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

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TITLE PAGE
Protocol Title: A Phase I, Open-Label, Single-Dose, Two-Part Study to Assess the 
Pharmacokinetics of Gepotidacin (GSK2140944) in Male and Female Adult Participants
with Varying Degrees of Hepatic Impairment and in Matched Control Participants with 
Normal Hepatic Function
Protocol Number: BTZ117352
Short Title: Pharmacokinetics Study of Gepotidacin (GSK2140944) in Adult 
Participants with Varying Degrees of Hepatic Impairment and in Matched Control 
Participants with Normal Hepatic Function
Compound Number:
GSK2140944
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
 MD
PPD
7551 Metro Center Drive, Suite 300
Austin, TX 78744
Safety Hotline (24 hours): 
Safety Fax Number: 
Email: 
Secondary Medical Monitor
 MD
GlaxoSmithKline
1250 South Collegeville Road
Collegeville, PA 19426
Telephone Number: 
 (primary) or 
 (after business hours)
Fax Number: 
Regulatory Agency Identifying Number: IND 111885
Approval Date: 15-FEB-2018
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................16
3.3.3.
Overall Benefit:Risk Conclusion...................................................16
4.
OBJECTIVES AND ENDPOINTS...........................................................................16
5.
STUDY DESIGN ....................................................................................................17
5.1.
Overall Design ............................................................................................17
5.2.
Number of Participants ...............................................................................19
5.3.
Participant and Study Completion...............................................................19
5.4.
Scientific Rationale for Study Design ..........................................................19
5.5.
Dose Justification........................................................................................19
6.
STUDY POPULATION...........................................................................................20
6.1.
Inclusion Criteria.........................................................................................20
6.2.
Exclusion Criteria........................................................................................21
6.3.
Lifestyle Restrictions...................................................................................24
6.3.1.
Meals and Dietary Restrictions ....................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................25
6.3.3.
Activity .........................................................................................25
6.4.
Screen Failures...........................................................................................25
7.
TREATMENTS.......................................................................................................26
7.1.
Treatments Administered............................................................................26
7.2.
Dose Modification .......................................................................................26
7.3.
Method of Treatment Assignment ...............................................................26
7.4.
Blinding.......................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability..............................................28
7.6.
Treatment Compliance................................................................................28
7.7.
Concomitant Therapy..................................................................................28
7.7.1.
Permitted Therapy .......................................................................29
7.7.2.
Prohibited Therapy ......................................................................29
7.8.
Treatment after the End of the Study ..........................................................29
8.
DISCONTINUATION CRITERIA.............................................................................30
8.1.
Discontinuation of Study Treatment ............................................................30
8.1.1.
Liver Chemistry Evaluation Criteria..............................................30
8.1.2.
QTc Evaluation Criteria................................................................30
8.1.3.
Gastrointestinal Evaluation Criteria..............................................31
8.1.4.
Rash/Hypersensitivity Evaluation Criteria.....................................31
8.2.
Withdrawal from the Study..........................................................................31
 
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8.3.
Lost to Follow Up........................................................................................31
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................32
9.1.
Efficacy Assessments.................................................................................32
9.2.
Adverse Events...........................................................................................32
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................33
9.2.2.
Method of Detecting AEs and SAEs.............................................33
9.2.3.
Follow-up of AEs and SAEs.........................................................33
9.2.4.
Regulatory Reporting Requirements for SAEs .............................34
9.2.5.
Pregnancy ...................................................................................34
9.3.
Treatment of Overdose...............................................................................34
9.4.
Safety Assessments ...................................................................................35
9.4.1.
Physical Examinations.................................................................35
9.4.2.
Vital Signs....................................................................................35
9.4.3.
Electrocardiograms......................................................................35
9.4.4.
Clinical Safety Laboratory Assessments ......................................35
9.5.
Pharmacokinetics .......................................................................................36
9.5.1.
Blood Sample Collection..............................................................36
9.5.2.
Urine Sample Collection ..............................................................36
9.5.3.
Saliva Sample Collection .............................................................36
9.5.4.
Sample Analysis ..........................................................................36
9.6.
Pharmacodynamics ....................................................................................37
9.7.
Genetics .....................................................................................................37
9.8.
Biomarkers .................................................................................................37
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................37
10. STATISTICAL CONSIDERATIONS........................................................................37
10.1.
Sample Size Determination ........................................................................37
10.2.
Populations for Analyses ............................................................................38
10.3.
Statistical Analyses.....................................................................................38
10.3.1.
Pharmacokinetic Analyses...........................................................38
10.3.2.
Safety Analyses...........................................................................39
10.3.3.
Other Analyses ............................................................................40
10.3.4.
Interim Analyses ..........................................................................41
11. REFERENCES.......................................................................................................42
12. APPENDICES........................................................................................................44
12.1.
Appendix 1: Abbreviations and Trademarks................................................44
12.2.
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................46
12.3.
Appendix 3: Study Governance Considerations..........................................50
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................54
12.5.
Appendix 5: Follow-up for Gastrointestinal Findings ...................................56
12.6.
Appendix 6: Clostridium Difficile Testing Procedure and Algorithm .............57
12.7.
Appendix 7: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................58
12.8.
Appendix 8: Clinical Laboratory Tests.........................................................63
12.9.
Appendix 9: Genetics..................................................................................65
 
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12.10. Appendix 10: DMID Adult Toxicity Tables for AE Assessment ....................66
 
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1.
SYNOPSIS
Protocol Title: A Phase I, Open-Label, Single-Dose, Two-Part Study to Assess the 
Pharmacokinetics of Gepotidacin (GSK2140944) in Male and Female Adult Participants
with Varying Degrees of Hepatic Impairment and in Matched Control Participants with 
Normal Hepatic Function
Short Title: Pharmacokinetics Study of Gepotidacin (GSK2140944) in Adult 
Participants with Varying Degrees of Hepatic Impairment and in Matched Control 
Participants with Normal Hepatic Function
Rationale:
In a previous absorption, distribution, metabolism, and excretion study for gepotidacin, 
the mean recovery of radioactivity in urine and feces accounted for approximately 31.2% 
and 52.5%, respectively, of [14C]-gepotidacin administered as a single oral dose. After 
oral administration, gepotidacin was eliminated mainly as parent in urine, accounting for 
approximately 20% of the administered dose. Elimination via metabolism (urine plus 
feces) accounted for a total of 13% to 19% of the dose.
It is expected that potential patients in future gepotidacin Phase III studies may have at 
least some degree of hepatic impairment. The results from this study will enable the 
development of appropriate dosing recommendations in patients with impaired hepatic 
function.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the plasma pharmacokinetic 
(PK) parameters of a 1500 mg oral dose of 
gepotidacin in normal healthy participants to 
participants with mild, moderate, and severe 
hepatic impairment

Plasma gepotidacin AUC(0-) and Cmax, 
as data permit
Secondary

To assess the safety and tolerability of 
gepotidacin administered as a 1500 mg oral 
dose in normal healthy participants 
compared with participants with mild, 
moderate, and severe hepatic impairment

12-lead safety electrocardiogram (ECG)
readings, change from baseline in vital sign 
measurements (blood pressure and heart 
rate), monitoring of AEs, toxicity grading of 
clinical laboratory test results, and physical 
examinations

To compare the secondary plasma PK 
parameters of a 1500 mg oral dose of 
gepotidacin in normal healthy participants 
with participants with mild, moderate, and 
severe hepatic impairment

Plasma gepotidacin AUC(0-t), Tmax, tlag,
CL/F, Vz/F, z, and t1/2, as data permit
 
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Objectives
Endpoints

To compare the urine PK parameters of a 
1500 mg oral dose of gepotidacin in normal 
healthy participants with participants with 
mild, moderate, and severe hepatic 
impairment

Urine primary PK endpoints include Ae 
total, fe%, and CLr of gepotidacin, as data 
permit. Urine secondary PK endpoints 
include Ae(t1-t2), AUC(0-12), AUC(0-24), 
and AUC(0-48) of gepotidacin, as data 
permit
Exploratory

To evaluate the saliva PK parameters of a 
1500 mg oral dose of gepotidacin in normal 
healthy participants compared with
participants with mild, moderate, and severe 
hepatic impairment

Saliva primary PK endpoints include 
AUC(0-) and Cmax of gepotidacin, as 
data permit. Saliva secondary PK 
endpoints include AUC(0-t), Tmax, z, 
t1/2, CL/F, Vz/F, and saliva to unbound 
plasma AUC(0-t) and AUC(0-) ratios
(RAUC) of gepotidacin, as data permit
Overall Design:
This is a Phase I, nonrandomized, open-label, parallel-group, multi-center, two-part study 
that will evaluate the pharmacokinetics, safety, and tolerability of a single 1500 mg oral
dose of gepotidacin in participants with normal hepatic function and in participants with 
mild, moderate, and severe hepatic impairment. Healthy participants with normal hepatic
function will be matched to hepatically impaired participants in terms of gender 
distribution, age (approximately ±10 years), and body mass index (approximately ±20%).
At Screening, participants will be enrolled to the appropriate groups based on the 
classification as defined in the Food and Drug Administration Guidance for Industry, 
Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling [DHHS, 2003]. Participants with hepatic 
impairment will be classified using the Child-Pugh system.
This will be a two-part study, in which PK objectives must be achieved (observed mean 
values: area under the concentration-time curve [AUC] <48 ghr/mL and maximum 
observed concentration [Cmax] <14 g/mL); and safety and tolerability will be reviewed 
before enrolling participants into the next part of the study. In Part 1, participants with 
moderate hepatic impairment and participants with normal hepatic function will be 
enrolled. Matching participants with normal hepatic function in Part 1 (Group D) will be 
enrolled following the completion of all Day 3 assessments of the respective matched 
hepatically impaired participant.
In Part 2, participants with mild (optional) and severe hepatic impairment and 
participants with normal hepatic function will be enrolled concurrently based on the PK, 
safety, and tolerability data of Part 1. Participants with mild hepatic impairment may be 
studied if there is a significant difference in pharmacokinetics between participants with 
moderate hepatic impairment and participants with normal hepatic function. Participants 
with severe hepatic impairment will be studied in Part 2 provided that the PK objectives 
are achieved in Part 1 (observed mean values in participants with moderate impairment 
 
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do not exceed the threshold: AUC <48 ghr/mL and Cmax <14 g/mL). The dose may 
be adjusted for participants with severe hepatic impairment if either PK parameter is 
predicted to exceed the threshold. Based on emergent data from Part 1, matching 
participants with normal hepatic function in Part 2 (Group E) may be enrolled (e.g., if a 
change in dose is needed or if the demographic data of the mild and/or severe hepatic 
impairment groups is not well matched to the moderate control data [Group D]).
For participants with normal hepatic function and participants with mild, moderate, and 
severe hepatic impairment: participants will participate in 1 treatment period and blood,
urine, and saliva samples will be collected up to approximately 48 hours after dosing for 
PK analysis of gepotidacin concentrations.
Number of Participants:
For the target sample size of 8 evaluable participants each in mild, moderate, and severe 
hepatic impairment groups, the maximum number of evaluable participants in this study 
is 48 (assuming 24 matching participants with normal hepatic function for the 
24 hepatically impaired participants).
Due to the potential difficulty in identifying eligible participants with severe hepatic 
impairment, the sponsor may stop the study prior to full enrollment in Part 2 provided 
that a minimum of 6 evaluable participants with severe hepatic impairment have been 
enrolled.
Treatment Groups and Duration:
Participants will be screened within 30 days prior to entry to the clinic and will be 
assigned to a study group based on the degree of hepatic impairment using the 
Child-Pugh classification system:
Part 1:

Group B: Participants with moderate hepatic impairment (Child-Pugh score 7 to 9)

Group D: Participants with normal hepatic function
Preliminary PK, safety, and tolerability results from participants in Part 1 will be 
reviewed before enrolling participants into the next part of the study.
Part 2:

Group A: Participants with mild hepatic impairment (Child-Pugh score 5 to 6)
(optional)

Group C: Participants with severe hepatic impairment (Child-Pugh score 10 to 15)

Group E: Participants with normal hepatic function (optional)
Participants in Parts 1 and 2 will enter the clinic at Check-in (Day −1) before study drug 
administration (Day 1). Participants will receive a single oral dose of study drug as 
follows: gepotidacin 1500 mg administered as 2 × 750 mg tablets. All participants will be 
discharged from the clinic on Day 3 after all scheduled PK and safety assessments have 
 
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been completed, and will return to the clinic for a Follow-up Visit approximately 10 days 
(±5 days) after dose administration. The duration of the study (from Screening to the 
Follow-up Visit) will be approximately 44 days.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Time and Events Table
Procedure1
Screening 
(up to 30 days 
prior to Day -1)
Check-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
postdose) or 
Early Termination
Notes
–1
1
2
3
Confined to clinic
X
X
X
X
Participants will be admitted to the clinic on 
Day –1 and will be discharged on Day 3. 
Confinement will be 4 days and 3 overnight 
stays
Informed consent
X
Inclusion and exclusion criteria
X
X
Recheck clinical status before enrollment 
and/or study drug administration
Demographics
X
Complete physical examination including 
height and weight
X
Abbreviated physical examination
X
X
X
Medical history (includes substance 
usage and history of hepatic disease)
X
Substances: drugs, alcohol, and caffeine. 
Participants with hepatic impairment should 
be on a stable regimen of chronic 
medications 7 days before study drug 
administration on Day 1
Past and current medical conditions 
(including hepatic impairment medical 
history, Child-Pugh score, and Clcr)
X
Child-Pugh as defined in the FDA Guidance 
for Industry: Pharmacokinetics in Patients 
with Impaired Hepatic Function
[DHHS 2003]
Pregnancy test
X
X
X
Urine (or serum) pregnancy test (if 
WOCBP), as appropriate (see Table 5)
FSH
X
Estradiol and FSH at Screening (for women 
of non-childbearing potential), as 
appropriate (see Table 5)
 
 
 
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Procedure1
Screening 
(up to 30 days 
prior to Day -1)
Check-in
Treatment Period
(Days)
Follow-up 
(10 [±5] days 
postdose) or 
Early Termination
Notes
–1
1
2
3
HIV antibody, hepatitis B surface antigen, 
and hepatitis C antibody testing
X
If test has otherwise been performed within 
3 months before study drug administration, 
testing at Screening is not required
Drug and alcohol screen
X
X
See Table 5
Laboratory assessments (include liver 
chemistries)
X
X
X
X
Including serum chemistry, hematology, and 
urinalysis. Results from 24 hours after 
dosing should be available before discharge 
on Day 3
12-lead ECG
X
X
X
X
X
X
See Table 2 for timing of assessments
Vital signs
X
X
X
X
X
X
Respiratory rate and body temperature 
collected at Screening only
See Table 2 for timing of assessments
Genetic sample
X
Informed consent for optional substudies 
(e.g., genetics research) must be obtained 
before collecting a PGx sample. The PGx 
sample can be collected anytime, but 
Day −1 is recommended
Study drug administration
X
Blood collection for pharmacokinetics
X
X
X
See Table 2 for time points
Urine collection for pharmacokinetics
X
X
X
Participants with normal hepatic function 
and participants with hepatic impairment will 
have different collection intervals
See Table 2 for time points
Saliva collection for pharmacokinetics 
X
X
X
See Table 2 for time points
AE/SAE review
X
X
==================
X
Concomitant medication review
X
==================
X
AE = adverse event, Clcr = estimated creatinine clearance; ECG = electrocardiogram, FDA = Food and Drug Administration; FSH = follicle-stimulating hormone; HIV = human 
immunodeficiency virus; PGx = pharmacogenetic, SAE = serious AE; WOCBP = women of childbearing potential.
1
When coinciding with safety and/or pharmacokinetic assessments, electrocardiograms, vital signs, and pharmacokinetic blood collections should be performed in said order.
 
 
 
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Table 2
Safety and PK Assessments
Procedure1
Treatment Period
Time point (hours)
Predose
0
0.5
1
1.5
2
2.5
3
4
6
8
12
242
362
482
12-lead electrocardiogram
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Study drug administration
X
Blood collection for 
pharmacokinetics
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine collection for 
pharmacokinetics (participants
with normal hepatic function)3
X
X
X
X
X
X
X
X
X
X
Urine collection for 
pharmacokinetics (participants
with hepatic impairment)4
X
X
X
X
X
X
X
Saliva collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1
When coinciding with safety and/or pharmacokinetic assessments, electrocardiograms, vital signs, and pharmacokinetic blood collections should be performed in said order.
2
The 24-, 36-, and 48-hour postdose time points correspond to time points on Day 2 and 3, respectively.
3
Urine collection intervals for participants with normal hepatic function (Group D and Group E, if applicable) include 0 (pre-dose), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 
hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours.
4
Urine collection intervals for participants with hepatic impairment (Group A, Group B, and Group C) include 0 hour (pre-dose), 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 36, 
and 36 to 48 hours.

The timing and number of planned study assessments, including: safety and pharmacokinetic assessments may be altered during 
the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring.

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by 
the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
 
 
 
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3.
INTRODUCTION
Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor, which 
inhibits bacterial DNA replication and has in vitro activity against susceptible and 
drug-resistant pathogens associated with a range of conventional and biothreat infections.
Gepotidacin has demonstrated in vitro activity and in vivo efficacy against conventional 
and biothreat pathogens, including isolates resistant to existing classes of antimicrobials. 
Gepotidacin selectively inhibits bacterial DNA gyrase and topoisomerase IV by a unique 
mechanism, which is not utilized by any currently approved human therapeutic agent. 
Structural data with a type II topoisomerase, DNA gyrase, reveals the novel binding 
mode of the class and distinguishes it from the binding mode of the quinolone 
antibacterials [Bax, 2010]. As a consequence of its novel mode of action, gepotidacin is 
active in vitro against target pathogens carrying resistance determinants to established 
antibacterials, including fluoroquinolones.
3.1.
Study Rationale
In a previous absorption, distribution, metabolism, and excretion (ADME) study for 
gepotidacin (see GSK Document Number 2014N189951_00 Study ID BTZ115774), the 
mean recovery of radioactivity in urine and feces accounted for approximately 31.2% and 
52.5%, respectively, of [14C]-gepotidacin administered as a single oral dose. After oral 
administration, gepotidacin was eliminated mainly as parent in urine, accounting for 
approximately 20% of the administered dose. Elimination via metabolism (urine plus 
feces) accounted for a total of 13% to 19% of the dose.
It is expected that potential patients in future gepotidacin Phase III studies may have at 
least some degree of hepatic impairment. The results from this study will enable the 
development of appropriate dosing recommendations in patients with impaired hepatic
function.
3.2.
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.
3.3.
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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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Gepotidacin
Gastrointestinal (GI) Effects
Lower GI effects (soft stools, flatulence, and diarrhoea) are 
the most common GI-associated adverse events (AEs) 
reported in human participants dosed with gepotidacin.
In the Phase I studies, out of approximately 400 healthy 
participants who have received gepotidacin, Clostridium
difficile has been reported in 8 participants.
Exclusion criterion and close monitoring of clinical 
parameters and AEs will be conducted to mitigate and 
assess GI effects.
Patients with significant GI symptoms will obtain the 
appropriate work-up (Appendix 5).
Participant evaluation criteria: Participants experiencing 
Grade 3 or Grade 4 AEs will be followed as appropriate 
until resolution of the AE (see Section 8.1.3).
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. 
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 
(participant with normal hepatic function) or >480 msec 
(hepatically impaired participant) 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 8.1.2).
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Acetylcholinesterase (AChE) Inhibition
In a mass spectrometry model performed with gepotidacin, 
AChE was inhibited with a concentration of inhibitor where 
the response (or binding) was reduced by half (inhibitory 
concentration) of approximately 5 µg/mL (7.5 µg/mL of 
total drug concentration).
At higher doses, some 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.
Rash/Hypersensitivity
A fine, mild, generalized pruritic macular skin rash was 
seen in 3 of 8 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 8.1.4).
 
 
 
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3.3.2.
Benefit Assessment
Since this Phase I study is being conducted in healthy participants with normal hepatic
function and in participants with mild, moderate, and severe hepatic impairment, 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.
3.3.3.
Overall Benefit:Risk Conclusion
The risk of adverse events (AEs) is minimized for the populations being investigated in 
the proposed study by careful selection of dose and participants for the study; the 
relatively short duration of study drug exposure; and the extent of safety monitoring 
incorporated into the study.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the plasma pharmacokinetic 
(PK) parameters of a 1500 mg oral dose of 
gepotidacin in normal healthy participants to
participants with mild, moderate, and severe 
hepatic impairment

Plasma gepotidacin AUC(0-) and Cmax, 
as data permit
Secondary

To assess the safety and tolerability of 
gepotidacin administered as a 1500 mg oral 
dose in normal healthy participants
compared with participants with mild, 
moderate, and severe hepatic impairment

12-lead safety electrocardiogram (ECG)
readings, change from baseline in vital sign 
measurements (blood pressure and heart 
rate), monitoring of AEs, toxicity grading of 
clinical laboratory test results, and physical 
examinations

To compare the secondary plasma PK 
parameters of a 1500 mg oral dose of 
gepotidacin in normal healthy participants
with participants with mild, moderate, and 
severe hepatic impairment

Plasma gepotidacin AUC(0-t), Tmax, tlag, 
CL/F, Vz/F, z, and t1/2, as data permit

To compare the urine PK parameters of a 
1500 mg oral dose of gepotidacin in normal 
healthy participants with participants with 
mild, moderate, and severe hepatic 
impairment

Urine primary PK endpoints include Ae 
total, fe%, and CLr of gepotidacin, as data 
permit. Urine secondary PK endpoints 
include Ae(t1-t2), AUC(0-12), AUC(0-24), 
and AUC(0-48) of gepotidacin, as data 
permit
 
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Objectives
Endpoints
Exploratory

To evaluate the saliva PK parameters of a 
1500 mg oral dose of gepotidacin in normal 
healthy participants compared with
participants with mild, moderate, and severe 
hepatic impairment

Saliva primary PK endpoints include 
AUC(0-) and Cmax of gepotidacin, as 
data permit. Saliva secondary PK 
endpoints include AUC(0-t), Tmax, z, 
t1/2, CL/F, Vz/F, and saliva to unbound
plasma AUC(0-t) and AUC(0-) ratios 
(RAUC) of gepotidacin, as data permit
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, nonrandomized, open-label, parallel-group, multi-center, two-part study 
that will evaluate the pharmacokinetics, safety, and tolerability of a single 1500 mg oral
dose of gepotidacin in participants with normal hepatic function and in participants with 
mild, moderate, and severe hepatic impairment. Healthy participants with normal hepatic
function will be matched to hepatically impaired participants in terms of gender 
distribution, age (approximately ±10 years), and body mass index (BMI; approximately 
±20%).
At Screening, participants will be enrolled to the appropriate groups based on the 
classification as defined in the Food and Drug Administration (FDA) Guidance for 
Industry, Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, 
Data Analysis, and Impact on Dosing and Labeling [DHHS, 2003]. Participants with 
hepatic impairment will be classified using the Child-Pugh system. For more details see 
Section 7.3.
This will be a two-part study, in which PK objectives must achieved (observed mean 
values: area under the concentration-time curve [AUC] <48 ghr/mL and maximum 
observed concentration [Cmax] <14 g/mL); and safety and tolerability will be reviewed 
before enrolling participants into the next part of the study. In Part 1, participants with 
moderate hepatic impairment and participants with normal hepatic function will be 
enrolled. Matching participants with normal hepatic function in Part 1 (Group D) will be 
enrolled following the completion of all Day 3 assessments of the respective matched 
hepatically impaired participant (see Section 7.3).
In Part 2, participants with mild (optional) and severe hepatic impairment and 
participants with normal hepatic function will be enrolled concurrently based on the PK, 
safety, and tolerability data of Part 1. Participants with mild hepatic impairment may be 
studied if there is a significant difference in pharmacokinetics between participants with 
moderate hepatic impairment and participants with normal hepatic function. Participants
with severe hepatic impairment will be studied in Part 2 provided that the PK objectives
are achieved in Part 1 (observed mean values in participants with moderate impairment
do not exceed the threshold: AUC <48 ghr/mL and Cmax <14 g/mL). The dose may 
be adjusted for participants with severe hepatic impairment if either PK parameter is 
predicted to exceed the threshold. Based on emergent data from Part 1, matching 
 
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participants with normal hepatic function in Part 2 (Group E) may be enrolled (e.g., if a 
change in dose is needed or if the demographic data of the mild and/or severe hepatic 
impairment groups is not well matched to the moderate control data [Group D]) (see 
Section 7.3).
Due to the potential difficulty in identifying eligible participants with severe hepatic 
impairment, the sponsor may stop the study prior to full enrollment in Part 2 provided 
that a minimum of 6 evaluable participants with severe hepatic impairment have been 
enrolled. See the study schematic in Figure 1 for more details.
For participants with normal hepatic function and participants with mild, moderate, and 
severe hepatic impairment: participants will participate in 1 treatment period and blood,
urine, and saliva samples will be collected for PK analysis of gepotidacin concentrations 
according to the Schedule of Activities (SoA; Section 2). Blood, urine, and saliva 
samples will be collected up to approximately 48 hours after dosing.
Figure 1
BTZ1117352 Study Schematic
PK = pharmacokinetic
1
Based on emergent data from Part 1, participants with mild hepatic impairment (Group A) may not be enrolled in 
Part 2 if there is not a significant difference between participants with moderate hepatic impairment and 
participants with normal hepatic function. 
2
If AUC and/or Cmax are predicted to exceed the threshold, the dose may be adjusted for participants with severe 
hepatic impairment (Group C). Due to the potential difficulty in identifying eligible participants with severe hepatic 
impairment, the sponsor may stop the study prior to full enrollment in Part 2 provided that a minimum of 
6 evaluable participants with severe hepatic impairment have been enrolled.
3
Based on emergent data from Part 1, matching participants with normal hepatic function in Part 2 (Group E) may 
be enrolled (e.g., if a change in dose is needed or if the demographic data of the mild and/or severe hepatic 
impairment groups is not well matched to the moderate control data [Group D]).
Part 1
Group B: Participants with moderate hepatic impairment
Group D: Participants with normal hepatic function
PK requirements to continue to Part 2
Observed Mean Values:
AUC <48 ghr/mL
Cmax <14 g/mL
(Based on emerging data, and/or data that are not expected to 
exceed these requirements in participants with severe hepatic 
impairment or may require dose adjustment, participants in 
Part 2 will be enrolled.)
Part 2
Group A: Participants with mild hepatic impairment (optional)1
Group C: Participants with severe hepatic impairment2
Group E: Participants with normal hepatic function (optional)3
 
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5.2.
Number of Participants
For the target sample size of 8 evaluable participants each in mild, moderate and severe 
hepatic impairment groups, the maximum the number of evaluable participants in this 
study is 48 (assuming 24 matching participants with normal hepatic function for the 
24 hepatically impaired participants).
Due to the potential difficulty in identifying eligible participants with severe hepatic 
impairment, the sponsor may stop the study prior to full enrollment in Part 2 provided 
that a minimum of 6 evaluable participants with severe hepatic impairment have been 
enrolled.
If participants prematurely discontinue the study, additional replacement participants may
be recruited at the discretion of the Sponsor in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the Follow-up Visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study design is commonly used when evaluating the pharmacokinetics of a drug 
entity in participants with impaired hepatic function. It is based on recommendations 
given in the FDA Guidance for Industry, Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling 
[DHHS, 2003].
Gepotidacin exhibits linear and time-independent pharmacokinetics, which indicates a 
single-dose study is adequate to achieve study objectives.
In the human ADME study (see report of study BTZ115774), total recovery of 
radioactivity was approximately 84% (31.2% in urine and 52.5% in feces) after oral 
administration. Radioactivity was eliminated in higher proportions in feces for oral doses, 
suggesting hepatic impairment could affect clearance of the parent compound. The 
absolute oral bioavailability was approximately 44%.
5.5.
Dose Justification
The oxidative metabolism of gepotidacin is mediated primarily by cytochrome P450 
enzyme 3A4 (CYP3A4). In a clinical drug-drug interaction study when itraconazole 
(inhibitor of both p-glycoprotein and CYP3A4) was co-administered with gepotidacin, a 
weak drug-drug interaction (40% increase in Cmax and 50% increase in AUC[0-∞]) was 
observed (see GSK Document Number 2014N199850_00 Study ID BTZ117349). 
Therefore, the mean Cmax and AUC following a single oral dose of gepotidacin 1500 mg 
are not expected to exceed those observed in healthy adult participants who received 
 
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gepotidacin 3000 mg (see GSK Document Number 2012N137722_00
Study ID BTZ114595).
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 80 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Healthy participants must be in clinically stable health as determined by the 
investigator based on medical history, clinical laboratory results (serum chemistry, 
hematology, urinalysis, and serology), vital sign measurements, 12-lead 
electrocardiogram (ECG) results, and physical examination findings.
3.
Hepatically impaired participants must have chronic (>6 months), stable (no acute 
episodes of illness within the previous 1 month prior to screening due to 
deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due 
to any etiology. Participants must also remain stable throughout the Screening 
period.
4.
Hepatically impaired participants will be classified using the Child-Pugh 
classification system (see Table 3). Participants must have a Child-Pugh score of 5 to 
6 (mild hepatic impairment), 7 to 9 (moderate hepatic impairment), or 10 to 
15 (severe hepatic impairment) with known medical history of liver disease (with or 
without a known history of alcohol abuse) and previous confirmation of liver 
cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, 
computed tomography scan, magnetic resonance imaging, or ultrasonography) 
associated with unambiguous medical history. If imaging study or biopsy is not 
available, then the participant should have one of the following: 
i. Physical findings such as hepatomegaly, ascites, palmar erythema, spider 
angiomata, abdominal venous collaterals, gynecomastia, or other physical 
manifestations of hepatic disease
OR
ii. Laboratory findings: alanine aminotransferase (ALT) or aspartate 
aminotransferase elevation (> upper limit of normal [ULN]), alkaline 
phosphatase, or total bilirubin, or international normalized ratio (INR) elevation 
(>ULN) or an albumin value that is below the lower limit of normal laboratory 
reference range.
 
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5.
Participants with hepatic impairment may be taking medications which, in the 
opinion of the investigator, are believed to be therapeutic, and these medications 
should not interfere with the conduct of the study. Participants with hepatic 
impairment should be on stable regimen of chronic medications for at least 7 days 
prior to dosing until completion of the Follow-Up Visit.
6.
Participants with hepatic impairment must have platelet counts 30,000 × 109/L of 
blood and have not had any major bleeding episodes within the past 6 months.
Weight
7.
Body weight 45 kg and BMI within the range 18.5 to 40 kg/m2 (inclusive).
Sex
8.
Male or female
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 2 of this 
protocol from Day -1 until completion of the Follow-up Visit.
b. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 2),
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR
ii.
A WOCBP who agrees to follow the contraceptive guidance in Appendix 2
from 30 days prior to study drug administration and until completion of the 
Follow-up Visit.
Informed Consent
9.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Participant has a clinically significant abnormality in past medical history or at the 
Screening physical examination (excluding hepatic insufficiency and other related 
medical conditions within the hepatically impaired populations which should be 
stable for at least 1 month before study drug administration) 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 significant cardiac, renal, 
neurologic, gastrointestinal, respiratory, hematologic, or immunologic disease.
 
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2.
Participant has any surgical or medical condition (active or chronic) that may 
interfere with drug absorption, distribution, metabolism, or excretion of the study 
drug, or any other condition that may place the 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.
Participant has used a systemic antibiotic within 7 days of Screening.
5.
Participant has a confirmed history of Clostridium difficile infection or a positive 
C. difficile toxin test within 2 months before Screening.
6.
Participant has a history of drug and/or alcohol abuse within 6 months before 
Screening, as determined by the investigator, or participant has a positive drug 
screen at Screening or upon admission to the clinic. For participants with hepatic 
impairment, and a positive drug screen result related to the use of prescription 
medications is allowed per investigator review and approval, and 
tetrahydrocannabinol use is allowed per investigator review and approval.
7.
History of sensitivity to any of the study drugs, components thereof, or a history of 
drug or other allergy that, in the opinion of the investigator or GSK medical monitor, 
contraindicates their participation.
8.
History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic 
uses heparin to maintain intravenous cannula patency).
Prior/Concomitant Therapy
9.
Participant has used medications known to affect the elimination of serum creatinine 
(e.g., trimethoprim or cimetidine) or competitors of renal tubular secretion 
(e.g., probenecid) within 30 days before dosing.
10. Participants must abstain from taking prescription or nonprescription drugs 
(including vitamins and dietary or herbal supplements), unless specified in 
Section 7.7.1, within 7 days (or 14 days if the drug is a potential strong enzyme 
inducer) or 5 half-lives (whichever is longer) prior to study drug administration 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 (including 
participants with hepatic impairment that will be on medications during the study) 
will be discussed with the sponsor or medical monitor on a case-by-case basis and
the reasons will be documented.
Prior/Concurrent Clinical Study Experience
11. Previous exposure to gepotidacin within 12 months prior to study drug 
administration.
12. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to study drug administration in the 
current study: 30 days, 5 half-lives, or twice the duration of the biological effect of 
the investigational product (whichever is longer).
 
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Diagnostic Assessments
13. Participant with normal hepatic function has presence of hepatitis B surface antigen 
or positive hepatitis C antibody test result at Screening or within 3 months prior to 
study drug administration. Participant with hepatic impairment has evidence of 
recent, acute infection with hepatitis B and/or hepatitis C within preceding 6 months. 
Hepatically impaired participants with chronic hepatitis B or C (duration >6 months) 
are eligible for enrolment.
14. A positive test for human immunodeficiency virus antibody.
15. Participant must be able to abstain from alcohol and limit use of nicotine and/or 
nicotine-containing products (up to 5 cigarettes/day is acceptable for participants 
with hepatic impairment) for 24 hours before the start of dosing until after collection 
of the final PK sample. A positive alcohol or cotinine test is not exclusionary for 
participants with hepatic impairment.
16. Participant has clinically significant abnormal findings in serum chemistry, 
hematology, or urinalysis results obtained at Screening or Day –1, other than those 
associated with underlying hepatic conditions or other stable medical conditions 
consistent with the disease process in participants with hepatic impairment.
17. Participant with normal hepatic function has a baseline corrected QT interval using 
the Fridericia formula (QTcF) of >450 milliseconds (msec) and participant with 
hepatic impairment has a baseline QTcF of >480 msec.
Other Exclusions
18. Donation of blood in excess of 500 mL within 12 weeks prior to dosing or 
participation in the study would result in donation of blood or blood products in 
excess of 500 mL within a 56-day period.
19. Participant is unable to comply with all study procedures, in the opinion of the 
investigator.
20. The participant should not participate in the study, in the opinion of the investigator 
or Sponsor.
Supplemental Exclusion Criteria for Hepatically Impaired Participants
21. Participants with a pre-existing condition (except hepatic impairment) interfering 
with normal GI anatomy or motility that could interfere with the absorption, 
metabolism, and/or excretion of the study drugs. Participants with a history of 
inflammatory bowel disease should be excluded. Participants with a history of 
pepticulceration or pancreatitis within the preceding 6 months of screening should be 
excluded.
22. Participants with any previous GI surgery (except appendectomy or gall bladder 
removal >3 months prior to Screening) may be enrolled in this study only if, in the 
opinion of the investigator and the medical monitor, it is not expected to interfere 
with the study procedures or to pose an additional safety risk to the participant.
 
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23. Participants receiving lactulose who are medically unable to halt lactulose 
administration from 8 hours before dosing with study drug to 4 hours after dosing 
with study drug.
24. Participants with clinically active severe encephalopathy (grade 3 or 4 as defined in 
Table 3) as judged by the investigator or significant central nervous system disease 
(e.g., dementia or seizures) which the investigator considers will interfere with the 
informed consent, conduct, completion, or results of this trial or constitutes an 
unacceptable risk to the participant. Participants with a prior history of severe 
encephalopathy who are currently treated for this condition will receive the 
appropriate score for encephalopathy.
25. Participants with estimated creatinine clearance (Clcr) 50 mL/min (calculated by 
the Cockcroft-Gault Formula). If the result calculated by Cockcroft-Gault is between 
40 and 50 mL/min, then the site may complete a 24-hour urine collection to more 
specifically calculate the Clcr. A Clcr value 50 mL/min via 24-hour urine collection 
is also exclusionary.
26. History of gastric or esophageal variceal bleeding within the past 6 months and for 
which varices have not been adequately treated with medication and/or surgical 
procedures.
27. Participants with electrolyte imbalance whose serum sodium levels are 
125 mmol/L; potassium levels are 2.5 mmol/L; or calcium levels are
6.1 mmol/L.
28. Presence of hepatopulmonary or hepatorenal syndrome.
29. Primary cholestatic liver diseases.
30. History of liver transplantation or participants in the severe hepatic impairment 
group that are expecting a liver transplant during the study participation period.
31. Participants with signs of active bacterial infection (including active spontaneous 
bacterial peritonitis).
32. Participants with transjugular intrahepatic portosystemic shunt placement within the 
past 3 months.
33. Participants with unstable cardiac function or participants with hypertension whose 
blood pressure that is not well controlled (based on the investigator’s discretion).
34. Diabetic participants whose diabetes that is not controlled (based on the 
investigator’s discretion).
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Participants will fast (no food or drink except water) for approximately 8 to 10 hours 
before dosing and will receive a standard breakfast approximately 30 minutes before 
dose administration. Participants should consume the breakfast within 30 minutes or 
less. Standard meals will be provided during the study treatment period at times that 
do not interfere with study procedures.
 
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
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.
6.3.2.
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.

Participants will be instructed to limit use of nicotine and/or nicotine-containing 
products for 24 hours before the start of dosing until after collection of the final PK 
sample. Up to 5 cigarettes/day is acceptable.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered 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, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants should be assigned the same participant 
number as for the initial screening.
For eligibility purposes, clinical laboratory evaluations or vital sign measurements may 
be repeated once if an abnormal result is observed at the initial reading. Moreover, 
12-lead ECG abnormalities may need to be confirmed by repeated measurements. In the 
event that the participation in the study is delayed and some screening procedures had 
been performed outside the prescribed screening window, outdated screening procedures 
can be repeated.
For inclusion and Child-Pugh categorization, clinical laboratory results that are deemed 
inconsistent with the usual stage of hepatic impairment may be repeated.
Participants who do not qualify based on a reversible medical condition or mild 
inter-current illness may be re-evaluated after further testing/examination or rescreened 
after the condition has resolved.
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study treatment name:
Gepotidacin
Formulation description:
Immediate-release tablets containing gepotidacin (free 
base) an inactive formulation excipients
Dosage formulation:
Tablet
Unit dose strength/
Dosage level:
750 mg/
1500 mg (2 × 750 mg)
Route of administration 
Oral
Dosing instructions:
Dose with 240 mL of water in the fed state (within 
30 minutes after a standard breakfast). Up to additional 
1000 mL of water may be given to assist in swallowing 
tablets
Physical description:
A capsule-shape, white film-coated tablet with no 
identifying markings
Manufacturer/
Source of procurement:
GlaxoSmithKline
7.2.
Dose Modification
Based on emerging data from Part 1, the dose may be reduced for participants with severe 
hepatic impairment if either PK parameter is predicted to exceed the threshold
(AUC <48 ghr/mL and Cmax <14 g/mL).
7.3.
Method of Treatment Assignment
This will be a nonrandomized, open-label study. At Screening, participants will be 
assigned to a study group based on the degree of hepatic impairment using the 
Child-Pugh classification system as shown in Table 3.
 
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Table 3
Child-Pugh Classification System
Finding
Points Scored for Each Observed Finding1
1
2
3
Encephalopathy grade2
None
1 or 2
3 or 4
or
Participant receiving 
medication(s) to prevent 
encephalopathy
Ascites
Absent
Slight
Moderate
or
Participant receiving 
medication(s) to control 
ascites
Serum bilirubin (mg/dL)
<2
2 to 3
>3
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Prothrombin time (seconds prolonged)
Or
Prothrombin time INR
<4
<1.7
4 to 6
1.7 to 2.3
>6
>2.3
INR = international normalized ratio.
1
For each category (encephalopathy grade, ascites, serum bilirubin, serum albumin, and prothrombin time or 
prothrombin time INR), points will be assigned based on the participant’s condition and the criterion met. The 
Child-Pugh class will be assigned based on the sum of these points as follows: 
Child-Pugh Class A (mild hepatic impairment): 5 to 6 points
Child-Pugh Class B (moderate hepatic impairment): 7 to 9 points
Child-Pugh Class C (severe hepatic impairment): 10 to 15 points
2
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate behavior, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity
In Part 1, participants with moderate hepatic impairment (Group B) will be enrolled as 
they become eligible for the study and receive their allocated participant numbers in the 
order in which they are enrolled. Healthy participants with normal hepatic function 
(Group D) will be matched to the participants with moderate hepatic impairment in terms 
of gender distribution, age (±10 years), and BMI (±20%) and will be enrolled following 
the completion of all Day 3 assessments of the respective matched hepatically impaired 
participant.
In Part 2, participants with mild (optional) and severe hepatic impairment (Groups A 
and C, respectively) will be enrolled concurrently as they become eligible for the study 
and receive their allocated participant numbers in the order in which they are enrolled 
within their respective groups. Based on emergent data from Part 1, healthy participants 
with normal hepatic function in Part 2 (Group E) may be enrolled (e.g., if a change in 
dose is needed [see Section 7.2] or if the demographic data [gender, age, and BMI] of the 
mild and/or severe hepatic impairment groups is not well matched to the moderate 
control data [Group D]). Enrollment of healthy participants with normal hepatic function 
in Part 2 will be performed in the same manner as Part 1.
 
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Participants will be given a participant number that will be a unique identifier. Once a 
participant number has been assigned, the number will not be reused even if the 
participant withdraws from the study before receiving gepotidacin.
7.4.
Blinding
This will be an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the 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 treatment 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 treatment 
are provided in the Study Reference Manual (SRM).
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.
6.
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.
7.6.
Treatment 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 clinic staff. 

When participants are dosed at the clinic, they will receive study treatment directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the clinic staff other than the person administering the 
study treatment. Clinic personnel will examine each participant’s mouth to ensure 
that the study treatment was ingested.
7.7.
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:
 
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
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.
7.7.1.
Permitted Therapy
In healthy participants with normal hepatic function, acetaminophen at doses of 
2 grams/day is 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.
Participants with hepatic impairment may be taking medications which, in the opinion of 
the investigator, are believed to be therapeutic, and these medications should not interfere 
with the conduct of the study. Participants with hepatic impairment should be on stable 
regimen of chronic medications for at least 7 days prior to study drug administration until 
completion of the Follow-Up Visit.
Hormonal replacement medications for postmenopausal women and hormonal 
contraceptives are allowed.
7.7.2.
Prohibited Therapy
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements), unless specified in Section 7.7.1, within 
7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to study drug administration until completion of the Follow-Up Visit, 
unless, in the opinion of the investigator and GSK, the medication will not interfere with 
the study.
Participants with hepatic impairment are prohibited from receiving lactulose from 8 hours 
before dosing with study drug until 4 hours after dosing with study drug.
Due to the potential for acetylcholinesterase inhibition with gepotidacin, the following 
medications are prohibited:

Succinylcholine or other depolarizing muscle relaxants.

Acetylcholinesterase inhibitors as required for myasthenia gravis including 
edrophonium, pyridostigmine, neostigmine, etc.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants and participants with mild, moderate, and severe 
hepatic impairment are eligible for study participation.
 
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The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Evaluation Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Although stopping criteria for continued dosing of investigational product are not 
applicable for single dose studies, if participants are found to have values consistent with 
usual stopping parameters, it is appropriate to institute evaluation and monitoring criteria 
according to standard GSK criteria. Therefore, liver function tests should be evaluated 
according to stopping criteria and work up instituted if defined parameters are reached.
The following liver chemistry evaluation criterion will be applied for healthy 
participants:

ALT 3 × ULN
Liver safety required actions and follow-up assessments can be found in Appendix 4.
8.1.2.
QTc Evaluation Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on corrected QT 
interval using the Fridericia formula (QTcF), then QTcF must be used for 
discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception.

The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief (e.g., 5 to 10 minute) recording period.
A participant who develops either of the bulleted criteria below will be monitored, as 
appropriate:

QTcF >500 msec

Change from baseline of QTc >60 msec
 
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For participants with underlying bundle branch block, follow the QTc evaluation
criteria listed below:
Baseline QTc with Bundle Branch Block
QTc with Bundle Branch Block Evaluation 
Criteria
<450 msec
>500 msec
450 to 480 msec
≥530 msec
See the SoA for data to be collected at the time of early withdrawal and follow-up and for 
any further evaluations that need to be completed.
8.1.3.
Gastrointestinal Evaluation Criteria
Participants experiencing Grade 3 or Grade 4 AEs (confluent pseudomembranes or 
ulcerations OR mucosal bleeding with minor trauma; tissue necrosis OR diffuse 
spontaneous mucosal bleeding OR life-threatening consequences, e.g., aspiration, 
choking) will be followed as appropriate until resolution of the AE(s).
Furthermore, participants who experience diarrhoea or enteritis should be evaluated with 
additional fecal occult blood tests and stool cultures as deemed appropriate by the 
investigator as outlined in Appendix 5 and Appendix 6.
8.1.4.
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).
8.2.
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.

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.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
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.
 
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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 with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

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 treatment.

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 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.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
Efficacy will not be evaluated in this study.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 7.
 
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The investigator and any 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 treatment or the study,
or that caused the participant to discontinue the study (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the Follow-Up Visit at 
the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the Follow-Up Visit at the 
time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the electronic case report form (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 7. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. 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 treatment or study participation, the 
investigator must promptly notify the sponsor.

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 7.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
9.2.3.
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 3.3.1), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 7.
 
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9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment 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 treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a 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.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment 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 2.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
There is only one dose of study medication administered during this study, and it is 
administered at the clinic; therefore, overdoses are not anticipated. There is no specific 
antidote for overdose with a bacterial topoisomerase inhibitor. 
In the event of an overdose, the investigator should:
1.
Contact the medical monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
gepotidacin 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 treatment if requested by the medical monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
 
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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.4.1.
Physical Examinations

A complete 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.
9.4.2.
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. Baseline body 
temperature and respiratory rate will be collected at Screening only.
9.4.3.
Electrocardiograms

Single 12-lead ECG will be obtained in a semi-supine position after 5 minutes rest as 
outlined in the SoA (Section 2) using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2
for QTc evaluation criteria and additional QTc readings that may be necessary.
Electrocardiograms should be obtained prior to any vital sign measurements or blood 
draws scheduled on the same assessment day.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Appendix 8 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) 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 which 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 
the treatment period 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.
 
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
All protocol-required laboratory assessments, as defined in Appendix 8, must be 
conducted in accordance with the laboratory manual and the SoA.
9.5.
Pharmacokinetics
9.5.1.
Blood Sample Collection
The PK blood samples for the analysis of gepotidacin will be collected at the time points 
listed in the SoA (Section 2). The actual date and time of each blood sample collection 
will be recorded. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring.
For each sample, 3 mL of blood will be drawn via an indwelling catheter and/or direct 
venipuncture into tubes containing ethylenediaminetetraacetate anticoagulant. Details of 
PK blood sample processing, storage, and shipping procedures are provided in the SRM.
9.5.2.
Urine Sample Collection
The PK urine samples for the analysis of gepotidacin will be collected at the time points 
listed in the SoA (Section 2). The actual date and time of each urine sample collection 
will be recorded. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring.
Details of PK urine sample processing, storage, and shipping procedures are provided in 
the SRM.
9.5.3.
Saliva Sample Collection
The PK saliva samples for analysis of gepotidacin will be collected at the time points 
listed in the SoA (Section 2). The timing of saliva samples may be altered and/or samples 
may be obtained at additional time points to ensure thorough PK monitoring.
Details of PK saliva sample collection, processing, storage, and shipping procedures are 
provided in the SRM.
9.5.4.
Sample Analysis
Plasma, urine, and saliva analyses will be performed under the control of GSK Platform 
Technologies and Science (PTS), the details of which will be included in the SRM. 
Concentrations of gepotidacin will be determined in plasma, urine, and saliva samples 
using the currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).
Since plasma protein binding of gepotidacin is low (33%), only total drug concentrations 
will be reported for the PK analysis. However, in order to derive the saliva to unbound 
plasma AUC(0-t) and AUC(0-) ratios, a correction factor of 0.67 will be applied to the 
total plasma AUCs of gepotidacin.
 
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Once the plasma, urine, and saliva samples have been analyzed for gepotidacin, any 
remaining plasma, urine, and saliva may be analyzed for other compound-related 
metabolites and the results reported under a separate GSK-PTS-IVIVT protocol.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6-mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 9 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
The target sample size of 8 evaluable participants with normal hepatic function and 
8 evaluable hepatically impaired participants in each group was chosen based on 
feasibility, to address the objectives of the study. This sample size also complies with 
FDA guideline in a reduced study design involving control participants and moderate 
hepatic impairment patients.
The between-participant coefficient of variations (CVb%) of PK parameters from the 
1500 mg oral tablet on Day 1 in BTZ117351 study were 23.4%, 22.9%, and 43.6% for 
the AUC(0-t), AUC(0-), and Cmax respectively.
For a CVb% of 23.4%, 22.9%, and 43.6%, and a sample size of 8 participants with 
normal hepatic function and 8 participants with moderate hepatic impairment, it is 
estimated that the upper limits of the 90% confidence interval (CI) for the ratio of PK 
 
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parameters of hepatically impaired participants to normal participants are 22.5%, 22.0%, 
and 44.4% above the corresponding point estimates for the ratios of AUC(0-t), 
AUC(0-), and Cmax, respectively.
For the target sample size of 8 evaluable participants each in mild, moderate and severe 
hepatic impairment groups, the maximum the number of evaluable participants in this 
study is 48 (assuming 24 matching participants with normal hepatic function for the 
24 hepatically impaired participants).
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
PK Population
All participants who received at least 1 dose of gepotidacin and 
have evaluable PK data for gepotidacin
PK Parameter Population
All participants in the PK Population, for whom valid and evaluable 
PK parameters were derived. This population will be used in the 
assessment and characterization of PK parameters.
Safety
All participants who receive at least 1 dose of study drug and have 
at least 1 postdose safety assessment
10.3.
Statistical Analyses
10.3.1.
Pharmacokinetic Analyses
Plasma and urine concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods. Based on the individual concentration time data the 
following parameters will be estimated:
Plasma:
AUC(0-)
Area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
last quantifiable concentration
Cmax
Maximum observed concentration
λz
Terminal-phase rate constant
t1/2
Terminal phase half life 
Tmax
Time to first occurrence of Cmax
tlag
Lag time
CL/F
Apparent oral clearance
 
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Vz/F
Apparent volume of distribution
Urine:
Ae total
Total unchanged drug (total amount of drug excreted in urine), calculated 
by adding all the fractions of drug collected over all the allotted time 
intervals
Ae(t1-t2)
Amount of drug excreted in urine in a time intervals for predose, 0 to 6, 
6 to 12, 12 to 24, or 24 to 36, and 36 to 48 hours after dosing for 
participants with hepatic impairment; and predose, 0 to 2 hours, 2 to 
4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 
36 hours, and 36 to 48 hours for participants with normal hepatic function
fe%
Percentage of the given dose of drug excreted in urine, calculated as: 
fe% = (Ae total/Dose) × 100
CLr
Renal clearance of drug, calculated as: Ae total/AUC(0-t)
AUC(0-12)
Area under the concentration-time curve from time 0 (predose) to 12 hours
AUC(0-24)
Area under the concentration-time curve from time 0 (predose) to 24 hours
AUC(0-48)
Area under the concentration-time curve from time 0 (predose) to 48 hours
Plasma concentrations 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 coefficient of variation [CV]) will be presented by day 
and treatment. Mean and individual plasma concentration versus time profiles will be 
presented graphically on linear and semilogarithmic scales.
The natural log-transformed plasma AUC(0-∞) and Cmax values for gepotidacin in the 
hepatic impairment groups and normal hepatic function groups will be compared using an 
analysis of variance. Geometric mean ratios between hepatic impairment groups and 
normal hepatic function groups, and 90% CIs for the ratios of AUC(0-∞) and Cmax for 
gepotidacin will be presented.
The natural log-transformed urine AUC(0-48) and non-transformed CLr values for 
gepotidacin in the hepatic impairment groups and normal hepatic function groups will be 
compared using an analysis of variance. Geometric mean ratios between hepatic
impairment groups and normal hepatic function groups, and 90% CIs for the ratios of 
AUC(0-48) and least square mean difference between hepatic impairment groups and 
normal hepatic function groups, and 90% CIs for the difference of CLr for gepotidacin 
will be presented.
Detailed descriptions of the analyses in this study will be presented in the Reporting and 
Analysis Plan (RAP).
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population.
 
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All AEs and all drug-related AEs will be listed. The incidence of AEs will be
summarized by system organ class and preferred term for each group and overall. 
Separate summaries will be provided for AEs by overall frequency, study drug-related 
AEs, and common (5%) AEs. Serious AEs will be summarized and listed and AEs 
leading to withdrawal from the study will be listed. Listings for liver AEs, cardiovascular 
AEs, and rash/hypersensitivity AEs will be produced where an event has occurred. 
Cardiovascular-related medical conditions will be summarized.
Actual values and change from baseline for clinical chemistry and hematology results 
will be summarized by visit. A separate summary for urinalysis (dipstick) results will be 
generated. Clinical chemistry, hematology, and urinalysis toxicities of Grade 3 or higher 
and all clinical chemistry, hematology, and urinalysis data for participants with toxicities 
of Grade 3 or higher will be presented in data listings.
Twelve-lead ECG findings and changes from baseline in 12-lead ECG values will be 
summarized. Abnormal 12-lead ECG findings, all 12-lead ECG data for participants with 
abnormal ECG findings will be listed. In addition, all quantitative ECG values of 
potential clinical importance, and all ECG values for participants with any value of 
potential clinical importance will be listed. The frequency of maximum postdose value 
and change from baseline ECG parameter corrected QTc interval data will be 
summarized.
Change from baseline for vital sign measurements will be summarized by group and time 
point. Vital signs of potential clinical importance and all vital signs for participants with 
potential clinical importance values will be presented in data listings.
Liver monitoring/stopping events, medical conditions for participants with a liver 
stopping event, alcohol intake at onset of liver event, plasma concentration data for 
participants with a liver stopping event, liver biopsy details, and liver imaging details will 
be listed where an event has occurred.
No inferential hypothesis testing will be performed on the safety variables. No formal 
statistical analysis of safety data will be performed.
Detailed descriptions of the analyses in this study will be presented in the RAP.
10.3.3.
Other Analyses
Saliva:
AUC(0-)
Area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time 0 (predose) to time of 
last quantifiable concentration
Cmax
Maximum observed concentration
λz
Terminal-phase rate constant
t1/2
Terminal phase half life 
 
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Tmax
Time to first occurrence of Cmax
CL/F
Apparent oral clearance
Vz/F
Apparent volume of distribution
RAUC(0-t)
The ratio of the AUC(0-t) observed in saliva relative to the unbound 
AUC(0-t) in plasma, calculated as: RAUC(0-t) = AUC(0-t) 
saliva/unbound AUC(0-t) plasma
RAUC(0-)
The ratio of the AUC(0-∞) observed in saliva relative to the unbound 
AUC(0-∞) in plasma, calculated as: RAUC(0-∞) = AUC(0-∞) 
saliva/AUC(0-∞) plasma
Saliva concentrations of gepotidacin and the associated PK parameters will be listed, and 
summary statistics (n, mean, median, SD, minimum, maximum, and CV) will be 
presented by time point and group. Mean and individual saliva concentration versus time 
profiles will be presented graphically on linear and semilogarithmic scales.
The natural log-transformed saliva AUC(0-∞) and Cmax values for gepotidacin in the 
hepatic impairment groups and normal hepatic function groups will be compared using an 
analysis of variance. Geometric mean ratios between hepatic impairment groups and 
normal hepatic function groups, and 90% CIs for the ratios of AUC(0-∞) and Cmax for 
gepotidacin will be presented.
An exploratory analysis will be performed to explore the relationship between saliva and 
unbound plasma concentrations. Natural log-transformed saliva gepotidacin 
concentrations versus the natural log-transformed plasma gepotidacin concentrations will 
be plotted and a regression line will be fitted. A similar analysis will also be performed 
for the AUC(0-), AUC(0-t), and Cmax.
Detailed descriptions of the analyses in this study will be presented in the RAP.
10.3.4.
Interim Analyses
Preliminary plasma PK, safety, and tolerability results from participants in Part 1 will be 
reviewed by the sponsor before enrolling participants into the next part of the study.
Please see Section 10.3.1 for details about the estimation of PK parameters.
Participants with mild hepatic impairment may be enrolled in Part 2 if there is a 
significant difference in pharmacokinetics between participants with moderate hepatic 
impairment compared with participants with normal hepatic function. Participants with 
severe hepatic impairment will be enrolled in Part 2 provided that the PK requirements 
are met (observed mean values in participants with moderate impairment do not exceed 
the threshold: AUC <48 ghr/mL and Cmax <14 g/mL). The dose may be adjusted for 
participants with severe hepatic impairment if either PK parameter is predicted to exceed 
the threshold.
The RAP will describe the planned interim analyses in greater detail.
 
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11.
REFERENCES
Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA 
topoisomerase inhibition by a new class of antibacterial agents. Nature. 
2010;466(7309):935-40.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry:  Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation. July 2009. [28 screens]. Available from:  
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm174090.pdf
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry:  Pharmacokinetics in Patients with Impaired Hepatic 
Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. May 2003. 
[19 screens]. Available from:  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm072123.pdf
GlaxoSmithKline Document Number 2012N137722_00 Study ID BTZ114595. A 
randomized, single blind, placebo controlled study to evaluate safety, tolerability, and 
pharmacokinetics of single escalating oral doses of GSK2140944 in healthy adult 
subjects. 2012.
GlaxoSmithKline Document Number 2014N189951_00 Study ID BTZ115774. An 
open-label, non-randomized, two-period, cross-over, mass balance study to investigate 
the recovery, excretion and pharmacokinetics of 14C-GSK2140944 administered as a 
single intravenous and single oral dose to healthy adult male subjects. 2014.
GlaxoSmithKline Document Number 2014N198291_00 Study ID BTZ115198. A 
two part study to evaluate safety, tolerability, and pharmacokinetics of single and repeat 
IV doses of GSK2140944 in healthy adult subjects. 2014.
GlaxoSmithKline Document Number 2014N199850_00 Study ID BTZ117349. A 
single-center, three-part, open label study to evaluate the relative bioavailability of 
two formulations, food effect, and interaction with itraconazole following single dose of 
GSK2140944 in healthy subjects and effect of food on safety, tolerability, and 
pharmacokinetics following multiple doses of GSK2140944 in healthy elderly subjects. 
2015.
GlaxoSmithKline Document Number 2015N227098_00 Study ID BTZ115775: 
Population pharmacokinetic-pharmacodynamic analysis of a Phase I, randomized, 
double-blinded, placebo- and moxifloxacin-controlled, 4-period crossover study to 
evaluate the effect of GSK2140944 on cardiac conduction as assessed by 12-lead 
electrocardiogram in healthy volunteers. 2015.
 
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GlaxoSmithKline Document Number 2015N243789_00 Study ID BTZ116704. A 
Phase II, randomized, two-part, multicenter, dose-ranging study in adult subjects 
evaluating the safety, tolerability, and efficacy of GSK2140944 in the treatment of 
subjects with suspected or confirmed gram-positive acute bacterial skin and skin structure 
infections. 2015.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-protein adduct in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos 2009; 37(8):1779-84.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
z
terminal-phase rate constant
AChE
acetylcholinesterase
ADME
absorption, distribution, metabolism, and excretion
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 to 
infinity
AUC(0-t)
area under the concentration-time curve from time 0 to the 
time of the last quantifiable concentration (t)
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical 
Sciences
Clcr
creatinine clearance
CL/F
apparent oral clearance
CLr
renal clearance
Cmax
maximum observed concentration
CSR
Clinical Study Report
CVb%
between-participant coefficient of variation
CYP3A4
cytochrome P450 enzyme 3A4
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fe%
percentage of the given dose of drug excreted in urine
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GSK
GlaxoSmithKline
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
 
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INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MedDRA
Medical Dictionary for Regulatory Activities
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
RAUC(0-)
ratio of the AUC(0-∞) observed in saliva relative to the 
unbound AUC(0-∞) in plasma
RAUC(0-t)
ratio of the AUC(0-t) observed in saliva relative to the 
unbound AUC(0-t) in plasma
SAE
serious adverse event
SoA
schedule of activities
SRM
Study Reference Manual
t1/2
terminal phase half life
Tmax
time to first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution
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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12.2.
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of 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, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-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.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1:

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 4 when having 
penile-vaginal intercourse with a woman of childbearing potential 
 
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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4. 
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent 1
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation2

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation2

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation2

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. 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.)
NOTES: 
1.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
 
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2.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during 
the treatment period and until the Follow-up Visit.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum or urine pregnancy test at Screening and admission to the 
clinic

Additional pregnancy testing will be performed at the Follow-up Visit

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 10 mIU/mL will be performed and assayed in 
a certified laboratory OR and assayed in the central laboratory OR using the test kit 
provided by the central laboratory / provided by the sponsor /approved by the 
sponsor and in accordance with instructions provided in its package insert
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 participants who receive study treatment.

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. 

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.
 
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
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to GSK
as described in Appendix 7. 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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12.3.
Appendix 3: Study Governance Considerations
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, 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/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and 
all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators 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.
Informed Consent 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 
 
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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. 

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.
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. 

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.
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.
 
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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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.
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. 

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. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

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, 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 (CSR)/ 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. 
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 
 
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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.
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 
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 treatment development
 
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12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I Liver chemistry evaluation criteria have been designed to assure participant
safety and to evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry evaluation criteria and required follow up assessments for 
healthy participants only
Liver Chemistry Evaluation Criteria 
ALT-absolute
ALT ≥3 × ULN
If ALT ≥3 × ULN AND bilirubin1,2 2 × ULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin
2 × ULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
 
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Liver Chemistry Evaluation Criteria 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within 
24 to 72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
alcohol intake case report form
If ALT ≥3 × ULN AND bilirubin 2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised 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 treatment for that participant if ALT 3 × ULN and bilirubin 2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody
 
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12.5.
Appendix 5: Follow-up for Gastrointestinal Findings
Participants who experience diarrhoea or enteritis should be evaluated with additional 
fecal occult blood tests and stool cultures as deemed appropriate by the investigator. Any 
participant with a positive fecal occult blood test should be referred to a 
gastroenterologist for further evaluation at the discretion of the investigator.
Participants who experience an AE of diarrhoea or enteritis should have additional fecal 
occult blood testing, as well as a routine stool culture performed, which may include the 
recovery of pathogenic bacteria such as Salmonella, Shigella, Campylobacter, Yersinia, 
Vibrio, Staphylococcus aureus, Escherichia coli 0157, and enterohemorrhagic 
Escherichia coli.
In addition, if the participant meets the clinical criteria outlined in Appendix 6, 
Clostridium difficile toxin detection should be conducted. 
Note: Additional testing is at the discretion of the investigator if it is believed the 
GI signs/symptoms are due to cholinergic effects and/or if the GI signs/symptoms occur 
within 24 hours of the infusion.
 
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12.6.
Appendix 6: Clostridium Difficile Testing Procedure and 
Algorithm
 
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12.7.
Appendix 7: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

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 treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, serum 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 treatment 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 
treatment 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.
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).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been 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.
d.
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.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
 
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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.
g.
Is associated with liver injury and impaired liver function (healthy participants 
only) defined as:

ALT 3 × ULN and total bilirubin* 2 × ULN (>35% direct), or

ALT 3 × ULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3 × ULN 
and total bilirubin 2 × ULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants. If an INR measurement is obtained, the value is to 
be recorded on the SAE Form.
Recording 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 
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 
 
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for adult toxicity assessment (Appendix 10).

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 treatment 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 treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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.
 
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
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
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 the investigational product (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 PPD medical monitor by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the PPD 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 at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.8.
Appendix 8: Clinical Laboratory Tests
Hematology, serum chemistry, urinalysis, and additional parameters to be tested are listed 
in Table 5.

The tests detailed in Table 5 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 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.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
AST
Total and direct bilirubin
Creatinine
Sodium
ALT
Total Protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Creatine kinase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

Clcr (Section 6.2)

Prothrombin time and prothrombin time international normalized ratio (INR) 
(Section 7.3)

Hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus

Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only)

Alcohol (via urine, blood alcohol, or breathalyzer test) and drug screen (via serum, 
urine, or saliva) to include, at a minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids, and benzodiazepines)
 
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Laboratory 
Assessments
Parameters

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential)2
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1 and Appendix 4 All events of ALT 3 × upper limit 
of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC.
 
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12.9.
Appendix 9: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to gepotidacin. They may also be 
used to develop tests/assays including diagnostic tests) related to gepotidacin or 
study treatments of this drug class. Genetic research may consist of the analysis of 
one or more candidate genes or the analysis of genetic markers throughout the 
genome [or analysis of the entire genome] (as appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to gepotidacin or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on gepotidacin (or study treatments of 
this class) continues but no longer than 15 years after the last participant last visit or 
other period as per local requirements.
 
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12.10.
Appendix 10: DMID Adult Toxicity Tables for AE 
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 NIAID DMID and modified to better meet the needs of 
participants in DMID trials.

For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide for Estimating Severity Grade” located above.

Criteria are generally grouped by body system.

Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria.
 
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 to 10.5 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 mm Hg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mm Hg systolic; correctable 
with oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mm Hg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
N/A = not applicable; Rx = therapy; BP = blood pressure; IV = intravenous; EKG = electrocardiogram
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment responsive
Paroxysmal cough; uncontrolled with treatment
N/A
Bronchospasm, 
Acute
Transient; no treatment; 
FEV1 70 to 80% of peak flow
Requires treatment; normalizes with 
bronchodilator; FEV1 50 to 70% of peak 
flow
No normalization with bronchodilator; FEV1 25 
to 50% of peak flow; or retractions present
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen 
therapy
N/A = not applicable; FEV1 = forced expiratory volume in 1 second.
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; maintains 
reasonable intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or needing IV 
fluids
Physiologic consequences requiring 
hospitalization or requiring parenteral nutrition
Constipation
Requiring stool softener or 
dietary modification
Requiring laxatives
Obstipation requiring manual evacuation 
or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 
4 loose stools/day or mild 
diarrhea lasting <1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week
>7 loose stools/day or bloody diarrhea; or 
orthostatic hypotension or electrolyte 
imbalance or >2L IV fluids required
Hypotensive shock or physiologic 
consequences requiring hospitalization
Oral discomfort/
Dysphagia
Mild discomfort; no difficulty 
swallowing
Some limits on eating/drinking
Eating/talking very limited; unable to 
swallow solid foods
Unable to drink fluids; requires IV fluids
IV = intravenous.
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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2017N352027_00
CONFIDENTIAL
BTZ117352
72
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C to 38.5C or 100.0F to 101.5F
38.6C to 39.5C or 101.6F to 102.9F
39.6C to 40.5C or 103F 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
 
 
 
2018N388749_00