reconstituted solution: A clear, dark brown to dark 
brownish-yellow solution after reconstitution, free 
from visible particulate matter.
Manufacturer/Source of procurement:
GlaxoSmithKline
6.2.
Treatment Assignment
This is a nonrandomized, open-label study. Clinic personnel will enroll the subject into 
the study once a subject has met all eligibility requirements.
At Screening, subjects will be enrolled to the appropriate groups based on the 
classification as defined in the FDA draft guidance for industry, “Pharmacokinetics in 
Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on 
Dosing and Labeling” [DHHS, 2010]. 
 
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Subjects with normal renal function and subjects with renal impairment (or ESRD) will 
be assigned to a study group based on their eGFR calculated using the isotope dilution 
mass spectrometry-traceable Modification of Diet in Renal Disease formula as follows:

eGFR (mL/min/1.73 m2) = 175 × (serum creatinine) – 1.154 × (age) – 0.203 × 
(0.742 if female) × (1.212 if African American)
In addition, subjects with normal renal function will be classified based on estimated Clcr 
by the Cockcroft-Gault equation.
CLcr in mL/min is estimated from a spot serum creatinine (mg/dL) determination using 
the following formula: 

Clcr (mL/min) = [140 − age (years)] × weight (kg) ÷ 72 × serum creatinine (mg/dL) 
(× 0.85 for female patients)
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. However, based on emerging 
data from Part 1 (or Period 1 for Group F), the Part 2 (or Period 2 for Group F) dose may 
be reduced.
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
A description of the methods and materials required for the preparation of gepotidacin
will be detailed in a Study Specific Technical Agreement/Memo or pharmacy manual 
which will be accompanied by a Quality Agreement.

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. 
 
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
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.
Gepotidacin will be administered IV to subjects at the clinic. Administration will be 
documented in the source documents and reported in the electronic case report form 
(eCRF).
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.
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 eCRF
 
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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 subjects; subjects with mild, moderate, and severe renal 
impairment; and subjects with ESRD are eligible for study participation.
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition, whether or not GSK is providing 
specific post-study treatment.
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, pummelos, pomegranate juice, exotic citrus fruits, grapefruit hybrids, or 
fruit juices from 7 days prior to the first dose of study medication until after the final 
dose.
6.10.2.
Caffeine and Alcohol

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. 
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
In subjects with normal renal function, acetaminophen at doses of ≤2 grams/day is 
permitted; and in subjects with renal impairment or ESRD, acetaminophen at doses of 
≤2 grams/day is permitted for use with the approval of the investigator. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor.
 
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Subjects with renal impairment and subjects with ESRD may be taking medications that 
are considered therapeutic, and these medications should not interfere with the conduct of 
the study. Subjects with renal impairment should be on a stable regimen of chronic 
medications 7 days before the first dose of study drug on Day 1 until completion of the 
Follow-up Visit.
All concomitant medication use will be documented on the concomitant medication page 
in the eCRF.
6.11.2.
Prohibited Medications and Nondrug Therapies
Subjects with normal renal function, subjects with renal impairment, and subjects with 
ESRD must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements), unless specified in Section 6.11.1, 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. 
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 Tables 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 Tables, 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 
 
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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 (ICF). 

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 Tables
Table 2
Time and Events Table (Groups A, B, C, D, and E)
Procedure
Screening 
(up to 30 days 
prior to Day -1)
Check-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
post-last dose)
or Early 
Termination
Notes
–1
1
2
3
Confined to clinic
X
X
X
X
Subjects will be admitted to the clinic on 
Day –1 and will be discharged on Day 3. 
Confinement will be 4 days and 
3 overnight stays
Informed consent
X
Inclusion and exclusion criteria
X
X
Demographics
X
Complete physical examination including 
height and weight
X
Abbreviated physical examination
X
X
X
Medical history (includes substance 
usage and history of renal disease)
X
Substances: drugs, alcohol, and 
caffeine. Subjects with renal impairment 
should be on a stable regimen of 
chronic medications 7 days before the 
first dose of study drug on Day 1.
Past and current medical conditions 
(including renal impairment medical 
history and eGFR)
X
eGFR as defined in the FDA draft 
guidance for industry, 
“Pharmacokinetics in Patients with 
Impaired Renal Function” [DHHS, 2010]. 
Subjects with normal renal function will 
also be classified based on Clcr.
Serum or urine pregnancy test/FSH
X
X
X
Serum (or urine) pregnancy test (if 
WCBP); estradiol and FSH at 
Screening, as appropriate
HIV antibody, hepatitis B surface antigen,
and hepatitis C antibody testinga
X
Drug and alcohol screen
X
X
See Table 6.
 
 
 
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Procedure
Screening 
(up to 30 days 
prior to Day -1)
Check-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
post-last dose)
or Early 
Termination
Notes
–1
1
2
3
Laboratory assessments (include liver 
chemistries)
X
X
X
X
Including serum chemistry, hematology
and urinalysis. Results from 24 hours 
after dosing should be available before 
discharge on Day 3.
12-lead ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Respiratory rate and body temperature 
collected at Screening only.
Genetic sampleb
X
Collect a pharmacogenomics (PGx) 
sample only if the subject has a signed 
consent specific for this purpose. The 
PGx sample can be collected anytime, 
but Day –1 is recommended.
Study drug administration
X
Blood collection for pharmacokinetics
X
X
X
See Table 3 for time points.
Urine collection for pharmacokinetics
X
X
X
Subjects with normal renal function and 
subjects with renal impairment will have 
different collection intervals. See Table 
3 for time points.
Saliva collection for pharmacokineticsc
X
X
X
See Table 3 for time points.
AE/SAE review
X
X
==================
X
Concomitant medication review
X
==================
X
AE = adverse event, Clcr = estimated creatinine clearance; eGFR = estimated glomular filtration rate, ECG = electrocardiogram, FSH = follicle stimulating hormone; HIV = human 
immunodeficiency virus; PGx = pharmacogenetic, SAE = serious AE; WCBP = women of childbearing potential.
a
If test has otherwise been performed within 3 months before the first dose of study treatment, testing at Screening is not required.
b
Informed consent for optional substudies (e.g., genetics research) must be obtained before collecting a sample.
c
Subjects in Part 1 only. It should be noted that subjects with renal impairment may be on medications that may prevent saliva collections.
 
 
 
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Table 3
Safety and PK Assessments (Groups A, B, C, D, and E)
Treatment Period
Time point (hours)
Procedurea
Predose
0
0.25
0.5
1
1.5
2
2.5
3
4
6
8
12
24b
36b
48b
12-lead electrocardiogram
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Treatment administration 
2-hour IV gepotidacin infusion
X
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for 
pharmacokinetics (subjects 
with normal renal function)c
X
X
X
X
X
X
X
X
X
X
Urine collection for 
pharmacokinetics (subjects 
with renal impairment)d
X
X
X
X
X
X
X
Saliva collectionse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
When coinciding with safety and/or pharmacokinetic assessments, electrocardiograms, vital signs, and pharmacokinetic blood collections should be performed in said order.
b
The 24-, 36-, and 48-hour postdose time points correspond to time points on Day 2 and 3, respectively.
c
Urine collection intervals for subjects with normal renal function (Group A and Group D) 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.
d
Urine collection intervals for subjects with renal impairment (Group B, Group C, and Group E) include 0 hour (pre-dose), 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 36, and 
36 to 48 hours.
e
Subjects in Part 1 only. It should be noted that subjects with renal impairment may be on medications that may prevent saliva collections. 
 
 
 
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Table 4
Time and Events Tables (Group F)
Procedurea
Screening 
(up to 
30 days prior 
to Day -1)
Check
-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
post-last 
dose) or 
Early 
Termination
Notes
1
2
–1
1
2
3
4 to 6
7
8
9
10
Confined to clinicb
X
X
X
X
X
X
X
X
Subjects will be admitted 
to the clinic on Day –1 
and Day 7, and will be 
discharged on Day 3 
(Period 1) and Day 10
(Period 2). Confinement 
will be 8 days and 
6 overnight stays) total.
Informed consent
X
Inclusion and exclusion 
criteria
X
X
X
Demographics
X
Complete physical 
examination including 
height and weight
X
Abbreviated physical 
examination
X
X
X
X
Medical history (includes 
substance usage and 
history of renal disease)
X
Substances: drugs, 
alcohol, and caffeine.
Subjects with renal 
impairment should be on 
a stable regimen of 
chronic medications 
7 days before the first 
dose of study drug on 
Day 1.
 
 
 
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Procedurea
Screening 
(up to 
30 days prior 
to Day -1)
Check
-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
post-last 
dose) or 
Early 
Termination
Notes
1
2
–1
1
2
3
4 to 6
7
8
9
10
Past and current medical 
conditions (including renal 
impairment medical 
history and eGFR)
X
eGFR defined in the 
FDA draft guidance for 
industry, 
“Pharmacokinetics in 
Patients with Impaired 
Renal Function” 
[DHHS, 2010].
Serum or urine pregnancy 
test/FSH
X
X
X
X
Serum (or urine) 
pregnancy test (if 
WCBP); estradiol and 
FSH at Screening as 
appropriate.
HIV antibody, hepatitis B 
surface antigen, and 
hepatitis C antibody 
testingc
X
Drug and alcohol screen
X
X
X
See Table 6.
Laboratory assessments 
(include liver chemistries)
X
X
X
X
X
X
Including serum 
chemistry, and 
hematology. Results 
from 24 hours after 
dosing should be 
available before 
discharge on Day 3 
(Period 1) and Day 10 
(Period 2)
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Respiratory rate and 
body temperature 
collected at Screening 
only.
 
 
 
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Procedurea
Screening 
(up to 
30 days prior 
to Day -1)
Check
-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
post-last 
dose) or 
Early 
Termination
Notes
1
2
–1
1
2
3
4 to 6
7
8
9
10
Genetic sampled
X
Collect a 
pharmacogenomics 
(PGx) sample only if the 
subject has a signed 
consent specific for this 
purpose. The PGx 
sample can be collected 
anytime, but Day –1 is 
recommended.
Study drug administration
Xb
Xb
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
See Table 5 for time 
points.
Urine collection for 
pharmacokinetics
X
X
X
X
X
X
See Table 5 for time 
points. Subjects may not 
be able to produce a 
urine sample.
Dialysate collections for 
pharmacokinetics
X
X
X
See Table 5 for time 
points.
AE/SAE review
X
X
==================================
X
Concomitant medication 
review
X
==================
=================
X
Footnotes continued on the next page.
 
 
 
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AE = adverse event, eGFR = estimated glomular filtration rate, ECG = electrocardiogram, FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus, 
PGx = pharmacogenetic, SAE = serious AE; WCBP = women of childbearing potential.
a
For subjects on hemodialysis (Part 2 [optional], Group F), assessments performed on scheduled hemodialysis days are to be done before hemodialysis (except for PK sample 
collection, which will be done before and after hemodialysis).
b
Subjects in Group F will participate in 2 treatment periods, with dosing in these periods separated by a washout period of at least 7 days. Subjects in Group F will enter the clinic at 
Check-in (Day –1, Period 1 and Day 7, Period 2) before each study drug administration (Day 1, Period 1 and Day 8, Period 2). On Day 1 (Period 1) and Day 8 (Period 2), subjects 
in Group F will receive a single dose of study drug as follows: gepotidacin 750 mg administered as a 2-hour IV infusion starting approximately 2 hours before initiation of the last 
hemodialysis session of the week (Period 1) and gepotidacin 750 mg administered as a 2-hour IV infusion starting within 2 hours after completion of the last hemodialysis session 
of the week (Period 2). Subjects in Group F will be discharged from the clinic on Day 10, Period 2.
c
If test has otherwise been performed within 3 months prior to first dose of study treatment, testing at Screening is not required.
d
Informed consent for optional substudies (e.g., genetics research) must be obtained before collecting a sample.
 
 
 
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Table 5
Safety and Pharmacokinetic Assessments (Group F)
Treatment Periods 1 and 2
Time point (hours)a
Procedurea
Predose
0
0.25
0.5
1
1.5
2
2.5
3
4
6
8
12
24b
36b
48b
12-lead electrocardiogram
X
Xc
X
X
X
X
X
X
Vital signs
X
Xc
X
X
X
X
X
X
Treatment administration 2-hour 
IV gepotidacin infusiond
X
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for 
pharmacokineticse
X
X
X
X
X
X
X
Dialysate collection for 
pharmacokineticsf
X
X
X
X
X
a
When coinciding with safety and/or pharmacokinetic assessments, electrocardiograms, vital signs, and pharmacokinetic blood collections should be performed in said order.
b
The 24-, 36-, and 48-hour postdose time points correspond to time points on Day 2 and 3, respectively.
c
Performed post infusion.
d
Subjects in Group F will participate in 2 treatment periods, with dosing in these periods separated by a washout period of at least 7 days. Subjects in Group F will enter the clinic at 
Check-in (Day –1, Period 1 and Day 7, Period 2) before each study drug administration (Day 1, Period 1 and Day 8, Period 2). On Day 1 (Period 1) and Day 8 (Period 2), subjects 
in Group F will receive a single dose of study drug as follows: gepotidacin 750 mg administered as a 2-hour IV infusion starting approximately 2 hours before initiation of the last 
hemodialysis session of the week (Period 1) and gepotidacin 750 mg administered as a 2-hour IV infusion starting within 2 hours after completion of the last hemodialysis session 
of the week (Period 2). Subjects in Group F will be discharged from the clinic on Day 10, Period 2.
e
It should be noted that subjects in Group F may not be able to produce urine samples due to their medical condition. All sampling times are relative to the start of the infusion.
f
Dialysate fluid will be collected on Day 1 after dosing (Period 1 only) over each 1-hour collection interval of the hemodialysis session.
 
 
 
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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 Tables
(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 an 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 and SAEs 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 Tables (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 to not introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
an 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 nonserious 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 and nonserious AEs related to 
study treatment (even for noninterventional postmarketing 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 an 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 7 days post-last 
dose.
 
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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 pulse rate. Baseline body 
temperature and respiratory rate will be collected at Screening only.
7.3.5.
Electrocardiogram

Single 12-lead ECGs will be obtained at each time point 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 withdrawal 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 Tables
(Section 7). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, clinic 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 
clinic by the laboratory responsible for the assessments.
If additional nonprotocol 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, serum chemistry, urinalysis, and additional parameters to be tested are listed 
in Table 6. 
Table 6
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 
AST
Total and direct bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Creatine kinase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening Tests
eGFR (Section 6.2)
Clcr (Section 6.2)
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) and drug screen (via serum, urine, or saliva) to include, at a 
minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines).
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
The PK blood samples for the analysis of gepotidacin will be collected at the time points 
listed in Section 7.1, Time and Events Tables. 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
The PK urine samples for the analysis of gepotidacin will be collected at the time points 
listed in Section 7.1, Time and Events Tables. 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.
Saliva Sample Collection
The PK saliva samples for parent analysis of gepotidacin will be collected from subjects 
in Part 1 at the time points listed in Section 7.1, Time and Events Tables. The timing of 
saliva samples may be altered and/or samples may be obtained at additional time points 
to ensure thorough PK monitoring.
Details of PK saliva sample collection, processing, storage, and shipping procedures are 
provided in the SRM.
7.4.4.
Dialysate Sample Collection
The PK dialysate samples for analysis of gepotidacin will be collected at the time points 
listed in Section 7.1, Time and Events Tables (Table 4 and Table 5; Group F only). The 
timing of dialysate samples may be altered and/or samples may be obtained at additional 
time points to ensure thorough PK monitoring.
Details of PK dialysate sample collection, processing, storage, and shipping procedures 
are provided in the SRM.
7.4.5.
Sample Analysis
Plasma, urine, saliva, and dialysate 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, urine, saliva, and dialysate 
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, urine, saliva, and dialysate have been analyzed for gepotidacin, any 
remaining plasma, urine, saliva, and dialysate may be analyzed for other 
compound-related metabolites and the results reported under a separate 
PTS-DMPK/Scinovo, GSK protocol.
 
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7.5.
Optional Pharmacokinetic Markers
With the subject’s consent, if a kidney or bladder tissue sample is collected for a 
nonstudy purpose, excess tissue may be collected during this study and may be used for 
the purposes of measuring drug concentrations of gepotidacin.
7.6.
Genetics
Depending on the clinical study results, optional 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 
Tables (Table 2 and Table 4). 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.

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
9.1.
Hypotheses
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the PK of gepotidacin in subjects with mild, moderate, severe renal 
impairment and in subjects with ESRD (on dialysis and not on dialysis) compared with 
matched subjects with normal renal function.
 
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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The target sample size of 16 evaluable subjects with normal renal function and 
8 evaluable renally impaired subjects was chosen based on feasibility, to address the 
objectives of the study. This sample size is considered sufficient to determine whether the 
pharmacokinetics in subjects with renal impairment is meaningfully different from 
subjects with normal renal function.
The between-subject variations of PK parameters from 1000 mg 2-hour IV administration 
on Day 1 in the BTZ115198 study were 26.3%, 27.4%, and 27.6% for the Cmax, from 
AUC from time 0 to infinity (AUC(0-∞)), and AUC(0-t), respectively [see report of 
Study BTZ115198].
For a between-subject coefficient of variation of 26.3%, 27.4%, and 27.6%, and a sample 
size of 16 subjects for the subjects with normal renal function and 8 subjects for the 
renally impaired group, it is estimated that the half width of the 90% confidence interval
(CI) for the difference on log-scale will be within 21.77%, 22.75%, and 23.00% of the 
point estimate for Cmax, AUC(0-∞), and AUC(0-t), respectively. 
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, 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 one 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 internally at GSK after the 
approximate sample size has been reached in Part 1 and Part 2 (optional).
 
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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Pharmacokinetic Analyses
Plasma, urine, and saliva 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 from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
last quantifiable concentration
CL
Systemic clearance 
Cmax
Maximum observed concentration
λz
Terminal-phase rate constant
t1/2
Terminal phase half life 
Tmax
Time to first occurrence of Cmax
Vss
Volume of distribution at steady-state of parent drug
Vz
Volume of distribution of the terminal phase
Urine:
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 a time intervals for predose, 0 to 6, 
6 to 12, 12 to 24, or 24 to 36, and 36 to 48 hours after dosing for subjects 
with renal impairment; and 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 with normal renal function
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)
Dialysate (Subjects with ESRD on dialysis; Group F subjects in Part 2):
Arem(0-1)
Amount of drug removed by hemodialysis from time 0 to 1 hour after the 
start of hemodialysis
Arem(1-2)
Amount of drug removed by hemodialysis from time 1 to 2 hours after the 
start of hemodialysis
 
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Arem(2-3)
Amount of drug removed by hemodialysis from time 2 to 3 hours after the 
start of hemodialysis
Arem(3-4)
Amount of drug removed by hemodialysis from time 3 to 4 hours after the 
start of hemodialysis (or to the end of dialysis if less than 4 hours)
Arem(0-4)
Cumulative amount of drug removed by hemodialysis from time 0 to 
4 hours after the start of hemodialysis (or to the end of dialysis if less than 
4 hours)
AUC(t0-t1)
Partial area under the curve estimated from predialyzer samples collected 
from start of dialysis (t0) to end of dialysis (t1)
CLD
Dialysis clearance, calculated as the total amount of the analyte recovered 
in the dialysate over 4 hours (or the total dialysis interval if less than 
4 hours) divided by the partial area under the curve during the period of 
dialysis, which will be calculated using the predialyzer samples
Frem%(0-4)
Fraction (%) of the dose removed by hemodialysis from 0 to 4 hours after 
the start of hemodialysis (or to the end of dialysis if less than 4 hours)
Plasma concentrations (all subjects), urine concentrations, and dialysate concentrations 
(Group F) of gepotidacin and the associated PK parameters will be listed, and summary 
statistics (n, mean, median, standard deviation [SD], minimum, maximum, and 
coefficient of variation [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 in the renal 
impairment groups and normal renal function groups will be compared using an analysis 
of variance. Geometric mean ratios between renal impairment groups and normal renal 
function groups, and 90% CIs for the ratios of AUC(0-∞) and Cmax for gepotidacin will 
be presented.
Linear regression analysis will be used to evaluate the relationships between estimated 
renal function and relevant PK parameters (e.g., AUC, Cmax, and CL). If the data permit 
the identification of linear functions that fit the data well, the resulting slopes will provide 
a comparison of any difference in the response of the gepotidacin IV treatment as renal 
function changes.
If the appropriate number of subjects with severe renal impairment and/or subjects with 
ESRD not on dialysis cannot be enrolled, or their eGFR values cluster at the higher end 
of the range, the PK profiles in subjects with ESRD on hemodialysis may be modeled to 
understand the pharmacokinetics for the other groups of subjects with renal impairment at 
the lower end of the range (<15 mL/min/1.73 m2), as well as for subjects with ESRD not 
on hemodialysis.
Detailed descriptions of the analyses in this study will be presented in the Reporting and 
Analysis Plan (RAP).
 
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9.4.2.
Secondary Analyses
9.4.2.1.
Safety Analyses
The following safety evaluations will be performed:

Monitoring for AEs

Changes in routine clinical laboratory parameters including hematology, serum 
chemistry, 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 (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 (TEAEs) will be defined as any AEs, regardless of relationship 
to investigational product, that occur after the dose of investigational product. The 
TEAEs 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 AEs leading to discontinuation and 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 actual values and 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 interval >500 msec or increase in QTc 
from the Screening ECG of ≥60 msec, will be summarized by group. Physical 
examination findings will be listed.
Detailed descriptions of the analyses in this study will be presented in the RAP.
 
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9.4.3.
Other Analyses
9.4.3.1.
Exploratory Analyses
Saliva (subjects in Part 1 only):
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 
last quantifiable concentration
CL
Systemic clearance 
Cmax
Maximum observed concentration
λz
Terminal-phase rate constant
t1/2
Terminal phase half life 
Tmax
Time to first occurrence of Cmax
Vz
Volume of distribution of the terminal phase
Saliva concentrations (subjects in Part 1 only; as data permit) 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 saliva concentration versus time profiles will be presented graphically on 
linear and semilogarithmic scales.
An exploratory analysis will be performed to explore the relationship between saliva and 
plasma concentrations. Natural log-transformed saliva gepotidacin concentrations versus 
the natural log-transformed plasma gepotidacin concentrations will be plotted and a 
regression line will be fitted. A similar analysis will also be performed for the AUC(0-), 
AUC(0-t), and Cmax.
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 clinic, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
 
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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.
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.
 
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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 Clinic 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 one 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 in 
 
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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:  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 Biologics Evaluation and Research 
(US). Draft Guidance for Industry:  Pharmacokinetics in Patients with Impaired Renal 
Function – Study Design, Data Analysis, and Impact on Dosing and Labeling. March 
2010. [21 screens]. Available from:  http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-drugs-gen/documents/document/ucm204959.pdf
GlaxoSmithKline Document Number 2012N131922_00. An in vitro study of b1ood cell 
association of GSK2140944 in mouse, rat, dog, monkey, and human. 2012.
GlaxoSmithKline Document Number 2012N156820_00. Elimination and tissue 
distribution of radioactivity in the male intact and male bile duct-cannulated long evans 
rat following a single intravenous (100 mg free base/kg) or oral (150 mg free base/kg) 
administration of [14C]-GSK2140944 mesylate dehydrate. 2013.
GlaxoSmithKline Document Number 2013N170240_00. In vitro protein binding of 
[14C]-GSK2140944 in human plasma. 1995.
GlaxoSmithKline Document Number 2014N189951_00 Study ID BTZ115774. An 
open-label, non-randomized, two-period, cross-over, mass balance study to investigate 
the recovery, excretion and pharmacokinetics of 14C-GSK2140944 administered as a 
single intravenous and single oral dose to healthy adult male 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 CM2010/00033/02. GSK2140944 Investigator’s 
Brochure. 2014.
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.
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 
Arem
amount of drug removed by hemodialysis 
Arem(0-1)
amount of drug removed by hemodialysis from time 0 to 
1 hour after the start of hemodialysis
Arem(1-2)
amount of drug removed by hemodialysis from time 1 to 
2 hours after the start of hemodialysis
Arem(2-3)
amount of drug removed by hemodialysis from time 2 to 
3 hours after the start of hemodialysis
Arem(3-4)
amount of drug removed by hemodialysis from time 3 to 
4 hours after the start of hemodialysis (or to the end of 
dialysis if less than 4 hours)
Arem(0-4)
cumulative amount of drug removed by hemodialysis from 
time 0 to 4 hours after the start of hemodialysis (or to the 
end of dialysis if less than 4 hours)
AUC
area under the plasma concentration-time curve
AUC(0-)
area under the concentration-time curve from time 0 to 
infinity
AUC(0-t)
area under the concentration-time curve from time 0 to the 
time of the last quantifiable concentration (t)
AUC(t0-t1)
Partial area under the curve estimated from predialyzer 
samples collected from start of dialysis (t0) to end of 
dialysis (t1)
bpm
beats per minute
CI
confidence interval
CL
systemic clearance
Clcr
creatinine clearance
CLD
dialysis clearance
CLr
renal clearance
Cmax
maximum observed concentration
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomular filtration rate
ESRD
end-stage renal disease
FDA
United States Food and Drug Administration
fe%
percentage of the given dose of drug excreted in urine
 
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Frem%(0-4)
fraction (%) of the dose removed by hemodialysis from 0 to 
4 hours after the start of hemodialysis (or to the end of 
dialysis if less than 4 hours)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
mm Hg
millimeters of mercury
msec
millisecond
PBPK
physiologically-based pharmacokinetic
PK
pharmacokinetic
QTc
corrected QT interval; the measure of time between the start 
of the Q wave and the end of the T wave
QTcF
corrected QT interval using the Fridericia formula
RAP
Reporting and Analysis Plan
SAE
serious adverse event
SRM
Study Reference Manual
t1/2
terminal phase half life
Tmax
time to first occurrence of Cmax
ULN
upper limit of normal
Vss
volume of distribution at steady-state of parent drug
Vz
volume of distribution of the terminal phase
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
GSKDrug
MedDRA
SimCYP
 
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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
Genetic Research Objectives and Analyses
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.
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 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.
 
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
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 ICF. 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. 

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.
 
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
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, serum 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 condition 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 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, diarrhoea, 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
f.
Other situations:
 
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
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 an INR measurement is obtained, the value is to be 
recorded on the SAE Form.
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events Definition:
Investigators will be required to fill out the specific Cardiovascular event page of the 
eCRF for the following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.5.4.
Recording of Adverse Events and Serious Adverse Events
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF.

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.
12.5.5.
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 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.
 
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
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.

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.
12.5.6.
Reporting of Serious Adverse Events to GSK
SAE 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 
 
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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 [DAIDs], 
National Cancer Institute’s Common Toxicity Criteria, and World Health 
Organization) have been adapted for use by the DAIDs and modified to better meet 
the needs of participants in Division of Microbiology and Infectious Diseases 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; 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
Diarrhoea
Mild or transient; 3 to 4 loose 
stools/day or mild diarrhoea 
lasting <1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhoea 
lasting >1 week
>7 loose stools/day or bloody 
diarrhoea; 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.

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. 
 
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
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 diarrhoea 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 diarrhoea 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: Physiologically Based Pharmacokinetic Model 
Input Parameters
Parameters
Value
References /Resources
Molecular weight
448.5
Investigator Brochure
Compound type
Dibasic
Technical Evidence Document
pKa 1
8.83
Adamantis
pKa 2
6.2
Calculated using Adamantis
cLog P
0.16
Calculated using Adamantis
Fu Plasma
0.67
Study # GlaxoSmithKline Document Number 2013N170240_00
Blood:Plasma ratio
0.95
Study # GlaxoSmithKline Document Number 2012N131922_00
Vdss
1.30
Predicted Full PBPK with addtional organ compartment and Kp scalar 0.7
Additional organ Kp
100
Predicted value of pigmented tissue from QWBA Study #
GlaxoSmithKline Document Number 2012N156820_00
CYP3A4 fm
0.25
CYP3A4 CLint 
(L/min/pmole P450)
0.0434
SimCYP calculation based on CLi.v. of 43 L/hr with measured renal 
clearance of 16 L/hr  with CYP3A4 fm = 0.25
Additional HLM CLint
(l/min/mg protein)
9.00
SimCYP calculation based on CLi.v. of 43 L/hr with measured renal 
clearance of 16 L/hr with CYP3A4 fm=0.25
CYP = cytochrome 450, Fu = fraction unbound; Vdss = volume of distribution at steady state; Kp = equilibrium 
partition coefficient of drug; PBPK = physiologically based pharmacokinetic model; QWBA = quantitative whole-body 
autoradioluminography
 
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