A Phase I, Double-Blind, Two-Part, Sequential Study to Evaluate the Pharmacokinetics of Gepotidacin Tablets in Healthy Adult and Adolescent Participants
Phase: PHASE1
Conditions: Infections, Bacterial
Sponsor: GlaxoSmithKline

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Protocol Title: A Phase I, Double-Blind, Two-Part, Sequential Study to Evaluate the 
Pharmacokinetics of Gepotidacin Tablets in Healthy Adult and Adolescent Participants
Protocol Number: 209611
Compound Number:
GSK2140944
Study Phase: Phase I
Short Title: Pharmacokinetics of Gepotidacin Tablets in Adults and Adolescents
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information: Please refer to the Study Reference 
Manual
Regulatory Agency Identifying Number: IND: 111885
Approval Date: 13-JUN-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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GlaxoSmithKline group of companies
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................11
2.
INTRODUCTION....................................................................................................22
2.1.
Study Rationale ..........................................................................................22
2.2.
Background ................................................................................................22
2.3.
Benefit/Risk Assessment ............................................................................23
2.3.1.
Risk Assessment .........................................................................24
2.3.2.
Benefit Assessment.....................................................................27
2.3.3.
Overall Benefit: Risk Conclusion..................................................27
3.
OBJECTIVES AND ENDPOINTS...........................................................................27
4.
STUDY DESIGN ....................................................................................................28
4.1.
Overall Design ............................................................................................28
4.2.
Scientific Rationale for Study Design ..........................................................29
4.3.
Justification for Dose ..................................................................................30
4.4.
End of Study Definition ...............................................................................30
5.
STUDY POPULATION...........................................................................................31
5.1.
Inclusion Criteria.........................................................................................31
5.2.
Exclusion Criteria........................................................................................32
5.3.
Lifestyle Considerations..............................................................................34
5.3.1.
Meals and Dietary Restrictions ....................................................34
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................34
5.3.3.
Activity .........................................................................................35
5.4.
Screen Failures...........................................................................................35
6.
STUDY INTERVENTION........................................................................................35
6.1.
Study Interventions Administered ...............................................................36
6.2.
Preparation/Handling/Storage/Accountability..............................................37
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................37
6.4.
Study Intervention Compliance ...................................................................38
6.5.
Concomitant Therapy..................................................................................39
6.6.
Dose Modification .......................................................................................39
6.7.
Intervention after the End of the Study........................................................39
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................39
7.1.
Discontinuation of Study Intervention..........................................................39
7.1.1.
Liver Chemistry Stopping Criteria ................................................40
7.1.2.
QTc Stopping Criteria ..................................................................40
7.1.3.
Gastrointestinal Evaluation Criteria..............................................41
7.1.4.
Rash/Hypersensitivity Evaluation Criteria.....................................41
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................41
7.3.
Lost to Follow Up........................................................................................42
 
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8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
8.1.
Efficacy Assessments.................................................................................43
8.2.
Safety Assessments ...................................................................................43
8.2.1.
Physical Examinations.................................................................43
8.2.2.
Vital Signs....................................................................................43
8.2.3.
Electrocardiograms......................................................................43
8.2.4.
Clinical Safety Laboratory Assessments ......................................44
8.3.
Adverse Events and Serious Adverse Events.............................................44
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................44
8.3.2.
Method of Detecting AEs and SAEs.............................................45
8.3.3.
Follow-up of AEs and SAEs.........................................................45
8.3.4.
Regulatory Reporting Requirements for SAEs .............................45
8.3.5.
Pregnancy ...................................................................................46
8.4.
Treatment of Overdose...............................................................................46
8.5.
Pharmacokinetics .......................................................................................46
8.6.
Pharmacodynamics ....................................................................................47
8.7.
Genetics .....................................................................................................47
8.8.
Biomarkers .................................................................................................47
8.9.
Medical Resource Utilization and Health Economics ..................................47
9.
STATISTICAL CONSIDERATIONS........................................................................47
9.1.
Statistical Hypotheses.................................................................................47
9.2.
Sample Size Determination ........................................................................47
9.3.
Populations for Analyses ............................................................................48
9.4.
Statistical Analyses.....................................................................................48
9.4.1.
Pharmacokinetic Analyses...........................................................48
9.4.2.
Safety Analyses...........................................................................50
9.4.3.
Other Analyses ............................................................................50
9.5.
Interim Analyses .........................................................................................50
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................51
10.1.
Appendix 1: Abbreviations and Trademarks................................................51
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................53
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................55
10.3.1.
Regulatory and Ethical Considerations ........................................55
10.3.2.
Financial Disclosure.....................................................................55
10.3.3.
Informed Consent/Assent Process...............................................56
10.3.4.
Data Protection............................................................................56
10.3.5.
Publication Policy.........................................................................57
10.3.6.
Dissemination of Clinical Study Data ...........................................57
10.3.7.
Data Quality Assurance ...............................................................57
10.3.8.
Source Documents ......................................................................58
10.3.9.
Study and Site Closure ................................................................58
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................60
10.4.1.
Definition of AE............................................................................60
10.4.2.
Definition of SAE..........................................................................61
10.4.3.
Recording and Follow-Up of AE and SAE....................................62
10.4.4.
Reporting of SAE to GSK.............................................................64
 
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10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................66
10.5.1.
Definitions:...................................................................................66
10.5.2.
Contraception Guidance: .............................................................67
10.5.3.
Collection of Pregnancy Information: ...........................................68
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................70
10.7.
Appendix 7: Clostridium difficile Testing Procedure and Algorithm..............72
10.8.
Appendix 8: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment...........................................73
11. REFERENCES.......................................................................................................80
 
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Phase I, Double-Blind, Two-Part, Sequential Study to Evaluate the 
Pharmacokinetics of Gepotidacin Tablets in Healthy Adult and Adolescent Participants
Short Title: Pharmacokinetics of Gepotidacin Tablets in Adults and Adolescents
Rationale: Single oral doses of gepotidacin (1500 and 3000 mg) were given to patients 
with gonorrhea in a completed Phase II study, and both doses achieved >95% efficacy; 
however, in vitro data and pharmacokinetic (PK)/pharmacodynamic modeling revealed 
that a higher dose would prevent the development of resistance and cover organisms with 
higher minimum inhibitory concentration (MIC).
The selected total daily dose for gonorrhea is 6000 mg delivered as two 3000 mg doses 
given either 6 or 12 hours apart in order to keep Cmax under a threshold of 14 µg/mL to 
mitigate the occurrence of adverse events (AEs) due to acetylcholinesterase (AChE) 
inhibition (mild and transient AEs of increased salivation, blurred vision, and slurred 
speech were observed following high intravenous [IV] doses as a 1 or 2 hour infusion 
during a previous study).
Although total daily oral 6000 mg doses have been given to healthy participants and 
patients as 2000 mg three times daily (TID) for up to 14 days and daily IV 4500 mg 
(equivalent to 9783 mg oral dose and based on absolute bioavailability of 46%) doses 
have been given to healthy participants as TID regimen for up to 10 days, the safety and 
PK of two 3000 mg doses given either 6 or 12 hours apart have not been characterized 
previously and gepotidacin has not been administered previously to adolescents. 
Therefore, this study will support inclusion of adolescents with a body weight ≥40 kg in 
future Phase III studies and will provide the safety and PK data of two 3000 mg doses 
separated by the selected dose intervals in Part 1 and Part 2.
Objectives and Endpoints:
Objectives
Endpoints
Primary
Part 1

To evaluate the pharmacokinetics of a 
single 1500-mg dose and two 3000-mg 
doses of gepotidacin given 6 and
12 hours apart in adult participants
1500 mg Single Dose

Plasma gepotidacin AUC(0-t), AUC(0-∞), 
AUC(0-24), AUC(0-48), and Cmax, as data 
permit
3000 mg Two Doses

Plasma gepotidacin AUC(0-t), AUC(0-τ), 
AUC(0-24), AUC(0-48), Ro (accumulation 
ratio), and Cmax, as data permit
 
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Objectives
Endpoints
Part 2

To evaluate the pharmacokinetics of a 
single 1500-mg dose and two 3000-mg 
doses of gepotidacin given at a dosing 
interval (to be determined) in 
adolescent participants
1500 mg Single Dose

Plasma gepotidacin AUC(0-t), AUC(0-∞), 
AUC(0-24), AUC(0-48), and Cmax, as data 
permit
3000 mg Two Doses

Plasma gepotidacin AUC(0-t), AUC(0-τ), 
AUC(0-24), AUC(0-48), Ro (accumulation 
ratio), and Cmax, as data permit
Parts 1 and 2

To assess the safety of gepotidacin in 
adult participants and adolescent 
participants

Adverse events, clinical laboratory tests, 
vital signs (systolic and diastolic blood 
pressure and heart rate), and 12-lead 
electrocardiogram readings
Secondary
Part 1

To assess the urine pharmacokinetics
of gepotidacin following a single 
1500-mg dose and two 3000-mg doses 
of gepotidacin given 6 and 12 hours 
apart in adult participants

Urine endpoints include Ae total, Ae(t1-t2), 
AUC(0-τ), AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data permit
Part 2

To assess the urine pharmacokinetics
of gepotidacin following a single 
1500-mg dose and two 3000-mg doses 
of gepotidacin given at a dosing interval 
(to be determined) in adolescent 
participants

Urine endpoints include Ae total, Ae(t1-t2), 
AUC(0-τ), AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data permit
Parts 1 and 2

To assess the plasma 
pharmacokinetics of gepotidacin

Plasma gepotidacin Tmax, tlag, and t1/2, 
as data permit
Overall Design: This is a Phase I, double-blind, single-center, randomized, sequential, 
two-part study. Part 1 is being conducted to evaluate the PK of the gepotidacin tablets in 
healthy adult participants. Part 2 will evaluate the PK of the gepotidacin tablets in healthy 
adolescent participants.
 
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Part 1: Pharmacokinetics in Healthy Adult Participants
Part 1 is a 3-period, fixed-sequence study that will assess the PK of a single 1500-mg 
dose (Period 1) and two 3000-mg doses of gepotidacin at Hours 0 and 12 (Period 2) and 
Hours 0 and 6 (Period 3) in healthy adult participants. 
Participants will be randomly assigned to receive either all active treatment (gepotidacin) 
or placebo for all 3 periods. Approximately 17 participants will be randomized (in a 
14:3 ratio) to receive a single dose of gepotidacin 1500 mg (Treatment A) or matching 
placebo (Treatment B) in Period 1, gepotidacin 3000 mg separated by 12 hours 
(Treatment C) or matching placebo (Treatment D) in Period 2, and gepotidacin 3000 mg 
separated by 6 hours (Treatment E) or matching placebo (Treatment F) in Period 3 to 
obtain 12 evaluable participants on active treatment and 2 evaluable participants on 
placebo.
Participants will participate in 3 treatment periods, and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations up to 48 to 60 hours after dosing.
This will be a two-part study in which the PK and safety data will be reviewed after 
completion of Part 1 before enrolling participants into Part 2. The dosing interval in 
Part 2, Period 2 will be based on the PK, safety, and tolerability data from Part 1.
Part 2: Pharmacokinetics in Healthy Adolescent Participants
Part 2 is a 2-period, fixed sequence study that will assess the PK of a single 1500-mg 
dose (Period 1) of gepotidacin and two 3000-mg doses (Period 2) of gepotidacin in 
healthy adolescent participants. The two 3000-mg doses will be separated by a time 
interval that will be determined based on data from Part 1. The number of PK samples 
and the PK sampling time points may be modified based on the adult PK data from 
Part 1.
Participants will be randomly assigned to receive either all active treatment (gepotidacin) 
or placebo for both periods. Approximately 17 participants will be randomized (in a 
14:3 ratio) to receive a single dose of gepotidacin 1500 mg (Treatment A) or matching 
placebo (Treatment B) in Period 1, and gepotidacin 3000 mg (Treatment G) or matching 
placebo (Treatment H) in Period 2 to obtain 12 evaluable participants on active treatment 
and 2 evaluable participants on placebo.
The interval for the two 3000-mg doses in Period 2 will be between 6 hours and 12 hours 
based on the PK and safety results from Part 1.
For Part 2 only, there may be a 7-day interval between doses in Period 1 and Period 2 to 
accommodate the adolescent population school schedule. Treatment Period 1 and 
Treatment Period 2 may be separated by no more than 10 days.
Participants will participate in 2 treatment periods and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations up to 48 hours after dosing.
 
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Disclosure Statement: This is a sequential clinical pharmacology study that is masking 
the participant and investigator to assigned treatment. 
Number of Participants: Approximately 17 adult participants will be randomly assigned 
to study intervention in Part 1 to ensure 12 evaluable participants on study drug with 
evaluable primary PK parameters and 2 participants on placebo with evaluable safety 
measurements. In Part 2, approximately 17 adolescent participants will be randomly 
assigned to study intervention to ensure 12 evaluable participants on study drug with 
evaluable primary PK parameters and 2 participants on placebo with evaluable safety 
measurements.
Intervention Groups and Duration: The treatments will be as follows:
Part 1 - Adult Participants

Treatment A: Single dose 1500 mg (Period 1)

Treatment B: Matching placebo (Period 1)

Treatment C: Two 3000 mg doses given at Hour 0 and Hour 12 (Period 2)

Treatment D: Two matching placebo doses given at Hour 0 and Hour 12
(Period 2)

Treatment E: Two 3000 mg doses given at Hour 0 and Hour 6 (Period 3)

Treatment F: Two matching placebo doses given at Hour 0 and Hour 6
(Period 3)
Note: All doses will be taken after a standard meal.
Part 2 - Adolescent Participants

Treatment A: Single dose 1500 mg (Period 1)

Treatment B: Matching placebo (Period 1)

Treatment G: Two 3000 mg doses (Period 2; exact dosing interval to be 
determined after Part 1 is complete)

Treatment H: Two matching placebo doses (Period 2; exact dosing interval to be 
determined after Part 1 is complete)
Note: All doses will be taken after a standard meal.
The duration of the study, including Screening, is approximately 47 days for Part 1, and 
52 days for Part 2.
Data Monitoring Committee: No
 
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1.2.
Schema
A summary of the overall study design is presented in Figure 1.
Figure 1
Study Design Schematic
 
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1.3.
Schedule of Activities (SoA)
Table 1
Screening Visit - Parts 1 and 2
Procedure
Screening (up to 28 days before Day -1)
Outpatient visit
X
Informed consent/assent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
12-lead electrocardiogram
X
Vital sign measurements2
X
Medication/drug/alcohol history
X
Past and current medical conditions  
X
Serum pregnancy test
X
Follicle-stimulating hormone (as needed, to confirm postmenopausal 
status; Part 1 only)
X
Drug, alcohol, and cotinine screen
X
HIV, Hepatitis B and C screening
X
Serious adverse event review
X
HIV = human immunodeficiency virus.
1
A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.
2
Respiratory rate and oral temperature collected at Screening only.
 
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Table 2
Schedule of Activities - Part 1 (Adult Participants)
Procedure1
Check
-in
Treatment Period 1
(Days)
Treatment Period 2
(Days)
Treatment Period 3
(Days)
Follow-up 
(7 [±3] days 
after last 
dose) or 
Early 
Termination
Notes
–1
1
2
3
4
5
6
7
8
9
10
11
Confined to clinic
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion and 
exclusion criteria
X
Recheck clinical 
status before 
study 
intervention
Brief physical 
examination2
X
X
X
Pregnancy test
X
X
Urine pregnancy 
test (if WOCBP), 
as appropriate 
(see Table 10)
Drug, alcohol, and 
cotinine screen
X
See Table 10
Laboratory 
assessments
X
X
X
X
X
Including serum 
chemistry, 
hematology, and 
urinalysis (see 
Appendix 2)
12-lead ECG3
X
X
X
X
X
X
X
X
X
X
X
See Table 3, 
Table 4, and 
Table 5 for 
timing of 
assessments
 
 
 
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Procedure1
Check
-in
Treatment Period 1
(Days)
Treatment Period 2
(Days)
Treatment Period 3
(Days)
Follow-up 
(7 [±3] days 
after last 
dose) or 
Early 
Termination
Notes
–1
1
2
3
4
5
6
7
8
9
10
11
ECG Holter
monitoring4
X
X
X
X
X
X
X
X
X
See Table 3, 
Table 4, and 
Table 5 for 
timing of 
assessments
Vital signs
X
X
X
X
X
X
X
X
X
X
X
See Table 3, 
Table 4, and 
Table 5 for 
timing of 
assessments
Study intervention
X
X
X
See Table 3, 
Table 4, and 
Table 5 for time 
points
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
X
X
X
See Table 3, 
Table 4, and 
Table 5 for time 
points
Urine collection for 
pharmacokinetics
X
X
X
X
X
X
X
X
X
See Table 3, 
Table 4, and 
Table 5 for time 
points
AE/SAE review
X
===================================================================================
X
Concomitant 
medication review
X
===================================================================================
X
 
 
 
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AE = adverse event, ECG = electrocardiogram, SAE = serious AE; WOCBP = woman of childbearing potential.
1
When coinciding with safety and/or pharmacokinetic assessments, ECGs, vital signs, and pharmacokinetic blood collections should be performed in said order.
2
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
3
Triplicate 12-lead ECGs will be measured on Day -1.
4
ECG Holter monitoring will begin approximately 12 hours prior to first dose until 24 hours after first dose of each treatment period.
Table 3
Safety and PK Assessments - Part 1, Period 1 (Adult Participants)
Procedure1
Treatment Period 1
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
24
36
48
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Study intervention
X
Blood PK sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK collection3
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours.
 
 
 
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Table 4
Safety and PK Assessments - Part 1, Period 2 (12-Hour Dose Interval, Adult Participants)
Procedure1
Treatment Period 2
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
12.5
13
13.5
14
14.5
15
16
18
20
24
36
48
60
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter 
monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Study 
intervention
X
X
Blood PK 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
collection3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 
20 to 24 hours, 24 to 36 hours, 36 to 48 hours, and 48 to 60 hours.
 
 
 
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Table 5
Safety and PK Assessments - Part 1, Period 3 (6-Hour Dose Interval, Adult Participants)
Procedure1
Treatment Period 3
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
6.5
7
7.5
8
8.5
9
10
12
14
18
24
36
48
60
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter 
monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Study 
intervention
X
X
Blood PK 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
collection3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, 10 to 12 hours, 12 to 14 hours, 14 to 18 hours, 18 to 24 hours, 
24 to 36 hours, 36 to 48 hours, and 48 to 60 hours.
 
 
 
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Table 6
Schedule of Activities - Part 2 (Adolescent Participants)
Procedure1
Check-in
Treatment Period 1
(Days)
Check-
in2
Treatment Period 2
(Days)
Follow-up 
(7 [±3] days 
after last 
dose) or Early 
Termination
Notes
–1
1
2
3
–1
1
2
3
Confined to clinic
X
X
X
X3
X
X
X
X3
Treatment Period 1 and 
Treatment Period 2 may be 
separated by 7 days but no 
more than 10 days.
Inclusion and exclusion 
criteria
X
X
Recheck clinical status 
before study intervention
Brief physical examination4
X
X
X
X
Pregnancy test
X
X
X
Urine pregnancy test (if 
WOCBP), as appropriate 
(see Table 10)
Drug, alcohol, and cotinine
screen
X
X
See Table 10
Laboratory assessments
X
X
X
X
X
Including serum chemistry, 
hematology, and urinalysis
(see Appendix 2)
12-lead ECG5
X
X
X
X
X
X
X
X
X
See Table 7, Table 8, and 
Table 9 for timing of 
assessments
ECG Holter monitoring6
X
X
X
X
X
X
See Table 7, Table 8, and 
Table 9 for timing of 
assessments
Vital signs
X
X
X
X
X
X
X
X
X
See Table 7, Table 8, and 
Table 9 for timing of 
assessments
Study intervention
X
X
See Table 7, Table 8, and 
Table 9 for time points
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
See Table 7, Table 8, and 
Table 9 for time points
 
 
 
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Procedure1
Check-in
Treatment Period 1
(Days)
Check-
in2
Treatment Period 2
(Days)
Follow-up 
(7 [±3] days 
after last 
dose) or Early 
Termination
Notes
–1
1
2
3
–1
1
2
3
Urine collection for 
pharmacokinetics
X
X
X
X
X
X
See Table 7, Table 8, and 
Table 9 for time points
AE/SAE review
X
===============================================================
X
Concomitant medication 
review
X
===============================================================
X
AE = adverse event, ECG = electrocardiogram, SAE = serious AE; WOCBP = woman of childbearing potential.
1
When coinciding with safety and/or pharmacokinetic assessments, ECGs, vital signs, and pharmacokinetic blood collections should be performed in said order.
2
Check-in procedures only necessary if participant leaves the clinic between Treatment Period 1 and Treatment Period 2.
3
Participants may be discharged from the clinic after the Hour 48 assessments.
4
A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).
5
Triplicate 12-lead ECGs will be measured on Day -1 (before each treatment period).
6
ECG Holter monitoring will begin approximately 12 hours prior to first dose until 24 hours after first dose of each treatment period.
 
 
 
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Table 7
Safety and PK Assessments - Part 2, Period 1 (Adolescent Participants)
Procedure1
Treatment Period 1
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
24
36
48
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Study intervention
X
Blood PK sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK collection3
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours.
Note: The number of PK samples and the PK sampling time points may be modified based on the adult PK data from Part 1.
 
 
 
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Table 8
Safety and PK Assessments - Part 2, Period 2 (if 6-hour dose interval is selected, Adolescent Participants)
Procedure1
Treatment Period 2
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
6.5
7
7.5
8
8.5
9
10
12
14
18
24
36
48
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter 
monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Study 
intervention
X
X
Blood PK 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
collection3
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, 10 to 12 hours, 12 to 14 hours, 14 to 18 hours, 18 to 24 hours, 
24 to 36 hours, and 36 to 48 hours.
Note: The number of PK samples and the PK sampling time points may be modified based on the adult PK data from Part 1.
 
 
 
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Table 9
Safety and PK Assessments - Part 2, Period 2 (if 12-hour dose interval is selected, Adolescent Participants)
Procedure1
Treatment Period 2
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
12.5
13
13.5
14
14.5
15
16
18
20
24
36
48
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG Holter 
monitoring
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Study 
intervention
X
X
Blood PK 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
collection3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG = electrocardiogram; PK = pharmacokinetic.
1
When coinciding with safety and/or PK assessments, ECGs, vital signs, and PK blood collections should be performed in said order.
2
Triplicate 12-lead ECGs will be measured at predose. Single 12-lead ECGs will be measured at all other time points.
3
Urine collection intervals include 0 (predose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 14 hours, 14 to 16 hours, 16 to 18 hours, 18 to 20 hours, 
20 to 24 hours, 24 to 36 hours, and 36 to 48 hours.
Note: The number of PK samples and the PK sampling time points may be modified based on the adult PK data from Part 1.

In Part 2, Period 2, the timing and number of planned study assessments, including safety, pharmacokinetic (PK), or other
assessments may be altered during the course of the study based on data from Part 1 (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring.

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging PK data from
Part 1 must be documented and approved by the GlaxoSmithKline (GSK) study team and then archived in the sponsor and site 
study files, but will not constitute a protocol amendment. The Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF)/assent. The changes will be approved by the competent 
authorities (CA) and the ethics committee (EC) before implementation.
 
 
 
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2.
INTRODUCTION
Gepotidacin (GSK2140944) is a first in class, novel triazaacenaphthylene antibacterial
that inhibits bacterial type II topoisomerases. It has activity versus key pathogens,
including drug-resistant strains associated with a range of conventional and biothreat
infections and is being developed with intravenous (IV) and oral formulations.
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
Single oral doses of gepotidacin (1500 and 3000 mg) were given to patients with 
gonorrhea in a completed Phase II study, and both doses achieved >95% efficacy; 
however, in vitro data and pharmacokinetic (PK)/pharmacodynamic modeling revealed 
that a higher dose would prevent the development of resistance and cover organisms with 
higher minimum inhibitory concentration (MIC).
The selected total daily dose for gonorrhea is 6000 mg delivered as two 3000 mg doses 
given either 6 or 12 hours apart in order to keep Cmax under a threshold of 14 µg/mL to 
mitigate the occurrence of adverse events (AEs) due to acetylcholinesterase (AChE) 
inhibition (mild and transient AEs of increased salivation, blurred vision, and slurred 
speech were observed following high IV doses as a 1 or 2 hour infusion during a previous 
study).
Although total daily oral 6000 mg doses have been given to healthy participants and 
patients as 2000 mg three times daily (TID) for up to 14 days and daily IV 4500 mg 
(equivalent to 9180 mg oral dose and based on absolute bioavailability of 46%) doses 
have been given to healthy participants as TID regimen for up to 10 days, the safety and 
PK of two 3000 mg doses given either 6 or 12 hours apart have not been characterized 
previously and gepotidacin has not been administered previously to adolescents. 
Therefore, this study will support inclusion of adolescents with a body weight ≥40 kg in 
future Phase III studies and will provide the safety and PK data of two 3000 mg doses 
separated by the selected dose intervals in Part 1 and Part 2.
2.2.
Background
Gepotidacin has demonstrated clinical efficacy in a Phase II study for acute bacterial skin 
and skin structure infections, and in a Phase II study for gonorrhea.
 
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A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the Investigator’s Brochure [GlaxoSmithKline Document 
Number CM2010/00033/06].
2.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
gepotidacin can be found in the Investigator’s Brochure. The following section outlines 
the risk assessment and mitigation strategy for this protocol.
 
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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Gepotidacin
Gastrointestinal (GI) Effects
Based on nonclinical data, gastrointestinal effects were 
mild ulceration of the nonglandular mucosa and minimal 
erosion and/or mural inflammation of the glandular mucosa 
in stomach (rat, oral study); moderate cecal ulceration and 
minimal colonic erosion (rat, IV study); and vomiting (dog).
Lower gastrointestinal effects (soft stools, flatulence, and 
diarrhea) are among the most common AEs reported in 
gepotidacin clinical studies.
Gastrointestinal effects observed in gepotidacin clinical 
studies, both Phase I studies and the Phase II ABSSSI 
study, included diarrhea (very common, ≥10%) and 
flatulence (common; ≥1% and <10%); all nonserious and 
mild in severity (see Section 6 of the Investigator’s 
Brochure).
In the Phase II urogenital gonorrhea study, the most 
frequently reported gastrointestinal AEs overall were 
diarrhea, flatulence, abdominal pain, and nausea. 
Comparing the treatment groups, the incidence of diarrhea 
and nausea was higher in the 3000-mg treatment group 
and incidence of flatulence was higher in the 1500-mg 
treatment group. 
Few occurrences of Clostridium difficile have been 
reported in clinical studies (see Section 6 of the IB). Of the 
282 healthy participants in Phase I studies who have 
received gepotidacin, C. difficile was reported in 
8 participants, including 2 elderly participants in 
association with soft stools or diarrhea. In the Phase I renal 
impairment and hepatic impairment studies and in the 
Phase II ABSSSI, urogenital gonorrhea, and uUTI studies, 
no cases of C. difficile-associated diarrhea were reported.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Suspected C. difficile infection will be managed according 
to a prespecified algorithm provided in Appendix 7.
Participant evaluation criteria: Participants experiencing 
Grade 3 or Grade 4 AEs will be followed as appropriate 
until resolution of the AE (see Section 7.1.3).
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiovascular Effects
Reversible increase in QT prolongation and a mild 
increase in heart rate in human participants.
In Study BTZ115775 (see GSK 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. 
No changes in QRS or QTc of clinical concern have been 
seen in the clinic (Phase I studies, including renal 
impairment and hepatic impairment studies, and Phase II 
ABSSSI and uUTI [acute cystitis] studies) (see Section 6 in 
the IB). There were electrocardiographic changes noted in 
a Phase I hepatic impairment study. The majority of 
participants with severe hepatic impairment had both 
predose and maximum postdose ECG parameter QTcB 
and QTcF values of <450 to ≤479 msec throughout the 
study. Cardiovascular events reported in the Phase II 
urogenital gonorrhea study were ECG ST segment 
elevation and palpitations (1 participant each) in the 
1500-mg treatment group and tachycardia (1 participant) in 
the 3000-mg treatment group.
Exclusion criteria, close monitoring of clinical parameters, 
and AEs will be conducted and stopping criteria will be 
utilized to mitigate and assess cardiovascular effects.
Note: Participants with baseline QTcF interval >450 msec 
will be excluded.
Participant monitoring criteria: Participants experiencing a 
QTcB and/or QTcF >500 msec and/or a change from 
baseline in QTc >60 msec (see Section 7.1.2).
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 participants have experienced 
effects consistent with increased cholinergic tone, including 
central nervous system and GI effects (increased 
salivation, slurred speech, blurred vision, dizziness, 
light-headedness, and GI upset). These effects appear to 
be related to Cmax and are significantly attenuated when 
Cmax is below 14 g/mL.
Coadministration of anticholinergics and administration in 
participants with certain concomitant conditions will be 
excluded.
Close monitoring of clinical parameters and AEs will be 
conducted to assess effects potentially related to AChE 
inhibition. The Cmax is expected to 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
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was 
seen in 3 of 6 participants following 10 days of dosing 
1500 mg 3 times daily (see GSK Document Number 
2014N198291_00 Study ID BTZ115198).
Rash was reported as an AE for 4 of 122 participants (3%) 
and consisted of mild, related urticaria; moderate, related 
rash maculopapular; mild, related rash; mild, related 
urticaria; and mild, not related arthropod bite (see GSK 
Document Number 2015N243789_00 Study ID 
BTZ116704).
There has been no other evidence of hypersensitivity in 
human participants to date.
Exclusion criterion:
History of sensitivity to any of the study drugs, components 
thereof, or a history of drug or other allergy that, in the 
opinion of the investigator or GlaxoSmithKline medical 
monitor, contraindicates their participation.
Participant monitoring:
Participants will be monitored closely for cutaneous effects 
throughout the study, and specialist advice will be sought 
as needed to evaluate any clinically significant finding.
Participant evaluation criteria:
Grade 3 or higher rash or Grade 2 rash with evidence of 
systemic involvement (see Section 7.1.4).
bpm = beats per minute; ABSSSI = acute bacterial skin and skin structure infection; AE = adverse event; Cmax = maximum concentration; ECG = electrocardiogram; IB = Investigator’s 
Brochure; IV = intravenous; ΔΔQTcF = placebo-corrected change-from-baseline in corrected QT interval using the Fridericia formula; QTc = corrected QT interval; QTcB = QT interval 
corrected for heart rate according to Bazett; QTcF = interval corrected for heart rate according to Fridericia; uUTI = uncomplicated urinary tract infection.
 
 
 
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2.3.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy adult and adolescent participants, 
there is no direct clinical benefit to study participants. Participation in this study will 
contribute to the process of developing new antibiotic therapies in areas of growing 
unmet need.
2.3.3.
Overall Benefit: Risk Conclusion
The risk of AEs is minimized for the populations being investigated in the proposed study 
by careful selection of dose and participants for the study, the relatively short duration of 
study drug exposure, and the extent of safety monitoring incorporated into the study.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Part 1

To evaluate the pharmacokinetics of a 
single 1500-mg dose and two 3000-mg 
doses of gepotidacin given 6 and 
12 hours apart in adult participants
1500 mg Single Dose

Plasma gepotidacin AUC(0-t), AUC(0-∞), 
AUC(0-24), AUC(0-48), and Cmax, as data 
permit
3000 mg Two Doses

Plasma gepotidacin AUC(0-t), AUC(0-τ), 
AUC(0-24), AUC(0-48), Ro (accumulation 
ratio), and Cmax, as data permit
Part 2

To evaluate the pharmacokinetics of a 
single 1500-mg dose and two 3000-mg 
doses of gepotidacin given at a dosing 
interval (to be determined) in 
adolescent participants
1500 mg Single Dose

Plasma gepotidacin AUC(0-t), AUC(0-∞), 
AUC(0-24), AUC(0-48), and Cmax, as data 
permit
3000 mg Two Doses

Plasma gepotidacin AUC(0-t), AUC(0-τ), 
AUC(0-24), AUC(0-48), Ro (accumulation 
ratio), and Cmax, as data permit
Parts 1 and 2

To assess the safety of gepotidacin in 
adult participants and adolescent 
participants

Adverse events, clinical laboratory tests, 
vital signs (systolic and diastolic blood 
pressure and heart rate), and 12-lead 
electrocardiogram readings
 
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Objectives
Endpoints
Secondary
Part 1

To assess the urine pharmacokinetics
of gepotidacin following a single 
1500-mg dose and two 3000-mg doses 
of gepotidacin given 6 and 12 hours 
apart in adult participants

Urine endpoints include Ae total, Ae(t1-t2), 
AUC(0-τ), AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data permit
Part 2

To assess the urine pharmacokinetics
of gepotidacin following a single 
1500-mg dose and two 3000-mg doses 
of gepotidacin given at a dosing interval 
(to be determined) in adolescent 
participants

Urine endpoints include Ae total, Ae(t1-t2), 
AUC(0-τ), AUC(0-24), AUC(0-48), fe%, 
and CLr of gepotidacin, as data permit
Parts 1 and 2

To assess the plasma 
pharmacokinetics of gepotidacin

Plasma gepotidacin Tmax, tlag, and t1/2, 
as data permit
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I, double-blind, single-center, randomized, sequential, two-part study. 
Part 1 is being conducted to evaluate the PK of the gepotidacin tablets in healthy adult 
participants. Part 2 will evaluate the PK of the gepotidacin tablets in healthy adolescent 
participants.
Part 1: Pharmacokinetics in Healthy Adult Participants
Part 1 is a 3-period, fixed-sequence study that will assess the PK of a single 1500-mg 
dose (Period 1) and two 3000-mg doses of gepotidacin at Hours 0 and 12 (Period 2) and 
Hours 0 and 6 (Period 3) in healthy adult participants. 
Participants will be randomly assigned to receive either all active treatment (gepotidacin) 
or placebo for all 3 periods. Approximately 17 participants will be randomized (in a 
14:3 ratio) to receive a single dose of gepotidacin 1500 mg (Treatment A) or matching 
placebo (Treatment B) in Period 1, gepotidacin 3000 mg separated by 12 hours 
(Treatment C) or matching placebo (Treatment D) in Period 2, and gepotidacin 3000 mg 
separated by 6 hours (Treatment E) or matching placebo (Treatment F) in Period 3 to 
obtain 12 evaluable participants on active treatment and 2 evaluable participants on 
placebo.
 
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Participants will participate in 3 treatment periods, and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the Schedule of 
Activities (SoA; see Section 1.3).
This will be a two-part study in which the PK and safety data will be reviewed after 
completion of Part 1 before enrolling participants into Part 2. The dosing interval in 
Part 2, Period 2 will be based on the PK, safety, and tolerability data from Part 1.
Part 2: Pharmacokinetics in Healthy Adolescent Participants
Part 2 is a 2-period, fixed sequence study that will assess the PK of a single 1500-mg 
dose (Period 1) of gepotidacin and two 3000-mg doses (Period 2) of gepotidacin in 
healthy adolescent participants. The two 3000-mg doses will be separated by a time 
interval that will be determined based on data from Part 1. The number of PK samples 
and the PK sampling time points may be modified based on the adult PK data from 
Part 1.
Participants will be randomly assigned to receive either all active treatment (gepotidacin) 
or placebo for both periods. Approximately 17 participants will be randomized (in a 
14:3 ratio) to receive a single dose of gepotidacin 1500 mg (Treatment A) or matching 
placebo (Treatment B) in Period 1 and gepotidacin 3000 mg (Treatment G) or matching 
placebo (Treatment H) in Period 2 to obtain 12 evaluable participants on active treatment 
and 2 evaluable participants on placebo.
The interval for the two 3000-mg doses in Period 2 will be between 6 hours and 12 hours 
based on the PK and safety results from Part 1.
Participants will participate in 2 treatment periods, and blood and urine samples will be 
collected for PK analysis of gepotidacin concentrations according to the SoA 
(see Section 1.3).
For Part 2 only, there may be a 7-day interval between doses in Period 1 and Period 2 to 
accommodate the adolescent population school schedule. Treatment Period 1 and 
Treatment Period 2 may be separated by no more than 10 days.
4.2.
Scientific Rationale for Study Design
Although total daily oral 6000 mg doses have been given to healthy participants and 
patients as 2000 mg TID for up to 14 days and daily IV 4500 mg (equivalent to 9180 mg 
oral dose and based on absolute bioavailability of 46%) doses have been given to healthy 
participants as TID regimen for up to 10 days, the safety and PK of two 3000 mg doses 
given either 6 or 12 hours apart have not been characterized previously and gepotidacin 
has not been administered previously to adolescents; this study will support inclusion of 
adolescents with a body weight ≥40 kg in future Phase III studies and will provide the 
safety and PK data of two 3000 mg doses separated by the selected dose intervals in 
Part 1 and Part 2.
 
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Both adult and adolescent (≥12 to <18 years of age) eligible participants will be enrolled 
in this double-blinded study. Adolescent participants will only be enrolled if allowed per 
the study site’s IRB and national regulatory guidelines, and enrollment will be contingent 
upon such approvals. Adolescent assent forms and adult consent forms will be developed 
with oversight from local governing IRB (see Appendix 3).
Part 1 is being conducted to evaluate the pharmacokinetics, safety, and tolerability of the 
gepotidacin tablet.
Part 2 will evaluate the pharmacokinetics, safety, and tolerability of the gepotidacin tablet
in adolescent participants. Testing gepotidacin in this specific population will provide 
PK, safety, and tolerability information needed for their inclusion in future pivotal 
Phase III studies.
4.3.
Justification for Dose
Selection of dose and dosing frequency for this study is justified based on observed safety 
efficacy and PK data following single oral dosing (1500 to 3000 mg), repeat oral twice 
daily (BID; 1500 to 2300 mg) and TID dosing (1500 to 2000 mg) in previous studies. In 
addition, exposures higher than anticipated in this study were achieved following single 
IV dosing of 1800 mg equivalent to an oral dose of 3913 mg (absolute bioavailability is 
46%) and repeat IV dosing of 1500 mg TID for 10 days (equivalent to an oral daily dose 
of approximately 9180 mg).
Based on PK modeling, gepotidacin will be administered for gonorrhea as two single oral 
3000-mg doses, given either 6 or 12 hours apart with a minimum body weight of 40 kg, 
to provide higher daily systemic exposures that allow coverage of Neisseria gonorrhoeae
isolates with higher gepotidacin MIC values, which are likely to be observed in the global 
Phase III study and reduce the risk of resistance emergence. Less than 3% of the 
population is expected to exceed the Cmax threshold of 14 µg/mL.
In the current study, gepotidacin will be administered as a single oral 1500-mg dose and 
2 oral 3000-mg doses. The two 3000-mg doses, given either 6 or 12 hours apart in Part 1 
and at the selected dose interval in Part 2, compared with the single 1500-mg dose, are
expected to provide valuable PK and safety data to guide Phase III studies and the 
prescribing information for the gepotidacin tablet.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the final date on which data were or are expected to be 
collected.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled visit shown in the SoA (see Section 1.3) for the last participant in 
the study.
 
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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the sponsor in consultation with the investigator.
Replacement participants will be assigned to the same randomization sequence as the 
participant who discontinued.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant in Part 1 must be ≥18 to ≤64 years of age inclusive, at the time of signing 
the informed consent.
2.
Participant in Part 2 must be ≥12 to <18 years of age inclusive, at the time of signing 
the informed consent/assent.
Type of Participant and Disease Characteristics
3.
Participants who are healthy as determined by the investigator or medically qualified 
designee based on medical evaluation including medical history, physical 
examination, clinical laboratory tests, vital sign measurements, and 12-lead 
electrocardiogram (ECG) results <450 millisecond (msec). A participant with 
clinical abnormality or laboratory parameters outside the reference range for the 
population being studied may be included only if the investigator feels and 
documents that the finding is unlikely to introduce additional risk factors and will not 
interfere with the study procedures.
Weight
4.
Body weight ≥40 kg and body mass index (BMI) within the range 18.5 – 32.0 kg/m2
(inclusive).
Sex
5.
Male and/or female
a.
Female Participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
o
Is not a woman of childbearing potential (WOCBP) 
OR
 
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o
Is a WOCBP and using a contraceptive method that is highly effective, with a 
failure rate of <1%, as described in Appendix 5 for at least 30 days prior to 
dosing until completion of the Follow-up Visit. The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the 
first dose of study intervention.

A WOCBP must have a highly sensitive negative pregnancy test before the first dose 
of study intervention.
Informed Consent
6.
Capable of giving signed informed consent/assent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF/assent
and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Clinically significant abnormality in the past medical history or at the Screening 
physical examination that in the investigator’s opinion may place the participant at 
risk or interfere with outcome variables of the study. This includes, but is not limited 
to, history or current cardiac, hepatic, renal, neurologic, gastrointestinal (GI), 
respiratory, hematologic, or immunologic disease.
2.
Any surgical or medical condition (active or chronic) that may interfere with drug 
absorption, distribution, metabolism, or excretion of the study intervention, or any 
other condition that may place the participant at risk, in the opinion of the 
investigator.
3.
Female participant has a positive pregnancy test result or is lactating at Screening or 
upon admission to the clinic.
4.
Use of any systemic antibiotic within 30 days of Screening.
5.
Within 2 months before Screening, either a confirmed history of Clostridium difficile
diarrhea infection or a past positive of C. difficile toxin test.
6.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
7.
History of drug and/or alcohol abuse within 6 months before Screening, as 
determined by the investigator, or has a positive drug screen at Screening or upon 
admission to the clinic.
8.
History of sensitivity to any of the study drug, components thereof, or a history of 
drug or other allergy that, in the opinion of the investigator or GSK medical monitor 
contraindicates their participation.
9.
History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
uses heparin to maintain intravenous cannula patency).
 
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Prior/Concomitant Therapy
10. Participants must abstain from taking prescription or nonprescription drugs (except 
for hormonal contraceptives and/or acetaminophen), vitamins, and dietary or herbal 
supplements, unless specified in Section 6.5, within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to study 
intervention until completion of the Follow-up Visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study. Any 
exceptions will be discussed with the sponsor or medical monitor on a case-by-case 
basis and the reasons will be documented.
Prior/Concurrent Clinical Study Experience
11. Previous exposure to gepotidacin within 12 months prior to starting study 
intervention.
12. Participant has participated in a clinical trial and has received an investigational 
product prior to gepotidacin administration within 30 days, 5 half-lives, or twice the 
duration of the biological effect of investigational product (whichever is longer).
Diagnostic assessments
13. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result at 
Screening or within 3 months prior to starting study intervention.
14. Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN).
15. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. History of any kidney disease or current or chronic history of impaired renal function 
as indicated by an estimated creatinine clearance <60 mL/min.
17. A positive test for human immunodeficiency virus antibody.
18. History of regular alcohol consumption within 6 months of screening defined as an 
average weekly intake of >21 units (or an average daily intake of >3 units) for males 
or an average weekly intake of >14 units (or an average daily intake >2 units) for 
females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 
30 mL of spirits, or 100 mL of wine.
19. Urinary cotinine level indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months before Screening.
20. Clinically significant abnormal findings in serum chemistry, hematology, or 
urinalysis results obtained at Screening or Day -1. 
21. Baseline corrected QT interval using the Fridericia formula (QTcF) of >450 msec.
Other Exclusions
22. Participant has donated blood in excess of 500 mL within 12 weeks prior to dosing 
or participation in the study would result in donation of blood or blood products in 
excess of 500 mL within a 56-day period.
 
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23. Participant is unable to comply with all study procedures, in the opinion of the 
investigator.
24. Participant should not participate in the study, in the opinion of the investigator or 
sponsor.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

All doses of study intervention (gepotidacin or placebo) should be after food 
consumption (a standard meal) and with approximately 240 mL of water. Up to 
480 mL of water is allowed if the participant has difficulty swallowing multiple 
tablets.

Prior to the morning dose, participants will fast (no food or drink except water) for 
approximately 8 to 10 hours before dosing and will receive a standard meal 
30 minutes prior to dose. Participants should consume this meal in 30 minutes or 
less. Dose administration will occur within 5 minutes of completion of meal 
consumption. Participants will not receive any further food until 2 hours after dosing. 
Standard meals will be provided during the study treatment period at times that do 
not interfere with study procedures.

For doses scheduled to occur 6 or 12 hours after the initial dose, participants will 
have the standard meal in the morning and will receive another standard meal 
(similar in calorie content and similar ratios of protein, carbohydrates, and fat as the 
previous meal) prior to the second dose. Participants should consume this meal in 
30 minutes or less. Dose administration will occur within 5 minutes of completion of 
meal consumption. Participants will not receive any further food until 2 hours after 
dosing.

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the start of dosing until after collection of the final PK sample.

No water is allowed until 2 hours after dosing, unless administered under the 
investigator’s direct order for treatment of an AE. Water is allowed ad libitum at all 
other times.

Standard meals will be provided during the study dosing period at specified times.
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before the start of dosing 
until after collection of the final PK sample.

Participants will abstain from alcohol for 24 hours before the start of dosing until 
after collection of the final PK sample. 

Use of tobacco products will not be allowed from 3 months before Screening until 
after the final Follow-up visit.
 
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5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during the study (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations, 
and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Participants should be assigned a new participant number for every 
screening/re-screening event.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
 
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6.1.
Study Interventions Administered
Intervention Name
Gepotidacin Tablets, 750 mg
Placebo (Matched to 
Gepotidacin Tablets)
Type 
Tablets containing gepotidacin 
mesylate (GSK2140944E) and 
inactive formulation excipients
Unit-dose gepotidacin 
placebo-to-match tablet
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
750 mg
Not applicable
Dosage Level(s)
Part 1, Period 1:
2 x 750 mg single dose
Each dose should be taken 
after food consumption and 
with water
Part 1, Periods 2 and 3:
4 x 750 mg two doses given 
either 6 or 12 hours after first 
dose (6000 mg total daily dose)
Each dose should be taken 
after food consumption and 
with water
Part 2, Period 1:
2 x 750 mg single dose
Each dose should be taken 
after food consumption and 
with water
Part 2, Period 2:
4 x 750 mg two doses given at 
an interval to be determined 
after review of safety and PK 
data from Part 1 (6000 mg total 
daily dose)
Each dose should be taken 
after food consumption and 
with water
Part 1, Period 1:
Administer 2 tablets as a single 
dose
Each dose should be taken 
after food consumption and 
with water
Part 1, Periods 2 and 3:
Administer 4 tablets (two 
doses); second dose given
either 6 or 12 hours after first 
dose
Each dose should be taken 
after food consumption and 
with water
Part 2, Period 1:
Administer 2 tablets as a single 
dose
Each dose should be taken 
after food consumption and 
with water
Part 2, Period 2:
Administer 4 tablets (two 
doses) given at an interval to 
be determined after review of 
safety and PK data from Part 1
Each dose should be taken 
after food consumption and 
with water
 
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Route of Administration
Oral
Oral
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
Packaging and Labeling
Gepotidacin will be provided in 
high-density polyethylene 
(HDPE) bottles. Each bottle will 
be labeled as required per 
country requirement.
Placebo will be provided in 
HDPE bottles. Each bottle will 
be labeled as required per 
country requirement.
6.2.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a double-blind study. The study treatment taken during the study will be 
double-blind. An unblinded pharmacist will dispense study intervention. Neither the 
participant nor immediate study personnel (i.e., investigators, PPD staff) will know which 
study treatment the participant is receiving. Participants who are randomly assigned to 
receive placebo will receive a matching placebo form of the active treatment. The 
matching placebos will look identical to the active form.
 
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In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a participant’s treatment assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact 
GSK prior to unblinding a participant’s treatment assignment unless this could delay 
emergency treatment of the participant. If a participant’s treatment assignment is 
unblinded, GSK must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and 
electronic case report form (eCRF), as applicable.
In Part 1 and Part 2, participants will be randomized in a 14:3 ratio to receive study 
intervention. Investigators will remain blinded to each participant’s assigned study
intervention throughout the course of the study.
Unblinded monitors and in the event of a quality assurance audit, the auditor will be 
allowed access to unblinded study intervention records at the site to verify that
randomization/dispensing has been done accurately.
A participant will be withdrawn if the participant’s intervention code is unblinded by the 
investigator. The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the eCRF.
To protect the safety of participants, GSK safety medical monitor may remain unblinded 
to participant treatment throughout the study and will monitor safety data in real time. 
Limited members of GSK staff (e.g., statistician, pharmacokineticist, and medical 
monitor) will be unblinded to study treatment at the end of Part 1 in order to determine 
which dosing frequency to take forward to Part 2.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.
 
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6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the Follow-up Visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study. 
Hormonal contraceptives and/or acetaminophen, at doses of 2 grams/day, are permitted 
for use any time during the study. Other concomitant medication may be considered on a 
case-by-case basis by the investigator in consultation with the medical monitor.
6.6.
Dose Modification
The interval for the two 3000-mg doses in Part 2, Period 2 will be between 6 hours and 
12 hours based on the PK and safety results from Part 1.
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment from GSK (gepotidacin or placebo)
after completion of the study because only healthy participants are eligible for study 
participation.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will
remain in the study to be evaluated for safety. See the SoA (see Section 1.3) for data to be 
collected at the time of discontinuation of study intervention.
 
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7.1.1.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Refer to Appendix 6 for required Liver Safety Actions and Follow-up Assessments.
7.1.2.
QTc Stopping Criteria
A participant who meets the following bulleted criteria based on triplicate ECG readings 
will be withdrawn from study treatment:

Corrected QT (QTc) >500 msec 

Change from baseline of QTc >60 msec
For participants with underlying bundle-branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle-Branch Block
Discontinuation QTc with Bundle-Branch 
Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.
 
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
For example, if a participant is eligible for the protocol based on corrected 
QTcF, then QTcF must be used for discontinuation of this individual participant
as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of ECG readings
obtained over a brief (e.g., 5 to 10 minute) recording period.  
See the SoA (see Section 1.3) for data to be collected at the time of intervention
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.3.
Gastrointestinal Evaluation Criteria
If a participant meets the criteria in Appendix 7, C. difficile toxin testing should be 
conducted.
7.1.4.
Rash/Hypersensitivity Evaluation Criteria
A participant presenting with a Grade 3 AE or higher rash (diffuse macular, 
maculopapular, OR morbilliform rash with vesicles or limited number of bullae; OR 
superficial ulcerations of mucous membrane limited to 1 site) or a Grade 2 rash (diffuse 
macular, maculopapular, or morbilliform rash; OR target lesions) with evidence of 
systemic involvement will be followed as appropriate until resolution of the AE(s).
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (see Section 1.3) for 
data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
 
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7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 3.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (see Section 1.3). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF/assent may be utilized for 
screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in 
the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.
 
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
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (see Section 1.3).
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include systolic and diastolic blood pressure and heart rate. Oral 
temperature and respiratory rate will be collected at Screening only. Each 
measurement will be recorded in the eCRF.
8.2.3.
Electrocardiograms

Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

Twelve-lead ECGs will be performed with the participant in a semi-supine 
position after a rest of at least 10 minutes.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession but no more than 
2 minutes apart. The full set of triplicates should be completed over a brief (e.g., 
5 to 10 minutes) recording period.

ECG Holter monitoring will be obtained as outlined in the SoA
(see Section 1.3). The Holter monitoring data will be sent to GSK and may be 
analyzed at a later date.
 
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8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (see Section 1.3) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those that are 
not associated with the underlying disease, unless judged by the investigator to 
be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or until completion of the Follow-up Visit
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF/assent until the 
Follow-up Visit at the time points specified in the SoA (see Section 1.3).

All AEs will be collected from the start of intervention until the Follow-up Visit 
at the time points specified in the SoA (see Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of eCRF, not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
 
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
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.

Care will be taken not to introduce bias when detecting AE and/or SAE. 
Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and nonserious AEs of special interest 
(as defined in Section 2.3.1), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 4.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
 
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8.3.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 
completion of the Follow-up Visit.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Treatment of 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 participant’s clinic status.
GlaxoSmithKline does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1.
Contact the medical monitor immediately.
2.
Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
gepotidacin can no longer be detected systemically (at least 3 days).
3.
Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study intervention if requested by the medical monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics

The PK blood and urine samples will be collected for measurement of plasma and 
urine concentrations of gepotidacin at the time points indicated in the 
SoA (see Section 1.3). The volume of blood required for each PK sample is 
approximately 3 mL for Part 1, and approximately 2 mL for Part 2. Instructions 
for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded.
 
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
Processing, storage, and shipping procedures for blood and urine samples are
provided in the SRM and/or laboratory manual.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
There is no formal research hypothesis that will be statistically tested in this study.
9.2.
Sample Size Determination
The PK parameter sample size for this study was based on feasibility; however, 
justification has been considered. For the 1500 mg single-dose regimen, the closest 
reference study was BTZ116778, with 1500 mg oral dose (immediate-release capsule) 
taken in fed state, resulting in a coefficient of variation (CV) for AUC(0-∞) and Cmax of 
21.5% and 40.3% respectively. Precision has been evaluated for a range of plausible 
sample sizes of 10, 12, and 15 participants exposed to the active dose (see table). The 
precision of sample size of 12 is deemed sufficient for the primary PK endpoint in this 
study. With 12 participants, the upper limit of the 95% confidence interval for AUC(0-∞) 
and Cmax will be approximately 14.5% and 28.0% above the geometric means, 
respectively.
There were 2 studies similar to the 3000 mg BID (at 6- or 12-hour intervals) dosing 
regimen. BTZ114595 studied PK profile after a 3000 mg single dose in the fasted state, 
with CV for AUC(0-∞) and Cmax being 31.5% and 36.0%, respectively. BTZ116576 
studied the 2-hour postdose concentration following a 3000 mg single dose in the fed 
state, with CV for the concentration being 42.9%. The estimate of AUC(0-∞) CV was 
higher after 3000 mg than the 1500 mg dose; however, AUC(0-∞) appeared less variable 
than Cmax consistently across doses, indicating that Cmax should be the main 
 
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consideration for precision. Despite slight differences in dosing regimens, both 3000 mg 
single-dose studies indicated the variability of Cmax approximately 40%, consistent with 
that of the 1500 mg single dose. Therefore, sample size justification for the 1500 mg 
single dose is also applicable for the 3000 mg dose.
Distance from 95% CI Upper Limit to the Geometric Mean (given numbers 
of participants exposed to the active dose)
n=10
n=12
n=15
AUC (0-∞)
CV=21.5%
16.4%
14.5%
12.5%
Cmax
CV=40.3%
32.0%
28.0%
24.0%
CI = confidence interval; CV = coefficient of variation.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF/assent.
Randomized
All participants who are randomized.
Safety
All participants who take at least 1 dose of study intervention. This 
population will be used for all demographic and safety summaries.
PK
Participants who receive at least 1 dose of gepotidacin and have
evaluable postdose plasma concentration data for gepotidacin. This 
primary analysis population will be used in the assessment and 
characterization of PK concentrations (summary tables and figures).
PK Parameter
All participants in the PK population who received gepotidacin for
whom valid and evaluable plasma PK parameters are derived for 
gepotidacin. This primary analysis population will be used in the 
assessment and characterization of PK parameters (summary and 
analysis tables and figures).
9.4.
Statistical Analyses
9.4.1.
Pharmacokinetic Analyses
Plasma and urine concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods. Based on the individual gepotidacin concentration-time data 
the following parameters will be estimated:
 
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Plasma:
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to 
time of the last quantifiable concentration
AUC(0-∞)
Area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
AUC(0-τ)
Area under the concentration-time curve from time 0 (predose) to 
time tau (tau = 12 and 6 for Part 1, Periods 2 and 3, respectively; 
for Part 2, tau will be between 6 and 12)                          
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 
24 hours postdose administration following the first dose
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 
48 hours postdose administration following the first dose
Cmax
Maximum observed concentration
Ro
Accumulation ratio, calculated as:
Ro for AUC = AUC(0-6) after second 3000 mg dose divided by 
AUC(0-6) after the first 3000 mg dose
Ro for Cmax = Cmax after second 3000 mg dose divided by Cmax 
after the first 3000 mg dose
t1/2
Terminal phase half-life
tlag
Lag time before observation of drug concentrations in sampled 
matrix
Tmax
Time to reach maximum observed plasma concentration
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 time intervals of predose, 
0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 
12 to 24 hours, 24 to 36 hours, 36 to 48 hours, and 48 to 60 hours
(Period 2 and Period 3) after dosing
AUC(0-τ)
Area under the concentration-time curve from time 0 (predose) to 
time tau (tau = 12 and 6 for Part 1, Periods 2 and 3, respectively; 
 
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for Part 2, tau will be between 6 and 12)                         
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 
24 hours postdose administration following the first dose
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 
48 hours postdose administration following the first dose
fe%
Percentage of the given dose of drug excreted in urine, calculated 
as:
fe% = (Ae total/Dose) × 100%
CLr
Renal clearance of drug, calculated as: Ae total/AUC(0-t)
Plasma and urine concentrations of gepotidacin and the associated PK parameters will be 
listed, and summary statistics (n, mean, median, standard deviation [SD], minimum, 
maximum, and CV) will be presented by Study Part and treatment. Mean and individual 
plasma concentration versus time profiles will be presented graphically on linear and 
semilogarithmic scales.
9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. No formal statistical analysis 
of the safety data will be conducted.
The details of the statistical analyses of safety and PK data will be provided in the 
reporting and analysis plan (RAP).
9.4.3.
Other Analyses
Not applicable.
9.5.
Interim Analyses
Preliminary plasma PK and safety results from participants in Part 1 will be reviewed by 
the sponsor before enrolling participants into the next part of the study. The dosing 
interval to be used when two gepotidacin doses are given in Part 2, Period 2 will be 
determined after a review of the PK and safety results from Part 1. The number of PK 
samples and the PK sampling time points may be modified based on the adult PK data 
from Part 1.
An ad hoc review of 12-lead ECG data may be performed between Part 1, Period 2 and 
Part 1, Period 3.
The RAP will describe the planned interim analyses in greater detail.
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AChE
acetylcholinesterase
AE
adverse event
Ae total
total unchanged drug
Ae(t1-t2)
amount of drug excreted in urine in a time interval
ALT
alanine aminotransferase 
AUC
area under the concentration-time curve
AUC(0-∞)
area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
AUC(0-24)
area under the concentration-time curve from time 0 (predose) to 
24 hours post dose administration following the first dose (plasma 
or urine)
AUC(0-48)
area under the concentration-time curve from time 0 (predose) to 
48 hours post dose administration following the first dose (plasma 
or urine)
AUC(0-t)
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration (plasma or urine)
AUC(0-τ)
area under the concentration-time curve from time 0 (predose) to 
time tau (plasma or urine)
BID
twice daily
BMI
body mass index
CA
Competent Authorities
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CLr
renal clearance of drug
Cmax
maximum observed concentration
CONSORT
Consolidated Standard of Reporting Trials
CV
coefficient of variation
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
fe%
percentage of the given dose of drug excreted in urine
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HDPE
high-density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
 
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HIV
human immunodeficiency virus
HRT
hormone replacement therapy
ICF
informed consent form
ICH
International Council for Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
MIC
minimum inhibitory concentration
mm Hg
millimeters of mercury
MSDS
Material Safety Data Sheet
msec
millisecond
NIAID
National Institute of Allergy and Infectious Disease
PK
pharmacokinetic
QTc
corrected QT interval; the measure of time between the start of 
the Q wave and the end of the T wave
QTcB
corrected QT interval using the Bazett formula
QTcF
corrected QT interval using the Fridericia formula
RAP
Reporting and Analysis Plan
Ro
accumulation ratio
SAE
serious adverse event
SD
standard deviation
SoA
schedule of activities
SRM
Study Reference Manual
τ 
tau is the dosing interval in hours
t1/2
terminal phase half-life
TID
three times daily
tlag
lag time before observation of drug concentrations
Tmax
time to reach maximum observed plasma concentration
ULN
upper limit of normal
uUTI
uncomplicated urinary tract infection
WOCPB
women of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
GSKDrug
MedDRA
 
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing should be conducted at the time points indicated in the 
SoA (see Section 1.3).

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study.
Table 10
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell Indices:
White blood cell count with 
differential:
Red Blood Cell Count
Mean corpuscular volume
Neutrophils
Hemoglobin
Mean corpuscular hemoglobin 
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry 1
Blood urea nitrogen
Aspartate aminotransferase
Chloride
Creatinine
Alanine aminotransferase
Carbon dioxide
Glucose (fasting)
Alkaline phosphatase
Total protein
Potassium
Total and direct bilirubin
Albumin
Sodium
Creatine phosphokinase
Magnesium
Calcium
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is abnormal)
 
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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serology: HIV-1 and -2 antigen/antibody immunoassay, Hepatitis B surface 
antigen (HBsAg), Hepatitis C (Hep C antibody)

Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Pregnancy

Follicle-stimulating hormone

Fecal occult blood test and stool cultures as appropriate for gastrointestinal 
adverse events (Appendix 7).
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Appendix 6. All events of ALT 3 ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).
Laboratory results that could unblind the study will not be reported to the investigative 
site or other blinded personnel until the study has been unblinded.
 
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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight 
Considerations
10.3.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF/assent form, Investigator Brochure, 
and other relevant documents (e.g., advertisements) must be submitted to an 
IRB/IEC by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
10.3.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
 
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10.3.3.
Informed Consent/Assent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Adolescent participants should be asked for their written assent to participate in 
the study.

As applicable, the IRB will be consulted before assent form development for 
guidance around age-appropriate groupings and any specific IRB requirements 
or local laws for conducting and documenting assent.

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.3.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 
 
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
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.3.5.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.3.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding.
10.3.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 
 
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
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF/assent, pertaining to the conduct 
of this study must be retained by the investigator for 25 years from the issue of 
the final clinical study report/equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.3.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
10.3.9.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
 
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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
 
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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
 
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leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.4.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:
 
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
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Cardiovascular and Gastrointestinal Adverse Events of Special Interest
Investigators will be required to fill out the specific cardiovascular or gastrointestinal 
event page of the eCRF for the following AEs and SAEs:
Cardiovascular Events:
Gastrointestinal Events:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and 
transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary 
embolism

Revascularization

Nausea

Vomiting

Dysphagia

Abdominal pain

Diarrhea

Flatulence

Feces soft

Constipation
10.4.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
 
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medical records to GSK in lieu of completion of the GSK AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported 
during the study according to the US National Institute of Allergy and Infectious 
Disease (NIAID) Division of Microbiology and Infectious Diseases (DMID) criteria 
for adult toxicity assessment (see Appendix 8).
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
 
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reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.4.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
 
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this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.
 
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10.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
10.5.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., müllerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement (>40 IU/L or mIU/mL) is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
 
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10.5.2.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) b

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral

injectable

Sexual abstinence

Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant.

ACCEPTABLE METHODSd

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action

Male or female condom with or without spermicidee

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c
 
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a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
d.
Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception.
e.
Male condom and female condom should not be used together (due to risk of failure with friction).
10.5.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive gepotidacin.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
 
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
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn 
from the study.
 
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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>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 
Actions
Follow Up Assessments

Immediately discontinue study intervention

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 SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 24 
hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 

Viral hepatitis serology3

Obtain international normalized ratio (INR)
and recheck with each liver chemistry 
assessment until the transaminases values 
show downward trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 24 hours of 
last dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH)

Fractionate bilirubin, if total 
bilirubin2xULN

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≥3xULN AND bilirubin 2xULN or INR 
 
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Liver Chemistry Stopping Criteria 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, and INR) and 
perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline
>1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants.
3.
Includes: Hepatitis A immunoglobulin (IgM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing), and Hepatitis E IgM antibody.
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.
 
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10.7.
Appendix 7: Clostridium difficile Testing Procedure and 
Algorithm
Note:  This algorithm is subject to investigator discretion when the clinical 
presentation and time course of diarrhea (e.g., during or within 12 hours immediately 
after dosing) do not fit the Clostridium difficile associated diarrhea definition; 
consideration should be given to diarrhea occurring in this early time frame to be 
suggestive of a cholinergic effect.
 
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10.8.
Appendix 8: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity:
GRADE 1
Mild
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required
GRADE 2
Moderate
Mild to moderate limitation in activity – some assistance may 
be needed; no or minimal medical intervention/therapy 
required
GRADE 3
Severe
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible
GRADE 4
Life-threatening
Extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, 
hospitalization or hospice care probable
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a Grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to,
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DAIDS) 
and modified to better meet the needs of participants in Division of Microbiology and 
Infectious Diseases (DMID) trials (November 2007).

For parameters not included in the following Toxicity Tables, study sites should refer 
to the “Guide for Estimating Severity Grade” located above.

Criteria are generally grouped by body system.
 
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 to 10.5 gm/dL
8.0 to 9.4 gm/dL
6.5 to 7.9 gm/dL
<6.5 gm/dL
Absolute Neutrophil Count
1000 to 1500 /mm3
750 to 999 /mm3`
500 to 749 /mm3
<500 /mm3
Platelets
75,000 to 99,999 /mm3
50,000 to 74,999 /mm3
20,000 to 49,999 /mm3
<20,000 /mm3
White Blood Cells
11,000 to 13,000 /mm3
13,000 to 15,000 /mm3
15,000 to 30,000 /mm3
>30,000 or <1000 /mm3
% Polymorphonuclear Leukocytes + 
Band Cells
>80%
90 to 95%
>95%
N/A
Abnormal Fibrinogen
Low: 100 to 200 mg/dL
High: 400 to 600 mg/dL
Low: <100 mg/dL
High: >600 mg/dL
Low: <50 mg/dL
High: N/A
Fibrinogen associated with gross bleeding or 
with disseminated coagulation
Fibrin Split Product
20 to 40 mcg/mL
41 to 50 mcg/mL
51 to 60 mcg/dL
>60 mcg/dL
Prothrombin Time (PT)
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated Partial Thromboplastin (APTT)
1.01 to 1.66 ULN
1.67 to 2.33 ULN
2.34 to 3 ULN
>3 ULN
Methemoglobin
5.0 to 9.9%
10.0 to 14.9%
15.0 to 19.9%
>20%
N/A=not applicable; ULN=upper limit of normal. 
 
 
 
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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 (AST)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase (ALT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Gamma to glutamyl transferase (GGT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alkaline Phosphatase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Amylase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
Lipase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
ULN=upper limit of normal.
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or
200 mg to 1 gm loss/day
2 to 3+ or
1 to 2 gm loss/day
4+ or
2 to 3.5 gm loss/day
Nephrotic syndrome or
>3.5 gm loss/day
Hematuria
Microscopic only
<10 RBC/HPF
Gross, no clots
>10 RBC/HPF
Gross, with or without clots,
or red blood cells casts
Obstructive or
required transfusion
HPF=high powered field; RBC=red blood cells.
 
 
 
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm
N/A
Asymptomatic, transient signs, no 
Rx required
Recurrent/persistent; symptomatic 
Rx required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension
Transient increase >20 mm/Hg;
no treatment 
Recurrent, chronic increase 
>20 mm/Hg;
treatment required 
Acute treatment required; 
outpatient treatment or 
hospitalization possible 
End organ damage or 
hospitalization required 
Hypotension
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mmHg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
BP=blood pressure; IV=intravenous; EKG=electrocardiogram; N/A=not applicable; Rx=therapy.
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment 
responsive
Paroxysmal cough; uncontrolled 
with treatment
N/A
Bronchospasm, Acute
Transient; no treatment; FEV1 70 
to 80% of peak flow
Requires treatment; normalizes with 
bronchodilator; FEV1 50 to 70% of 
peak flow
No normalization with 
bronchodilator; FEV1 25 to 50% of 
peak flow; or retractions present
Cyanosis: FEV1 <25% of peak flow; 
or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen therapy
FEV1=forced expiratory volume in 1 second; N/A=not applicable.
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; 
maintains reasonable 
intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or needing IV 
fluids
Physiologic consequences requiring 
hospitalization or requiring parenteral nutrition
Constipation
Requiring stool softener 
or dietary modification
Requiring laxatives
Obstipation requiring manual evacuation 
or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 
4 loose stools/day or mild 
diarrhea lasting <1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week
>7 loose stools/day or bloody diarrhea; or 
orthostatic hypotension or electrolyte 
imbalance or >2L IV fluids required
Hypotensive shock or physiologic 
consequences requiring hospitalization
Oral discomfort/
Dysphagia
Mild discomfort; no 
difficulty swallowing
Some limits on eating/drinking
Eating/talking very limited; unable to 
swallow solid foods
Unable to drink fluids; requires IV fluids
IV=intravenous.
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
Slight incoordination 
dysdiadochokinesis
Intention tremor, dysmetria, 
slurred speech; nystagmus
Locomotor ataxia
Incapacitated
Psychiatric
Mild anxiety or depression
Moderate anxiety or depression; 
therapy required; change in 
normal routine
Severe mood changes requiring therapy; 
or suicidal ideation; or aggressive 
ideation
Acute psychosis requiring 
hospitalization; or suicidal 
gesture/attempt or hallucinations
Muscle strength
Subjective weakness; no 
objective symptoms/signs
Mild objective signs/symptoms; no 
decrease in function
Objective weakness; function limited
Paralysis
Paresthesia
(burning, tingling, etc.)
Mild discomfort; no treatment 
required
Moderate discomfort; non-narcotic 
analgesia required
Severe discomfort; or narcotic analgesia 
required with symptomatic improvement
Incapacitating; or not responsive 
to narcotic analgesia
Neurosensory
Mild impairment in sensation 
(decreased sensation, e.g., 
vibratory, pinprick, hot/cold in 
great toes) in focal area or 
symmetrical distribution; or 
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 to 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25 to 50%; 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self
 
 
 
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11.
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part study to evaluate safety, tolerability, and pharmacokinetics of single and repeat IV 
doses of GSK2140944 in healthy adult subjects. 2014.
GlaxoSmithKline Document Number 2015N227098_00 Study ID BTZ115775: 
Population pharmacokinetic-pharmacodynamic analysis of a Phase I, randomized, 
double-blinded, placebo- and moxifloxacin-controlled, 4-period crossover study to 
evaluate the effect of GSK2140944 on cardiac conduction as assessed by 12-lead 
electrocardiogram in healthy volunteers. 2015.
GlaxoSmithKline Document Number 2015N243789_00 Study ID BTZ116704. A 
Phase II, randomized, two-part, multicenter, dose-ranging study in adult subjects 
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 CM2010/00033/06. Gepotidacin Investigator’s 
Brochure. 2019.
 
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