Clinical trial NCT03568942
Conditions: Infections, Bacterial
Keywords: gepotidacin GSK2140944 acute cystitis pharmacokinetics urinary tract infections
Sponsor: GlaxoSmithKline
Start date: 2018-07-23; Completion date: 2019-01-07
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor that is being developed for the treatment of uncomplicated urinary tract infections (UTIs; acute cystitis). This Phase IIa study will evaluate plasma and urine pharmacokinetics of gepotidacin in female subjects with acute cystitis. Eligible female subjects will receive twice daily (BID) dose of gepotidacin 1500 milligram (mg) for 5 days via oral route. Pre-treatment and post-treatment samples for pharmacokinetic (PK) assessments will be collected throughout the study. The total duration of the study is approximately 28 days.

Detailed description:

Arms: arm 1: Adult female subjects with suspected acute cystitis based on clinical presentation and pyuria (\>=10 WBC/mm\^3 or presence of leukocyte esterase) and/or nitrite will be included. Subjects will be administered 1500 mg gepotidacin BID for 5 days via the oral route.
Interventions: intervention 1: Gepotidacin
Intervention descriptions: intervention 1: Gepotidacin tablets will be available at a dose strength of 750 mg. Tablets will be administered BID with water after consumption of food.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Phase IIa Single-Center, Open-Label Study Evaluating the 
Pharmacokinetics of Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult Female 
Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)
Protocol Number: 206899
Short Title: Phase IIa Pharmacokinetic Study of Oral Gepotidacin (GSK2140944) in 
Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis) 
Compound Number:
GSK2140944
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address:
GlaxoSmithKline
1250 South Collegeville Road
PO Box 5089
Collegeville, PA 19426-0989
USA
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number:
IND 111885
Approval Date: 10-MAY-2018
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorized copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES ...................................................................................8
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................17
3.3.3.
Overall Benefit:Risk Conclusion...................................................17
4.
OBJECTIVES AND ENDPOINTS...........................................................................18
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................22
5.3.
Participant and Study Completion...............................................................22
5.4.
Scientific Rationale for Study Design ..........................................................22
5.5.
Dose Justification........................................................................................23
6.
STUDY POPULATION...........................................................................................24
6.1.
Inclusion Criteria.........................................................................................24
6.2.
Exclusion Criteria........................................................................................25
6.3.
Lifestyle Restrictions...................................................................................27
6.3.1.
Meals and Dietary Restrictions ....................................................27
6.3.2.
Caffeine and Alcohol....................................................................28
6.3.3.
Activity .........................................................................................28
6.4.
Screen Failures...........................................................................................28
7.
TREATMENTS.......................................................................................................28
7.1.
Treatments Administered............................................................................28
7.2.
Dose Modification .......................................................................................29
7.3.
Method of Treatment Assignment ...............................................................29
7.4.
Blinding.......................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability..............................................29
7.6.
Treatment Compliance................................................................................30
7.7.
Concomitant Therapy..................................................................................30
7.7.1.
Permitted Medications and Nondrug Therapies ...........................30
7.7.2.
Prohibited Medications and Nondrug Therapies...........................30
7.8.
Treatment after the End of the Study ..........................................................31
8.
DISCONTINUATION CRITERIA.............................................................................31
8.1.
Discontinuation of Study Treatment ............................................................31
8.1.1.
Liver Chemistry Stopping Criteria ................................................32
8.1.2.
QTc Stopping Criteria ..................................................................34
8.1.3.
Temporary Discontinuation ..........................................................34
8.1.4.
Rechallenge.................................................................................34
8.1.4.1.
Study Treatment Restart or Rechallenge....................34
 
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8.2.
Withdrawal from the Study..........................................................................35
8.3.
Lost to Follow-Up........................................................................................35
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
9.1.
Efficacy Assessments.................................................................................39
9.1.1.
Therapeutic Response Evaluation ...............................................39
9.1.2.
Bacteriology Samples ..................................................................39
9.1.2.1.
Microbiological Outcome and Response.....................40
9.1.3.
Clinical Evaluation .......................................................................43
9.2.
Adverse Events...........................................................................................45
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................45
9.2.2.
Method of Detecting AEs and SAEs.............................................46
9.2.3.
Follow-up of AEs and SAEs.........................................................46
9.2.4.
Regulatory Reporting Requirements for SAEs .............................46
9.2.5.
Adverse Events of Special Interest ..............................................47
9.2.6.
Cardiovascular and Death Events................................................47
9.2.7.
Pregnancy ...................................................................................47
9.3.
Treatment of Overdose...............................................................................47
9.4.
Safety Assessments ...................................................................................48
9.4.1.
Physical Examinations.................................................................48
9.4.2.
Vital Signs....................................................................................48
9.4.3.
Electrocardiograms......................................................................48
9.4.4.
Clinical Safety Laboratory Assessments ......................................49
9.5.
Pharmacokinetics .......................................................................................49
9.5.1.
Blood and Urine Samples ............................................................49
9.5.2.
Cervical, Rectal, and Pharyngeal Swab Specimens.....................50
9.6.
Pharmacodynamics ....................................................................................50
9.6.1.
Pharmacokinetics/Pharmacodynamics ........................................50
9.6.2.
Microbiome Assessments............................................................50
9.7.
Genetics .....................................................................................................51
9.8.
Biomarkers .................................................................................................51
9.9.
Health Economics or Medical Resource Utilization and Health 
Economics..................................................................................................51
10. STATISTICAL CONSIDERATIONS........................................................................51
10.1.
Sample Size Determination ........................................................................51
10.2.
Populations for Analyses ............................................................................52
10.3.
Statistical Analyses.....................................................................................52
10.3.1.
Pharmacokinetic Analyses...........................................................52
10.3.2.
Safety Analyses...........................................................................53
10.3.3.
Exploratory Analyses ...................................................................54
10.3.4.
Interim Analyses ..........................................................................55
11. REFERENCES.......................................................................................................56
12. APPENDICES........................................................................................................59
12.1.
Appendix 1: Abbreviations and Trademarks................................................59
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................61
12.3.
Appendix 3: Study Governance Considerations..........................................63
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................67
 
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12.5.
Appendix 5: Division of Microbiology and Infectious Diseases Adult 
Toxicity Tables for Adverse Event Assessment...........................................72
12.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................80
12.7.
Appendix 7: Genetics..................................................................................83
12.8.
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................84
12.9.
Appendix 9: Algorithm for the Microbiological Intent-to-Treat 
Population...................................................................................................87
12.10. Appendix 10: Clinical Signs and Symptoms Scoring for Acute 
Cystitis........................................................................................................88
 
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1.
SYNOPSIS
Protocol Title: A Phase IIa Single-Center, Open-Label Study Evaluating the 
Pharmacokinetics of Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult Female 
Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)
Short Title: Phase IIa Pharmacokinetic Study of Oral Gepotidacin (GSK2140944) in 
Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)
Rationale:
Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial type II 
topoisomerase inhibitor, is being developed for the treatment of uncomplicated urinary 
tract infections (acute cystitis). This Phase IIa study is designed primarily to evaluate 
plasma and urine pharmacokinetics of gepotidacin in female participants with acute 
cystitis. As this pharmacokinetic (PK) study will be conducted in female participants with 
acute cystitis, the exploratory clinical and microbiological efficacy of gepotidacin will 
also be assessed. 
Objectives and Endpoints:
Objectives
Endpoints
Primary

To determine the plasma PK parameters 
of gepotidacin following repeat oral 
doses of gepotidacin (1500 mg [2 × 
750-mg tablets] twice daily [BID] for 
5 days) in adult female participants with 
acute cystitis 

Plasma gepotidacin area under the 
concentration-time curve (AUC) from zero 
(predose) over the dosing interval (AUC[0-]), 
maximum plasma concentration (Cmax), and 
time of occurrence of Cmax (tmax) on Days 1 
and 4 and apparent steady state clearance 
(CLss/F) and accumulation ratio (Ro) on 
Day 4

Plasma predose concentration (C) of 
gepotidacin on Days 1 through 5 
Secondary

To determine the urine PK parameters 
of gepotidacin following repeat oral 
doses of gepotidacin in adult female 
participants with acute cystitis

Urine gepotidacin amount of drug excreted 
over 12 hours (Ae 12h), amount of drug 
excreted in urine in a time interval (Ae[t1-t2]), 
percentage of the given dose of drug excreted 
in urine (fe%), and renal clearance (CLr) of 
gepotidacin on Days 1 and 4

Urine predose concentration (C) on Days 1 
through 5

To assess the safety and tolerability of 
repeat oral doses of gepotidacin in adult 
female participants with acute cystitis

Treatment-emergent adverse events and 
serious adverse events and change from 
baseline results for physical examinations, 
vital sign measurements, electrocardiograms, 
and clinical laboratory tests
Note: Exploratory objectives are described in the main protocol text.
 
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Overall Design:

Study 206889 is a Phase IIa single center, open-label study evaluating the PK of 
repeat oral doses of gepotidacin in adult female participants with clinical signs and 
symptoms of acute cystitis.

All participants who meet the study entry criteria and provide informed consent will 
receive oral gepotidacin. 

Pretreatment and posttreatment PK collections will be performed throughout the 
study. Appropriate safety, efficacy, microbiological, and exploratory assessments will 
also be conducted throughout the study.

Participants will be confined to the clinic from Baseline through the On-Therapy 
Visit. Participants will return to the clinic for the Test-of-Cure (TOC) and Follow-up 
Visits. 

At any time during the study, participants experiencing new or continuing signs and 
symptoms of acute cystitis will be assessed and treated per the investigator’s 
judgement.
Number of Participants:
Approximately 25 to 30 participants will be enrolled to achieve approximately 
20 participants who complete the study assessments through Day 5 and are evaluable for 
the PK analyses.
Treatment Groups and Duration:

All participants will receive oral gepotidacin 1500 mg twice daily for 5 days (total of 
10 doses). 

The study duration is approximately 28 days comprising approximately 5 days of
confinement at the clinic followed by 2 outpatient visits as follows:

Clinic Confinement Visits
o
Baseline (Day -1 to Day 1 predose) Visit
o
On-Therapy (Day 1 to Day 5) Visit

Outpatient Visits
o
TOC (Day 10 to 13) Visit
o
Follow-up (Day 28) Visit
 
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2.
SCHEDULE OF ACTIVITIES
Table 1
Schedule of Activities
Visit
Baseline 
(includes a screening 
window of up to 24 hours
before the first dose of 
study treatment)
On-Therapy
Test-of-Cure
Follow-up
Study Day
-1
1
2
3
4
5a
10 to 13
283
Procedure
Predose
Postdose
Written informed consent
X
Inclusion and exclusion criteria
X
Admission to clinic
X
Participant demography
X
Physical examination (including height and weight at Baseline only)
X
X
X
Medical/surgical history
X
Diagnosis of presumptive acute cystitisb
X
Bacteriology samplesc
X
X
X
X
X
X
X
Record acute cystitis signs and symptomsd
X
X
X
X
X
X
X
12-lead ECGe
X
Xf
X
X
Vital sign measurementsg
X
Xf
X
X
X
X
X
Hematology, chemistry, and urinalysis
X
X
X
X
Serology (hepatitis B and C and HIV)h
X
Pregnancy testi
X
X
X
Administer study treatmentj
Xj
X
X
X
X
Xj
Blood and urine PK samplingk
X
X
X
X
X
X
Cervical, rectal, and pharyngeal PK sampling (optional)l
X
Genetic sample (optional)
Xm
Stool microbiome collection (optional)n
X
X
X
Vaginal and pharyngeal microbiome collection (optional)n
X
X
X
Serious adverse eventso,p
X
X
X
X
X
X
X
X
X
Adverse eventsp
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Discharge from clinic
Xa,j
Schedule/Reminder for next outpatient visit
Xq
Xr
Xr
 
 
 
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ECG=electrocardiogram; HIV=human immunodeficiency virus; PK=pharmacokinetic; TOC=Test-of-Cure; WBC=white blood cell.
a.
If a participant discontinues during the on-treatment confinement period, Day 5 assessments will be completed before the participant is discharged, with the exception of study 
treatment administration.
b.
Based on confirmation of pyuria (≥10 WBC/mm3 or the presence of leukocyte esterase) and/or nitrite from a pretreatment clean-catch midstream urine sample per local laboratory 
procedures. Note: Repeat baseline urine samples are allowed if contamination, defined as ≥10 squamous epithelial cells, is observed under microscopic evaluation.
c.
Participants will provide a clean-catch midstream urine sample pretreatment at Baseline (predose on Day 1), predose on Days 2 through 5 (i.e., before the time-matched dose); and 
at the TOC and Follow-up Visits for Gram stain, quantitative bacteriology culture, and in vitro antimicrobial susceptibility testing.
d.
Site staff will record clinical signs and symptoms of acute cystitis based on participant interview (see Appendix 10).
e.
Obtain a triplicate 12-lead ECG in semi-supine position at Baseline only. See Table 2 for single 12-lead ECG predose and postdose assessment time points on Days 1 and 4.
f.
Only repeat the ECG and vital sign assessments at predose on Day 1 if the baseline assessment was not within 4 hours of the first dose of study treatment.
g.
Take measurement of temperature, blood pressure, and pulse rate in semi-supine position.
h.
If serology testing was performed within 3 months prior to the first dose of study treatment and results were positive, testing at Baseline is not required. If testing was performed 
within 3 months and any result was negative, testing at Baseline is required.
i.
For women of childbearing potential, a negative serum pregnancy test is needed for eligibility at Baseline. A urine pregnancy test may be performed on Day 5 and at the TOC Visit.
j.
The first dose on Day 1 will only be administered after all baseline procedures have been completed. All doses of study treatment will be administered under site staff supervision 
and all doses will be administered with food (i.e., standardized meals or snacks as applicable). Participants should remain in the clinic to complete a total of 10 doses.
k.
See Table 2 for serial collection time points. Predose PK blood samples will be collected before each time-matched dose on Days 1 through 5. Predose PK urine samples will be 
collected 0 to 2 hours before each time-matched dose on Days 1 through 5. Only 1 sample is needed when serial and predose samples overlap. If a participant is switched to a 
different antibiotic before the end of study treatment, a final blood and urine PK sample should be collected prior to administration of the different antibiotic.
l.
Collection of cervical, rectal, and pharyngeal swab PK specimens is optional. Specimens will be collected on Day 4 at predose and at approximately 2 hours postdose. The 2-hour 
postdose collection should be as close as possible to the 2-hour postdose blood PK draw time on Day 4.
m.
Collect sample only if the participant has a signed consent specific for this purpose. Baseline (predose on Day 1) is the recommended time to collect the sample, but it can be 
collected at any time during the study.
n.
Collection of stool, vaginal, and pharyngeal microbiome specimens is optional. The pretreatment specimens may be collected any time from Day -1 to Day 1 predose. The 
posttreatment specimens on Day 5 and at Follow-up may be collected at any time. Posttreatment stool, vaginal, and pharyngeal microbiome specimens should only be collected 
from participants who had a corresponding baseline specimen collected for each specimen type. 
o.
Record serious adverse events from the time of consent.
p.
Record adverse events from the time of the first dose of study treatment.
q.
Confirm return day/time for the TOC and Follow-up Visits.
r.
Pre-visit reminder: Site staff will contact the participant 24±4 hours before the scheduled TOC and Follow-up Visits.
Note:
At the discretion of the investigator, for emergency purposes only, participants may temporarily leave the clinic on study days without serial PK collections and only at times that do not 
interfere with required study assessments. Participants will be instructed to follow the protocol restrictions. The investigator will ensure the participant is eligible to continue in the study 
upon return to the clinic. All doses of study treatment will be administered under site staff supervision in the clinic.
The timing and number of planned study assessments, including PK assessments may be altered during 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 institutional review board will be 
informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form.
 
 
 
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Table 2
Blood and Urine Pharmacokinetic Collections and Electrocardiogram Assessments on Days 1 and 4
Time point (hours)
Procedurea
Predose
0
0.5
1
1.5
2
3
4
6
8
10
12
12-lead electrocardiogramb
Xc
X
Administer study treatmentd
X
Xe
Blood collection for pharmacokineticsf
X
X
X
X
X
X
X
X
X
X
Urine collection for pharmacokineticsg
X
X
X
X
X
X
X
a.
Assessments scheduled at the same nominal time should occur in the following order: electrocardiogram, urine collection, blood collection. The timing of the assessments should 
allow the blood draw to occur at the exact nominal time.
b.
Obtain single 12-lead electrocardiogram in semi-supine position at predose and 2 hours postdose on Days 1 and 4. The predose and postdose electrocardiogram time points should 
be the same on both days.
c.
Only repeat the electrocardiogram assessment at predose on Day 1 if it was not performed within 4 hours of the baseline assessment.
d.
Study treatment will be administered under site staff supervision and with food (i.e., standardized meals or snacks as applicable). On Days 1 and 4, for the dose associated with serial 
PK collections, participants should be in a semi-supine position for approximately 3 hours after study treatment administration with only minor exceptions (e.g., urine PK collections).
e.
Collection of the PK samples should occur before this dose is administered.
f.
Blood PK samples will be collected at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose for the first dose of study treatment on Day 1 and for the time-matched dose on 
Day 4.
g.
Urine PK samples will be collected predose and at intervals of 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours postdose for the first dose of 
study treatment on Day 1 and for the time-matched dose on Day 4.
 
 
 
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3.
INTRODUCTION
Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial type II 
topoisomerase inhibitor, is being developed for the treatment of uncomplicated urinary 
tract infections (UTIs; acute cystitis). Gepotidacin is also being developed as an oral and 
intravenous treatment for infections caused by conventional and biothreat pathogens, 
including isolates resistant to existing classes of antimicrobials. The microbiological 
spectrum of activity of gepotidacin includes Escherichia coli, the key causative pathogen 
of acute cystitis, and Staphylococcus saprophyticus and Enterococcus faecalis.
Gepotidacin selectively inhibits bacterial DNA replication by interacting in a unique way 
on the GyrA subunit of bacterial DNA gyrase and the ParC subunit of bacterial 
topoisomerase IV. This interaction appears to be highly specific to bacterial 
topoisomerases as evidenced by weak in vitro inhibition of human topoisomerase II, 
supporting the selective activity of gepotidacin against the bacterial target. The novel 
mode of action of this new class antibacterial affords in vitro activity against most target 
pathogens resistant to established antibacterials, including fluoroquinolones.
3.1.
Study Rationale
This Phase IIa study is designed primarily to evaluate plasma and urine pharmacokinetics
of gepotidacin in female participants with acute cystitis.
This study is being conducted based on the need to identify new and effective oral 
antibiotic treatment options for acute cystitis, as such therapies are becoming limited due 
to the increase of multidrug-resistant (MDR) pathogens and extended-spectrum 
-lactamase (ESBL)-producing Enterobacteriaceae pathogens, which are impacting the 
efficacy of currently available oral antibacterial treatment options (see Section 3.2). 
Two Phase II studies have been conducted and the results demonstrated that gepotidacin 
was efficacious in the treatment of uncomplicated urogenital gonorrhea and acute 
bacterial skin and skin structure infections (ABSSSIs) (see Section 5.3.3 in the
investigator’s brochure [IB] for details).
3.2.
Background
Urinary tract infections are very common, with approximately 11% of women >18 years 
of age experiencing at least 1 episode of acute cystitis per year [Foxman, 2000]. Of these, 
half will experience more than 1 recurrent episode over their lifetime [Foxman, 2000]. 
The peak incidence of acute cystitis occurs in young, sexually active women ages 18 to 
29 years [Fihn, 2003]. The predominant uropathogen isolated in community-acquired 
UTIs is E. coli (75% to 90%) followed by S. saprophyticus (5% to 15%) [Stamm, 1993;
Talan, 2000; Foxman, 2010]. Klebsiella, Enterobacter, and Proteus species and 
enterococci are observed in only 5% to 10% of cases [Stamm, 1993; Talan, 2000;
Foxman, 2010].
Multidrug resistance, which is typically associated with nosocomial infections, has now 
emerged at the community level and has made treatment approaches for UTIs more 
difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. This has led to increasing patient 
 
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morbidity, increasing costs due to reassessment and retreatment, higher rates of 
hospitalization, and increased use of broad-spectrum antibiotics [Foxman, 2002; Gupta, 
2011a; Hooton, 2012]. Furthermore, ESBL-producing Enterobacteriaceae, which 
includes E. coli, is recognized as a serious threat by the Centers for Disease Control and 
Prevention (CDC) [CDC, 2013] and drug-resistant Enterobacteriaceae is a critical 
priority pathogen for the World Health Organization (WHO) [WHO, 2017]. One reason 
for this serious threat level is the growing rise in the MDR E. coli sequence type 
(ST)-131 clone [Johnson, 2012; Nicolas-Chanoine, 2014]. Spread of this ST-131 clone 
has led to UTIs and blood stream infections caused by MDR E. coli worldwide [Peirano, 
2010]. The availability of oral antimicrobials that are effective against ESBLs is limited 
and, for some outpatient infections, no oral options remain.
An in vitro evaluation of antimicrobial resistance of urinary E. coli isolates 
(n=12,253,679) among US outpatients between 2000 and 2010 was conducted using 
The Surveillance Network and found significant increases in the percentage of E. coli that 
were resistant to ciprofloxacin (3% to 17.1%) and trimethoprim-sulfamethoxazole 
(TMP-SXT) (17.9% to 24.2%), whereas there were minimal changes in the percentage of 
resistance to nitrofurantoin (0.8% to 1.6%) and ceftriaxone (0.2% to 2.3%) over time 
[Sanchez, 2012]. Another surveillance study, which looked at US susceptibility patterns 
and ESBL rates of E. coli from UTIs, showed an increase in ESBL rates from 7.8% to 
18.3% (p<0.0001) from 2010 to 2014 [Lob, 2016]. The expansion of ESBL-producing 
E. coli, which are usually co-resistant to TMP-SXT and fluoroquinolones, is of urgent 
concern globally as well [Oteo, 2010]. Recent global surveillance data of E. coli showed 
high resistance rates to third-generation cephalosporins and fluoroquinolones in all 
6 WHO regions [WHO, 2014]. An evaluation of the prevalence and susceptibility of 
acute cystitis pathogens in 9 European countries and Brazil from 2003 to 2006 showed 
that >10% of E. coli strains were MDR and 1.7% were ESBL producers [Schito, 2009]. A 
separate study in Brazil reported a prevalence of 7.6% ESBL-producing 
Enterobacteriaceae among pathogens from community-acquired UTIs [Abreu, 2013]. In 
China, the prevalence of ESBLs in urinary E. coli in women ranged from 5% to 10.6% 
depending on the age group [Ho, 2007]. 
Based on these resistant pathogen trends, guidelines for acute cystitis now recommend 
first-line antibiotic treatment with nitrofurantoin, TMP-SXT, fosfomycin, or 
pivmecillinam, assuming the drug is available and the patient does not have a concerning 
allergy history or tolerance issues [Gupta, 2011b]. Trimethoprim-sulfamethoxazole 
should not be used as a first-line treatment if the prevalence of resistance exceeds the 
20% threshold or if TMP-SXT was used for treatment of a UTI in the previous 3 months. 
If any of these are concerns for a patient, then fluoroquinolones or β-lactams are 
recommended.
Gepotidacin is a first-in-class, novel triazaacenaphthylene antibacterial that has 
demonstrated in vitro activity against uropathogens including E. coli (see Section 4.2 of 
the IB for details) and provides high and sustained urine concentrations for the treatment 
of UTIs. With its unique ability to selectively inhibit bacterial DNA replication by a 
means not utilized by any currently approved human therapeutic agent, gepotidacin 
warrants further study as a potential opportunity to address an unmet medical need by 
providing a new and effective oral treatment option for acute cystitis.
 
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This Phase IIa study is designed primarily to evaluate plasma and urine pharmacokinetics
of gepotidacin in female participants with acute cystitis.
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
gepotidacin is provided in the IB [GlaxoSmithKline Document 
Number CM2010/00033/05]. 
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of gepotidacin may be found in the IB 
[GlaxoSmithKline Document Number CM2010/00033/05]. A summary of risk 
assessments is provided in Section 3.3.1.
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Gepotidacin (e.g., GSK2140944)
Cardiovascular Effects
Based on nonclinical data, cardiovascular effects 
were reversible increase in heart rate and blood 
pressure (dog and monkey); reversible 10 to 
21 msec (4% to 9%) increase in QTc (monkey); 
and at the highest dose, a reversible 2 to 3 msec 
(6% to 8%) increase in QRS (monkey).
Based on a thorough QTc clinical study, 
gepotidacin may cause mild, reversible heart rate 
effects and QT prolongation.
In a thorough QTc study, infusion of gepotidacin 
at doses of 1000 and 1800 mg over 2 hours 
caused a mild increased heart rate effect of 
approximately 6 to 10 bpm and QT prolongation 
measured as ∆∆QTcF of 12 to 22 msec. The QT 
prolongation evolved during the infusion and was 
quickly reversed over 2 hours after the end of the 
infusion (see Section 5.2.6 and Section 6 of the 
IB).
No changes in QRS or QTc of clinical concern 
have been seen in the clinic (Phase I studies and 
Phase II ABSSSI study) (see Section 6 in the IB). 
Cardiovascular events reported in the Phase II 
urogenital gonorrhea study were ECG ST 
segment elevation and palpitations (1 participant 
each) in the 1500-mg treatment group and 
tachycardia (1 participant) in the 3000-mg 
treatment group.
See Section 6.2 for excluded cardiac conditions. 
Close monitoring of clinical parameters and AEs 
(Table 1) will be conducted, and treatment 
monitoring and evaluation criteria (Section 8.1.2) 
will be utilized to mitigate cardiovascular effects.
As a consequence, participants taking 
QT-prolonging drugs or strong CYP3A4 inhibitors 
and/or strong P-gp inhibitors will be excluded.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Gastrointestinal Effects
Based on nonclinical data, gastrointestinal 
effects were mild ulceration of the nonglandular 
mucosa and minimal erosion and/or mural 
inflammation of the glandular mucosa in stomach 
(rat, oral study); moderate cecal ulceration and 
minimal colonic erosion (rat, IV study); and 
vomiting (dog).
Lower gastrointestinal effects (soft stools, 
flatulence, and diarrhea) are among the most 
common AEs reported in gepotidacin clinical 
studies.
Gastrointestinal effects observed in gepotidacin
clinical studies, both Phase I studies and the 
Phase II ABSSSI study, included diarrhea (very 
common, ≥10%) and flatulence (common; ≥1% 
and <10%); all nonserious and mild in severity 
(see Section 6 of the IB).
In the Phase II urogenital gonorrhea study, the 
most frequently reported gastrointestinal AEs 
overall were diarrhea, flatulence, abdominal pain, 
and nausea. Comparing the treatment groups, 
the incidence of diarrhea and nausea was higher 
in the 3000-mg treatment group and incidence of 
flatulence was higher in the 1500-mg treatment 
group. 
Few occurrences of Clostridium difficile have 
been reported in clinical studies (see Section 6 of 
the IB). Of the 357 healthy participants in Phase I 
studies who have received gepotidacin, 
C. difficile was reported in 8 participants, 
including 2 elderly participants in association with 
soft stools or diarrhea. No participants in the 
Phase II ABSSSI or Phase II urogenital 
gonorrhea study received a diagnosis of 
C. difficile-associated diarrhea.
See Section 6.2 for excluded medical conditions. 
Close monitoring of clinical parameters and AEs 
(Table 1) will be conducted to mitigate and 
assess gastrointestinal effects. Suspected 
C. difficile infection will be managed according to 
a prespecified algorithm provided in the Study 
Reference Manual.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Acetylcholinesterase Inhibition
In a mass spectrometry model performed with 
gepotidacin, acetylcholinesterase was inhibited 
with an IC50 of approximately 5 g/mL 
(7.5 g/mL of total drug concentration).
Based on clinical data, caution should be used in 
participants who have a condition requiring 
medication that may be exacerbated by 
acetylcholinesterase inhibition or 
neuromuscular-blocking agents.
Adverse events consistent with 
acetylcholinesterase effects were reported 
infrequently in Phase I studies as single or 
combined AEs, including dizziness, abdominal 
pain, oropharyngeal discomfort, salivary 
hypersecretion, hot flush, diarrhea, fatigue, and 
nausea. In the Phase II ABSSSI study with IV or 
oral treatment with gepotidacin up to 10 days, 
AEs of diarrhea, nausea, dizziness 
(1 participant), salivary hypersecretion 
(1 participant), and hot flush (1 participant) were 
reported (see Section 6 of the IB).
In the Phase II study of urogenital gonorrhea 
(oral doses: 1500 or 3000 mg), treatment-related 
AEs potentially associated with 
acetylcholinesterase inhibition included dizziness 
(1 and 6 participants, respectively), hyperhidrosis 
(1 and 6 participants, respectively), and 
headache (2 participants in both).
Participants who have medical conditions or 
require medications that may be aggravated by 
inhibition of acetylcholinesterase will be excluded 
from participation in this study. See Section 6.2
for excluded medical conditions and 
Section 7.7.2, Prohibited Medications and 
Nondrug Therapies, for prohibited medications.
Close monitoring of clinical parameters and 
AEs will be conducted to assess effects 
potentially related to acetylcholinesterase 
inhibition (Table 1).
 
 
 
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3.3.2.
Benefit Assessment
Given gepotidacin’s spectrum of activity against E. coli, S. saprophyticus, and 
E. faecalis, as well as human safety data and the pharmacokinetic (PK) profile, it is 
anticipated that gepotidacin will benefit participants with acute cystitis.
Overall, all participants in this study will not only receive routine medical monitoring
appropriate for acute cystitis, but they will also receive heightened monitoring to ensure 
safety when participating in a clinical study.
The PK data from this study will be used to support the indication for gepotidacin as a 
potential new treatment option for acute cystitis.
3.3.3.
Overall Benefit:Risk Conclusion
Together with the known preclinical data for gepotidacin against E. coli, 
S. saprophyticus, and E. faecalis, cumulative safety results from Phase I and Phase II 
studies with oral gepotidacin treatment, and the PK data from this study will be used to 
support the indication for gepotidacin as a potential new treatment option for acute 
cystitis.
None of the potential or identified risks seen to date in participants dosed with 
gepotidacin preclude further clinical development. Mitigation strategies have been 
implemented to promptly identify and appropriately address risks in order to protect 
participant safety and to better characterize the safety profile of the study treatment 
(Section 3.3.1), including additional 12-lead ECG assessments during the study while 
participants are confined. Careful safety monitoring should also identify any emerging 
safety issues for gepotidacin and contribute to further benefit-risk profile development.
The investigator may, at his or her discretion, discontinue the participant from study 
treatment at any time and initiate appropriate alternative therapy.
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with gepotidacin are justified by the 
anticipated benefits that may be afforded to participants with acute cystitis.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine the plasma PK 
parameters of gepotidacin following 
repeat oral doses of gepotidacin 
(1500 mg [2 × 750-mg tablets] twice 
daily [BID] for 5 days) in adult female 
participants with acute cystitis 

Plasma gepotidacin area under the 
concentration-time curve (AUC) from zero 
(predose) over the dosing interval (AUC[0-]), 
maximum plasma concentration (Cmax), and 
time of occurrence of Cmax (tmax) on Days 1 
and 4 and apparent steady state clearance 
(CLss/F) and accumulation ratio (Ro) on 
Day 4

Plasma predose concentration (C) of 
gepotidacin on Days 1 through 5 
Secondary

To determine the urine PK parameters 
of gepotidacin following repeat oral 
doses of gepotidacin in adult female 
participants with acute cystitis

Urine gepotidacin amount of drug excreted 
over 12 hours (Ae 12h), amount of drug 
excreted in urine in a time interval (Ae[t1-t2]), 
percentage of the given dose of drug excreted 
in urine (fe%), and renal clearance (CLr) of 
gepotidacin on Days 1 and 4

Urine predose concentration (C) on Days 1 
through 5

To assess the safety and tolerability of 
repeat oral doses of gepotidacin in 
adult female participants with acute 
cystitis

Treatment-emergent AEs and serious AEs 
and change from baseline results for physical 
examinations, vital sign measurements, 
electrocardiograms (ECGs), and clinical 
laboratory tests
Exploratory

To explore the combined clinical and 
microbiological efficacy of gepotidacin 
in adult female participants with acute 
cystitis who have a qualifying baseline 
uropathogen

Therapeutic response (combined 
per-participant microbiological and clinical 
response) at the Test-of-Cure (TOC) Visit

To assess time to eradication of 
uropathogens in adult female 
participants with acute cystitis who 
have a qualifying baseline uropathogen

Microbiological outcome on Days 2 through 5; 
Microbiological outcome and response at the 
TOC and Follow-up Visits

To explore time to resolution of signs 
and symptoms in adult female 
participants with acute cystitis

Clinical outcome on Days 2 through 5; Clinical 
outcome and response at the TOC and 
Follow-up Visits

To assess the relapse rate 
(microbiological and clinical) of acute 
cystitis after treatment with gepotidacin 
in adult female participants with acute 
cystitis at the Follow-up Visit

Therapeutic response (combined 
per-participant microbiological and clinical 
response) at the Follow-up Visit
 
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Objectives
Endpoints

To explore the microbiological and 
antimicrobial susceptibility profile of 
uropathogens recovered from adult 
female participants with acute cystitis, 
including subsets of isolates resistant to 
other antimicrobials

Gram stain, quantitative bacteriology culture, 
and in vitro antimicrobial susceptibility test 
results at Baseline, Days 2 through 5, and at 
the TOC and Follow-up Visits

To explore gepotidacin plasma 
PK/pharmacodynamic (PD) 
relationships in adult female 
participants with acute cystitis

Relationship between gepotidacin exposure 
and clinical and microbiological response, if 
data permit

To explore the distribution of 
gepotidacin in cervical, rectal, and
pharyngeal tissue (swab specimens)

Gepotidacin concentration in cervical, rectal, 
and pharyngeal tissues, if data permit 
5.
STUDY DESIGN
5.1.
Overall Design
A study design schematic is depicted in Figure 1.

Study 206889 is a Phase IIa single center, open-label study evaluating the PK of 
repeat oral doses of gepotidacin in adult female participants with clinical signs and 
symptoms of acute cystitis.

All participants who meet the study entry criteria and provide informed consent will 
receive oral gepotidacin 1500 mg BID for 5 days (total of 10 doses). 

Pretreatment and posttreatment PK collections will be performed throughout the 
study. Appropriate safety, efficacy, microbiological, and exploratory assessments will 
also be conducted throughout the study.

The study duration is approximately 28 days comprising approximately 5 days of 
confinement at the clinic followed by 2 outpatient visits as follows (see Table 1 and 
Section 9 for study visit details):

Clinic Confinement Visits
o
Baseline (Day -1 to Day 1 predose) Visit
o
On-Therapy (Day 1 to Day 5) Visit

Outpatient Visits
o
Test-of-Cure (TOC) (Day 10 to 13) Visit
o
Follow-up (Day 28) Visit

Participants will be confined to the clinic from Baseline through the On-Therapy
Visit. Participants will return to the clinic for the TOC and Follow-up Visits.
Note: At the discretion of the investigator, for emergency purposes only, participants 
may temporarily leave the clinic on study days without serial PK collections and only 
 
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at times that do not interfere with required study assessments. Participants will be 
instructed to follow the protocol restrictions. The investigator will ensure the 
participant is eligible to continue in the study upon return to the clinic. All doses of 
study treatment will be administered under site staff supervision in the clinic.

Participants with a concomitant fungal infection can only be treated with topical 
antifungals per local standard of care.

At any time during the study, participants experiencing new or continuing signs and 
symptoms of acute cystitis will be assessed and treated per the investigator’s 
judgement. If a participant is switched to a different antibiotic before or during the 
TOC Visit, all TOC procedures should be completed before the other antibiotic is 
started. Any participant who discontinues from the PK portion of the study should 
return for the TOC and Follow up-Visits.
 
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Figure 1
Study Design Schematic
BID=twice daily; PK=pharmacokinetic; TOC=test of cure; WBC=white blood cell.
a.
Serial blood PK sampling will be performed for the first dose of study treatment on Day 1 and for the time-matched dose on Day 4. Blood samples will be collected predose and at 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose.
b.
Serial urine PK sampling will be performed for the first dose of study treatment on Day 1 and for the time-matched dose on Day 4. Urine samples will be collected predose and at 
intervals of 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours postdose.
c.
Predose PK blood samples will be collected before each time-matched dose on Days 1 through 5. Predose PK urine samples will be collected 0 to 2 hours before each 
time-matched dose on Days 1 through 5. Only 1 sample is needed when serial and predose samples overlap.
d.
Participants will check-out of the clinic after all study procedures have been performed, including a predose clean-catch midstream urine sample for Gram stain, quantitative 
bacteriology culture, and antimicrobial susceptibility testing, predose PK sample collections, and safety assessments. Participants should remain in the clinic to complete a total of 
10 doses. Participants will be instructed to return for the TOC (Day 10 to 13) and Follow-up (Day 28±3) Visits.
 
 
 
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5.2.
Number of Participants
Approximately 25 to 30 participants will be enrolled to achieve approximately 
20 participants who complete the study assessments through Day 5 and are evaluable for 
the PK analyses.
If participants prematurely discontinue the study, additional replacement participants may 
be recruited at the discretion of the sponsor and in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed study treatment if she has taken all doses 
of the study treatment and completed the TOC Visit. A participant is considered to have 
completed the study if she has completed all study visits 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 Phase IIa study is designed primarily to evaluate plasma and urine pharmacokinetics
of gepotidacin in participants with acute cystitis. Serial sample collections will be 
performed on Day 1 (first dose) and on Day 4.
As this PK study will be conducted in female participants with acute cystitis, the 
exploratory clinical and microbiological efficacy of gepotidacin will also be assessed. 
The time points and success definitions were based on the Food and Drug Administration 
(FDA) guidance for industry for developing drug treatments for uncomplicated and 
complicated UTIs [DHHS, 1998; DHHS, 2015] and the European Medicines Agency 
(EMA) addendum to the guideline on the evaluation of medicinal products indicated for 
treatment of bacterial infections [EMA, 2013].
Efficacy will be assessed daily during the On-Therapy Visit, at TOC, and at Follow-up. 
Clinical success is defined as the resolution of signs and symptoms of acute cystitis 
present at Baseline (and no new signs and symptoms) and no use of other antimicrobial 
therapy. Microbiological success is defined as the reduction of the qualifying bacterial 
uropathogen (defined in Appendix 9) recovered at Baseline to <103 colony-forming 
units (CFU)/mL as observed on quantitative urine culture. Therapeutic success refers to 
participants who have been deemed both a microbiological success and a clinical success 
(i.e., responders).
Adult (≥18 to 65 years of age) eligible female participants will be enrolled in this 
open-label Phase IIa PK study. This age range was selected to minimize variability in 
systemic exposures as well as baseline uropathogens. This study in acute cystitis is 
restricted to female participants per the FDA guidance [DHHS, 1998]. As described in 
Section 5.5, the dose of gepotidacin and the 5-day duration were selected to provide 
efficacious treatment for acute cystitis and is in alignment with current clinical practice.
 
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5.5.
Dose Justification
The oral gepotidacin dose in this study is 1500 mg BID (total daily dose of 3000 mg) for 
5 days. A 5-day dosing duration is in alignment with current treatment guidelines for 
efficacious antibacterial treatment of uncomplicated acute cystitis in women, which 
typically ranges from 3 to 7 days [Gupta, 2011b; GOV.UK, 2017; EAU, 2017]. The 
safety and tolerability at this oral dose and duration have been evaluated in Phase I 
studies and in a Phase II study (BTZ116704) (see Section 5 of the IB for details). 
Furthermore, high urine concentrations of gepotidacin are expected in this study based on 
a Phase I study (BTZ117351) where approximately 285 mg of unchanged gepotidacin 
was excreted in urine after a single, oral, 1500-mg (2 × 750-mg tablets) dose of 
gepotidacin.
The gepotidacin dose and duration for this Phase IIa PK uncomplicated UTI study were 
selected based on in vitro and in vivo studies including experimental animal 
pyelonephritis studies that simulated human PK exposures of gepotidacin to determine 
the efficacy of gepotidacin against isolates of E. coli, including MDR strains (see 
Section 4.2 of the IB for further details).
Additionally, preliminary data from a recently completed in vitro study to determine the 
PK/PD characteristics of gepotidacin against E. coli (dose-fractionation and dose-ranging 
studies) indicate that AUC/minimum inhibitory concentration (MIC) is the primary 
PK/PD index predictive of gepotidacin efficacy against E. coli. The magnitude of the 
ratio of the area under the free-drug concentration-time curve to MIC over 24 hours 
(fAUC/MIC) required to achieve net bacterial stasis as well as 1- and 2-log reductions in 
bacterial burden from baseline across multiple E. coli isolates with gepotidacin MIC 
values ranging from 1 to 4 g/mL, were 34.5, 41.3, and 49.7, respectively.
A set of duplicate 10-day hollow fiber infection model studies were also completed using 
E. coli isolate NCTC 13441 to determine the fAUC/MIC exposure of gepotidacin 
required to prevent the amplification of resistant subpopulation. An inverted-U shaped 
function described the relationship between drug resistance amplification and fAUC, with 
fAUC values ≥549 preventing resistance amplification to gepotidacin for E. coli in the 
hollow fiber infection model. This equates to an fAUC/MIC value ≥275 when applying 
the gepotidacin broth microdilution MIC of 2 g/mL for E. coli 13441, as determined in 
this study.
When taking the fAUC/MIC target of 275 for resistance supression into consideration 
with the concentrations of gepotidacin in human urine measured in a Phase I study 
(BTZ117351, minimum fAUC12h=807 µg.h/mL, so fAUC24h=1610 µg.h/mL) and, 
applying an MIC value of 4 g/mL, the minimum human urine fAUC/MIC achieved for 
the 1500 mg oral BID dose exceeds the fAUC/MIC resistance supression target of 275 by 
approximately 1.5-fold and 100% target attainment for an fAUC/MIC target of 275 
would be expected for participants with E. coli isolates with gepotidacin MICs ≤4 g/mL
following 1500 mg BID oral dosing.
In conclusion, minimum urine levels of gepotidacin are anticipated to be in excess of the 
fAUC/MIC target necessary for both efficacy and resistance suppression for E. coli as 
 
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determined from the in vitro PK/PD models. Given that the bladder is the primary site of 
infection in cystitis, the use of gepotidacin urine PK data, coupled with the robust in vivo
efficacy demonstrated in the human simulated PK pyelonephritis model, is appropriate 
for selecting the gepotidacin 1500 mg BID oral dose for 5 days for study in the treatment 
of participants with acute cystitis.
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
Otherwise healthy participants are eligible to be included in the study only if all of the 
following criteria apply:
Age
1.
Participant must be ≥18 to 65 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
The participant has 2 or more of the following clinical signs and symptoms of acute 
cystitis with onset ≤72 hours of the screening assessment: dysuria, frequency, 
urgency, or lower abdominal pain (see Appendix 10).
3.
The participant has pyuria (≥10 WBC/mm3 or the presence of leukocyte esterase)
and/or nitrite from a pretreatment clean-catch midstream urine sample based on local 
laboratory procedures.
Note: Repeat baseline urine samples are allowed if contamination, defined as 
≥10 squamous epithelial cells, is observed under microscopic evaluation. 
Sex
4.
The participant is female. A female participant is eligible to participate if she is not 
pregnant (Appendix 6), not breastfeeding, and at least 1 of the following conditions 
applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 6
OR
A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 from
the Baseline Visit through completion of the TOC Visit.
Informed Consent
5.
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.
 
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6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
The participant resides in a nursing home or dependent care-type facility.
2.
The participant has a body mass index ≥40.0 kg/m2 or a body mass index 
≥35.0 kg/m2 with obesity-related health conditions such as high blood pressure or 
uncontrolled diabetes.
3.
The participant has a history of sensitivity to the study treatment, or components 
thereof, or a history of a drug or other allergy that, in the opinion of the investigator 
or medical monitor, contraindicates her participation.
4.
The participant is immunocompromised or has altered immune defenses that may 
predispose the participant to a higher risk of treatment failure and/or complications 
(e.g., renal transplant recipients, participants with clinically significant persistent 
granulocytopenia [absolute neutrophil count <1000/L], and participants receiving 
immunosuppressive therapy, including corticosteroid therapy [>40 mg/day 
prednisolone or equivalent for >1 week or ≥20 mg/day prednisolone or equivalent 
for >6 weeks; or prednisolone or equivalent ≥10 mg/day for >6 weeks]). Participants 
with a known CD4 count of <200 cells/mm3 should not be enrolled. Note:  
Participants with a positive test for human immunodeficiency virus are eligible for 
study participation.
5.
The participant has uncontrolled diabetes, defined as a nonfasting glucose value 
>300 mg/dL or based on investigator judgment.
6.
The participant has any of the following:

A medical condition that requires medication that may be aggravated by 
inhibition of acetylcholinesterase, such as:
o
Poorly controlled asthma or chronic obstructive pulmonary disease at 
Baseline and, in the opinion of the investigator, not stable on current 
therapy
o
Acute severe pain, uncontrolled with conventional medical management
o
Active peptic ulcer disease
o
Parkinson disease
o
Myasthenia gravis
o
A history of seizure disorder requiring medications for control (this does 
not include a history of childhood febrile seizures)
OR

Any surgical or medical condition (active or chronic) that may interfere with 
drug absorption, distribution, metabolism, or excretion of the study drug (e.g., 
ileostomy or malabsorption syndrome). Participants who have had a gastric 
bypass or a cholecystectomy are excluded from the study.
 
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OR

Hemoglobin value <12 g/dL or a known uncorrected iron deficiency.
7.
The participant, in the judgment of the investigator, would not be able or willing to 
comply with the protocol or complete study follow-up.
8.
The participant has a serious underlying disease that could be imminently life 
threatening, or the participant is unlikely to survive for the duration of the study 
period.
Urinary Tract Infection/Renal/Urogenital Exclusions
9.
The participant has acute cystitis that is known or suspected to be due to fungal, 
parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas 
aeruginosa or Enterobacteriaceae (other than E. coli) as the contributing pathogen.
10. The participant has symptoms known or suspected to be caused by another disease 
process such as asymptomatic bacteriuria or chronic interstitial cystitis.
11. The participant has an anatomical or physiological anomaly that predisposes the 
participant to UTIs or may be a source of persistent bacterial colonization, including 
calculi, obstruction or stricture of the urinary tract, primary renal disease (e.g., 
polycystic renal disease), or neurogenic bladder, or the participant has a history of 
anatomical or functional abnormalities of the urinary tract (e.g., chronic 
vesico-ureteral reflux, detrusor insufficiency).
12. The participant has an indwelling catheter, nephrostomy, ureter stent, or other 
foreign material in the urinary tract.
13. The participant who, in the opinion of the investigator, has an otherwise complicated 
UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptoms onset 
≥96 hours before the screening assessment, or a temperature ≥101°F, flank pain, 
chills, or any other manifestations suggestive of upper UTI.
14. The participant has anuria, oliguria, or significant impairment of renal function 
(creatinine clearance <30 mL/min or clinically significant elevated serum creatinine).
15. The participant presents with vaginal discharge at Baseline (e.g., suspected sexually 
transmitted disease).
Cardiac Exclusions
16. The participant has congenital long QT syndrome or known prolongation of the 
corrected QT (QTc) interval. 
17. The participant has uncompensated heart failure, defined as New York Heart 
Association Class ≥III.
18. The participant has severe left ventricular hypertrophy.
19. The participant has a family history of QT prolongation or sudden death.
20. The participant has a recent history of vasovagal syncope or episodes of 
symptomatic bradycardia or bradyarrhythmia within the last 12 months.
21. The participant is taking QT-prolonging drugs or drugs known to increase the risk of 
torsades de points (TdP) per the www.crediblemeds.org “Known Risk of TdP” 
 
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category at the time of her Baseline Visit, which cannot be safely discontinued from 
the Baseline Visit to the TOC Visit; or the participant is taking a strong cytochrome 
P450 enzyme 3A4 (CYP3A4) inhibitor or a strong P-glycoprotein (P-gp) inhibitor.
Cardiac ECG Exclusion
22. The participant has a QTc >450 msec or a QTc >480 msec for participants with 
bundle-branch block. Note:  The QTc is the QT interval corrected for heart rate 
according to either Bazett or Fridericia formula, machine, or manual overread. 
Hepatic Exclusions
23. The participant has a known alanine transferase (ALT) value >2 × upper limit of 
normal (ULN).
24. The participant has a known bilirubin value >1.5 × ULN (isolated bilirubin >1.5 × 
ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
25. The participant has a current or chronic history of liver disease, or known hepatic or 
biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones), including symptomatic viral hepatitis or moderate-to-severe liver 
insufficiency (Child Pugh class B or C). Note:  Participants with asymptomatic viral 
hepatitis are eligible for study participation.
Prior Antibiotic/Antifungal Use Exclusion
26. The participant has received treatment with other systemic antimicrobials or 
systemic antifungals within 1 week before study entry.
Concomitant Medication Use Exclusion
27. The participant must agree not to use the medications or nondrug therapies from the 
Baseline Visit through the TOC Visit as detailed in Section 7.7.2.
Prior/Concurrent Clinical Study Experience
28. The participant has been previously enrolled in this study or has previously been 
treated with gepotidacin.
29. The participant has participated in a clinical trial and has received an investigational 
product within 30 days or 5 half-lives, whichever is longer.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Standard meals will be provided during the study dosing period at specified times that 
do not interfere with study procedures.

Study treatment will be taken with food (a meal or a snack) (see Section 7.1).

Participants will refrain from consumption of Seville oranges, grapefruit, or grapefruit 
juice (and/or pummelos, exotic citrus fruits, or grapefruit hybrids) from the Baseline 
Visit through collection of the final PK sample.
 
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6.3.2.
Caffeine and Alcohol

Participants will abstain from ingesting caffeine- or xanthine-containing products 
(e.g., coffee, tea, cola drinks, and chocolate) from the Baseline Visit through
collection of the final PK sample.

Participants will abstain from alcohol from the Baseline Visit through collection of 
the final PK sample.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests during the On-Therapy Visit; participants may 
engage in light recreational activities during the study (e.g., watch television, read).

On Days 1 and 4, for the dose associated with serial PK collections, participants 
should be in a semi-supine position for approximately 3 hours after study treatment 
administration with only minor exceptions (e.g., urine PK collections). Postdose 
compliance with a semi-supine position will be recorded in the source documents.
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 publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious AEs (SAEs).
Participants who are screen failures are not allowed to be rescreened for the same 
infection episode; however, participants who were screen failures for an earlier infection 
episode may be newly screened for a later infection episode and participate in the study if 
they meet all of the inclusion and exclusion criteria.
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
Participants will receive oral study treatment (gepotidacin 1500 mg [2 × 750-mg tablets]) 
BID for 5 days (10 total doses). All doses of study treatment will be administered under 
site staff supervision in the clinic and all doses will be administered with food (i.e., 
standardized meals or snacks as applicable). The first dose will be administered at the 
clinic by 2 PM on Day 1 (for practical reasons and participant convenience) and 
subsequent doses will be administered approximately every 12 hours. Participants should 
remain in the clinic to complete a total of 10 doses.
 
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Study Treatment Name:
Gepotidacin
Dosage Formulation:
Tablets containing gepotidacin and inactive 
formulation excipients
Unit Dose Strengths/Dosage 
Levels:
750 mg per tablet/1500 mg per dose (2 × 750-mg 
tablets)
Route of Administration:
Oral
Dosing Instructions:
Administer twice daily for 5 days:
1500 mg – 2 × 750-mg tablets 
(3000 mg total daily dose)
Each dose should be taken after food consumption 
and with water.
Packaging and Labeling:
Gepotidacin tablets will be provided in bottles. 
Each bottle will be labeled as required per country 
requirement.
Manufacturer:
GlaxoSmithKline
7.2.
Dose Modification
The study design does not allow for dose modifications.
7.3.
Method of Treatment Assignment
This is a nonrandomized, open-label study. Clinic personnel will enroll the participant
into the study once a participant has met all eligibility requirements.
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).
 
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
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet/equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, 
where this is required by local laws, or is available upon request from GSK.
7.6.
Treatment Compliance

Participants will receive study treatment in the clinic directly from the investigator or 
designee, under medical supervision. The date and time of each dose 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 study site 
staff other than the person administering the study treatment. Study site 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:

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 Medications and Nondrug Therapies
The use of H1 antihistaminics not associated with QT prolongation is allowed (e.g., 
loratadine, cetirizine, ebastine, and fexofenadine). The use of topical, nonsystemic 
antibacterials and topical, nonsystemic antifungals is allowed throughout the study.
7.7.2.
Prohibited Medications and Nondrug Therapies
At the time of enrollment and/or during the study from the Baseline Visit through the 
TOC Visit, the participant is prohibited from use of the following medications and 
nondrug therapies:

An investigational product within 30 days or 5 half-lives, whichever is longer, of the 
Baseline Visit.

Treatment with other systemic antimicrobials or systemic antifungals within 1 week 
before study entry. Treatment with systemic fluconazole or other systemic antifungals 
per local standard of care is only allowed after all TOC Visit procedures have been 
completed.
 
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
Immunosuppressive therapy, including corticosteroid therapy (>40 mg/day 
prednisolone or equivalent for >1 week or ≥20 mg/day prednisolone or equivalent for 
>6 weeks; or prednisolone or equivalent ≥10 mg/day for >6 weeks).

QT-prolonging drugs or drugs with known TdP risk, per the www.crediblemeds.org 
“Known Risk of TdP” category, at the time of their Baseline Visit, which cannot be 
safely discontinued from the Baseline Visit to the TOC Visit. Details regarding 
website access are provided in the SRM. 
Note:  Crediblemeds.org categorizes drugs into 4 categories. The only category for 
exclusion in this study is the “Known Risk of TdP” category; participants taking 
drugs that meet criteria of other categories are NOT excluded from participation.

Strong CYP3A4 inhibitors (a list of strong CYP3A4 inhibitors is provided in the 
SRM).

Strong P-gp inhibitors (a list of strong P-gp inhibitors is provided in the SRM).

St John’s wort is not permitted from 14 days before study entry through the TOC 
Visit.

Prescription, nonprescription, or supplements that may impact UTI clinical or 
microbiological efficacy outcomes including, but not limited to, Uva ursi, cranberry 
tablets, phenazopyridine, nonsteroidal anti-inflammatory drugs including 
cyclooxygenase 2 inhibitors, uricosuric drugs (such as probenecid and 
sulfinpyrazone).

Antacids administration is not permitted within 2 hours before or after study 
treatment administration.
Due to the gepotidacin’s property of acetylcholinesterase inhibition, the concomitant use 
of succinylcholine or other nondepolarizing paralytic agents is also prohibited. Caution 
should be used in participants who have a condition requiring medication that may be 
exacerbated by acetylcholinesterase inhibition or neuromuscular blocking agents.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after they discontinue or 
complete the study (i.e., after the Follow-up Visit). Participants experiencing signs and 
symptoms suggestive of infection recurrence or relapse at the Follow-up Visit will be 
assessed and treated per the investigator’s judgement.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants may voluntarily discontinue study treatment at any time. The investigator 
may also, at his or her discretion, discontinue the participant from study treatment at any 
time and initiate appropriate alternative therapy. Reasons for study treatment 
discontinuation may include the following:

Adverse event
 
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
Protocol deviation

Termination of the study by GSK

Investigator discretion

Lack of efficacy
Note:  Pathogen identification or in vitro resistance of recovered uropathogens is not a 
reason for study treatment discontinuation.
The reason for study treatment discontinuation will be recorded in the electronic case
report form (eCRF). Participants who discontinue study treatment for the reasons above 
will not be considered withdrawn from the study and should attend the TOC and 
Follow-up Visits as applicable. 
If a participant discontinues during the on-treatment confinement period, Day 5 
assessments (Table 1) will be completed before the participant is discharged. The 
participant will be instructed to return for the TOC and Follow-up Visits.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in Figure 2 and Figure 3.
OR

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the best 
interest of the participant.
 
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Figure 2
Liver Chemistry Stopping and Increased Monitoring Algorithm
Figure 3
Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3 x ULN but <8 x ULN
For details of the required assessments if a participant meets the above criterion, refer to
Appendix 8.
 
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8.1.2.
QTc Stopping Criteria
A participant who meets the following bulleted criteria based on the average of triplicate
ECG readings will be withdrawn from study treatment:

QTc >500 msec OR uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For participants with underlying bundle-branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle-Branch Block
Discontinuation QTc with Bundle-Branch 
Block
<450 msec
>500 msec
450 to 480 msec
≥530 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB 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 averaged QTc values of triplicate ECGs obtained over a 
brief (e.g., 5- to 10-minute) recording period.
See Table 1 for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.3.
Temporary Discontinuation
Temporary discontinuation of study treatment is not allowed. Participants who 
discontinue study treatment will not be considered withdrawn from the study and should 
attend the TOC and Follow-up Visits.
8.1.4.
Rechallenge
8.1.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
 
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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.

Reasons for study withdrawal include:

Participant lost to follow-up

Participant withdrew consent

Termination of the study by GSK

Investigator discretion

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 Table 1 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. 
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. 
 
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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in Table 1 and Table 2. 

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 Table 1 and 
Table 2, 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 Table 1.

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. Vital signs
3. Pharmacokinetic and bacteriology urine specimen collection
4. Pharmacokinetic and safety blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

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.

Participants will be confined to the clinic from Baseline through the On-Therapy 
Visit. Participants will return to the clinic for the TOC and Follow-up Visits.
Note: At the discretion of the investigator, for emergency purposes only, participants 
may temporarily leave the clinic on study days without serial PK collections and only 
at times that do not interfere with required study assessments. Participants will be
instructed to follow the protocol restrictions. The investigator will ensure the 
participant is eligible to continue in the study upon return to the clinic. All doses of 
study treatment will be administered under site staff supervision in the clinic.
 
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The study will comprise the following visits and clinical procedures:
Clinic Confinement Visits

Baseline (Day -1 to Day 1 predose) Visit: The Baseline Visit includes a 
screening window of up to 24 hours from the time of informed consent to the first 
dose of study treatment. Baseline assessments performed during the screening 
window do not need to be repeated before study treatment is started unless 
indicated as a Day 1 predose assessment in Table 1. 
Baseline assessments will be performed, including the following (see Table 1):
o
Participants will provide a pretreatment clean-catch midstream urine 
sample for confirmation of pyuria (≥10 WBC/mm3 or the presence of 
leukocyte esterase) and/or nitrite per local laboratory procedures.
Note: Repeat baseline urine samples are allowed if contamination, defined 
as ≥10 squamous epithelial cells, is observed under microscopic 
evaluation. 
o
Site staff will record clinical signs and symptoms of acute cystitis
(Appendix 10), clinical laboratory samples will be collected, vital signs 
will be measured, and a triplicate 12-lead ECG and complete physical 
examination will be performed. 
o
Participants who meet the eligibility criteria in time to support the first 
dose of study treatment by 2 PM will be admitted to the clinic on Day 1 
and On-Therapy procedures will begin. Participants who meet the 
eligibility criteria past the first dose time limit of 2 PM may be admitted 
that same day (Day -1) or the next morning (Day 1); dosing will start on 
the morning of Day 1.
Day 1 predose assessments will be performed (see Table 1 and Table 2), including 
the following:
o
An ECG will be performed and vital signs will be measured if the baseline 
assessment was not within 4 hours of the first dose of study treatment.
o
Participants will provide a pretreatment clean-catch midstream urine 
sample for Gram stain, quantitative bacteriology culture, and antimicrobial 
susceptibility testing.
o
Predose blood and urine PK samples will be collected.
o
A stool microbiome specimen will be obtained from participants who 
consent to provide such specimens.
o
Vaginal and pharyngeal swab microbiome specimens will be obtained 
from participants who consent to provide such specimens.

On-Therapy (Day 1 to Day 5) Visit: Participants will be confined to the clinic 
during the 5-day On-Therapy Visit period, and will receive oral gepotidacin 
1500 mg BID for 5 days (total of 10 doses) starting with the first dose on Day 1. 
All doses of study treatment will be administered under site staff supervision and 
 
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all doses will be administered with food (i.e., standardized meals or snacks as 
applicable).
o
The first dose of gepotidacin must be administered by 2 PM on Day 1 and 
subsequent doses will be administered approximately every 12 hours.
o
Only if medically appropriate per the investigator’s judgement, for 
participants who are enrolled after 2 PM, the first dose of study treatment 
will be postponed until the next morning; nonexclusionary pain 
medication will be allowed for these participants before study treatment is 
started.
o
Study assessments and PK collections on Days 1 through 5 will be 
performed relative to the time-matched dose as determined by the first 
dose of study treatment (e.g., if the first dose is at 11 AM on Day 1 for a 
participant, then their time-matched dose on subsequent days will be at 
11 AM; or, if the first dose is at 1 PM on Day 1 for a participant, then their 
time-matched dose on subsequent days will be at 1 PM). 
o
On Day 1, a single 12-lead ECG will be performed at 2 hours after the first 
dose of study treatment. On Day 4, a single 12-lead ECG will be 
performed at predose and 2 hours postdose (at the same ECG time points 
as on Day 1) (see Table 2).
o
Vital sign measurements will be taken daily from Days 2 through 5.
o
On Days 2 through 5, before the time-matched dose, clinical signs and 
symptoms of acute cystitis will be recorded (Appendix 10) and 
participants will provide a clean-catch midstream urine sample for Gram 
stain, quantitative bacteriology culture, and antimicrobial susceptibility 
testing.
o
Blood and urine PK collection (see Table 1, Table 2, and Section 9.5.1).
o
On Day 3, clinical laboratory samples will be collected for hematology, 
chemistry, and urinalysis.
o
On Day 4, at predose and at approximately 2 hours postdose, cervical, 
rectal, and pharyngeal swab PK specimens will be obtained from 
participants who consent to provide such specimens.
o
On Day 5, a stool microbiome specimen will be obtained from participants 
who consent to provide such specimens. 
o
On Day 5, vaginal and pharyngeal swab microbiome specimens will be 
obtained from participants who consent to provide such specimens.
o
On Day 5, after all study procedures have been performed, including a 
predose clean-catch midstream urine sample for Gram stain, quantitative 
bacteriology culture, and antimicrobial susceptibility testing, predose PK 
sample collections, and safety assessments, participants will be discharged 
from the clinic. Participants should remain in the clinic to complete a total 
of 10 doses. Participants will be instructed to return for the TOC (Day 10 
to 13) and Follow-up (Day 28±3) Visits.
 
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o
At any time during the study, participants experiencing new or continuing 
signs and symptoms of acute cystitis will be assessed and treated per the 
investigator’s judgement. If a participant is switched to a different 
antibiotic before or during the TOC Visit, all TOC procedures should be 
completed before the other antibiotic is started. Any participant who 
discontinues from the PK portion of the study should return for the TOC 
and Follow-up Visits.
Outpatient Visits

TOC (Day 10 to 13) Visit: Participants will return for the TOC Visit 5 to 8 days 
after completion of study treatment. Clinical signs and symptoms of acute cystitis 
will be recorded (Appendix 10) and samples for Gram stain, quantitative 
bacteriology culture, and antimicrobial susceptibility testing will be collected. 
Safety assessments will be performed and AEs and concomitant medication use 
will be recorded.

Follow-up (Day 28) Visit: Participants will return for the Follow-up Visit 
28 (±3) days after the start of study treatment. Clinical signs and symptoms of 
acute cystitis will be recorded (Appendix 10) and samples for Gram stain, 
quantitative bacteriology culture, and antimicrobial susceptibility testing will be 
collected. Adverse events and concomitant medication use will be recorded. A 
stool microbiome specimen will be obtained from participants who consent to 
provide such specimens. Vaginal and pharyngeal swab microbiome specimens
will be obtained from participants who consent to provide such specimens.
9.1.
Efficacy Assessments
Efficacy is an exploratory assessment in this study. Please refer to Section 9.5 for the 
primary PK assessments. 
9.1.1.
Therapeutic Response Evaluation
Therapeutic response (success/failure) is a measure of the overall efficacy response. A
therapeutic success refers to participants who have been deemed both a “microbiological 
success” (see Section 9.1.2.1) and a “clinical success” (i.e., “responders”) (see 
Section 9.1.3). All other combinations (other than clinical success + microbiological 
success) will be deemed failures for therapeutic response. 
Therapeutic response will be determined by statistical programming for TOC and 
Follow-up Visits.
9.1.2.
Bacteriology Samples
At the Baseline Visit (predose on Day 1), a pretreatment, clean-catch midstream urine 
sample must be obtained from all participants for Gram stain, quantitative bacteriological 
culture, and in vitro antimicrobial susceptibility testing. For inclusion in the micro-ITT 
Population (Section 10.2), a baseline qualifying bacterial uropathogen (defined in 
Appendix 9) is required. At the On-Therapy (Days 2 through 5 only), TOC, and 
Follow-up Visits, a clean-catch midstream urine sample will be obtained and sent to a 
 
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central laboratory for Gram stain, quantitative bacteriological culture, and in vitro 
antimicrobial susceptibility testing. Identification and susceptibility testing of isolates 
recovered from urine specimens at all visits will also be conducted at a designated 
laboratory. Additional tests, as needed, to further characterize recovered isolates will also 
be performed by a designated laboratory. Instructions for sample collection, processing, 
and shipment are provided in the SRM and the laboratory manual. The study site should 
follow the Microbiology Procedures section of the laboratory manual to minimize 
potential contamination of the specimens.
9.1.2.1.
Microbiological Outcome and Response
Only those participants who have a qualifying bacterial uropathogen (defined in 
Appendix 9) identified at Baseline will be evaluated for microbiological outcome and 
response. The microbiological outcome and response to study treatment will be 
determined by prespecified programmed algorithm for each participant/pathogen.
The microbiological outcome is determined by comparing the baseline culture results to 
the culture results at each subsequent visit (see Table 3, Table 4, and Table 5). The 
corresponding microbiological response (success or failure) “by pathogen” is then 
assigned, as shown in Table 4 and Table 5. Participant level microbiological response is a 
measure of the combined “by pathogen” response(s). Participant level microbiological 
success refers to participants who have been deemed a “microbiological success” for all 
of their “by pathogen” microbiological responses. All other combinations (other than all 
“microbiological successes”) are deemed failures for participant level microbiological 
response. Participant level microbiological response will be determined by statistical 
programming.
 
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Table 3
Microbiological Outcome by Pathogen at the On-Therapy Visit
Defining Criteria
Outcome

Any participant that receives administration of an alternative or additional antibacterial therapy 
during the On-Therapy Visit will be assigned a microbiological outcome of “unable to 
determine” from that day onward. 
A quantitative urine culture taken during the 
On-Therapy Visit (Days 2 through 5 only) 
shows that the qualifying bacterial 
uropathogen recovered at Baseline is reduced 
to <103 CFU/mL
Microbiological eradication
A quantitative urine culture taken during the 
On-Therapy Visit (Days 2 through 5 only) 
shows that the qualifying bacterial 
uropathogen recovered at Baseline grows 
103 CFU/mL
Microbiological persistence
A determination of the baseline qualifying
bacterial uropathogen microbiological 
outcome cannot be made (e.g., no urine 
culture taken, sample lost, etc.)
Unable to determine
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture during the 
On-Therapy Visit (Days 2 through 5 only) in a 
participant who is a clinical failure or unable to 
determine
Superinfection
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the On-Therapy 
Visit (Days 2 through 5 only) in a participant
who is a clinical success
Colonization
CFU=colony-forming units.
 
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Table 4
Microbiological Outcome and Response by Pathogen at the 
Test-of-Cure Visit
Defining Criteria
Outcome
Response

Any participant that receives administration of an alternative or additional antibacterial therapy 
before the TOC Visit will be assigned a microbiological outcome of “unable to determine” and 
a response of “microbiological failure.”

Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit.
A quantitative urine culture taken at the TOC 
Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline 
to <103 CFU/mL
Microbiological 
eradication
Microbiological 
success
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to persist at the 
On-Therapy Visit, grows ≥103 CFU/mL
Microbiological 
persistence
Microbiological failure
A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and 
which was also shown to be eradicated at the 
On-Therapy Visit, grows ≥103 CFU/mL
Microbiological 
recurrence
Microbiological failure
A determination of the baseline qualifying 
bacterial uropathogen microbiological 
response cannot be made (e.g., no urine 
culture taken, sample lost, etc.)
Unable to determine
Microbiological failure
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the TOC Visit in a 
participant who is a clinical failure
New infection
Microbiological failure
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the TOC Visit in a 
participant who is a clinical success
Colonization
Microbiological 
success
CFU=colony-forming units; TOC=Test-of-Cure.
 
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Table 5
Microbiological Outcome and Response by Pathogen at the 
Follow-Up Visit
Defining Criteria
Outcome
Response

Any participant that receives administration of an alternative or additional antibacterial therapy 
before the Follow-up Visit will be assigned a microbiological outcome of “unable to determine” 
and a response of “microbiological failure.”

Participants considered microbiological failures at the TOC Visit will also be considered 
microbiological failures at the Follow-up Visit.
A quantitative urine culture taken at the 
Follow-up Visit shows reduction of the 
qualifying bacterial uropathogen recovered at 
Baseline to <103 CFU/mL
Sustained 
microbiological 
eradication
Microbiological 
success
A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows 103 CFU/mL
Microbiological 
recurrence
Microbiological failure
A determination of the baseline qualifying 
bacterial uropathogen microbiological 
response cannot be made (e.g., no urine 
culture taken, sample lost, etc.)
Unable to determine
Microbiological failure
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who is a clinical failure
New infection
Microbiological failure
A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who is a clinical success
Colonization
Microbiological 
success
CFU=colony-forming units; TOC=Test-of-Cure.
9.1.3.
Clinical Evaluation
Clinical signs and symptoms of acute cystitis will be recorded by site staff based on 
participant interview per the Schedule of Activities table (Table 1) using the scoring 
system in Appendix 10. At Baseline, the participant must present with at least 2 signs and 
symptoms and have a total cumulative symptom score ≥2. At TOC, success is recorded as 
normal presentation of signs and symptoms with a total cumulative symptom score of 
zero and no new signs and symptoms of the infection under study.
The investigator will determine the clinical outcome by comparing the signs and 
symptoms of acute cystitis at the On-Therapy (Days 2 through 5 only), TOC, and 
Follow-up Visits to those present at Baseline. Clinical response (success or failure) will 
be determined at the TOC and Follow-up Visits, as summarized in Table 6. Clinical 
success at the On-Therapy (Days 2 through 5 only), TOC, and Follow-up Visits is 
defined as resolution of signs and symptoms of acute cystitis present at Baseline (and no 
new signs and symptoms) and no use of other antimicrobial therapy. For participants who 
 
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are clinical failures, additional questions may be asked regarding their acute cystitis signs 
and symptoms.
Table 6
Clinical Outcome and Response at the On-Therapy, Test-of-Cure, 
and Follow-Up Visits
Defining Criteria
Outcome
(Investigator-Determined)a
Response
On-Therapy Visit (Days 2 through 5 only)b
Resolution of or improvement in signs and 
symptoms of acute cystitis present at 
Baseline (and no new signs and 
symptoms)
Improvement is based on investigator 
judgement and is defined as no worsening 
in signs and symptoms of acute cystitis 
present at Baseline and no new signs and 
symptoms of acute cystitis and no use of 
other antimicrobial therapy for the current 
infection.
Clinical success
Not applicable
Worsening of signs and symptoms of 
acute cystitis present at Baseline or new 
signs and symptoms of acute cystitis or 
use of other antimicrobial therapy for the 
current infection
Clinical failure
Not applicable
Refusal to consent to a clinical 
examination or failed to attend the 
On-Therapy Visit (Days 2 through 5 only)
Unable to determine
Not applicable
Test-of-Cure Visit
Resolution of signs and symptoms of acute 
cystitis present at Baseline (and no new 
signs or symptoms) and no use of other 
antimicrobial therapy 
Clinical success
Success
Persistence of signs and symptoms of 
infection, reappearance of signs and 
symptoms, or use of other antimicrobial 
therapy for the current infection
Participants considered clinical failures at 
the TOC Visit will also be considered 
clinical failures at the Follow-up Visit.
Clinical failure
Failure
Refusal to consent to a clinical 
examination or failed to attend the TOC
Visit
Unable to determine
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Defining Criteria
Outcome
(Investigator-Determined)a
Response
Follow-up Visit
Resolution of signs and symptoms of acute 
cystitis demonstrated at the TOC Visit 
persist at the Follow-up Visit (and no new 
signs and symptoms) and no use of other 
antimicrobial therapy
Sustained clinical success
Success
Persistence of signs and symptoms of 
infection, reappearance of signs and 
symptoms, or use of other antimicrobial 
therapy for the current infection
Clinical failure
Failure
Signs and symptoms of acute cystitis 
absent at the TOC Visit re-occur at the 
Follow-up Visit and no use of other 
antimicrobial therapy
Clinical recurrence
Failure
Refusal to consent to a clinical 
examination or failed to attend the 
Follow-up Visit
Unable to determine
Failure
TOC=Test-of-Cure.
a.
The investigator will determine the clinical outcome by comparing the signs and symptoms of acute cystitis at the 
On-Therapy (Days 2 through 5 only), TOC, and Follow-up Visits) to those present at Baseline.
b.
A participant showing some improvement at the On-Therapy Visit (Days 2 through 5 only) but less than what 
would be considered a clinical success should remain on study treatment per protocol, but study treatment may 
be discontinued per predefined criteria (see Section 8.1) or if there has been no clinical improvement; study 
treatment may be replaced by a different antibiotic, at the discretion of the investigator.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 treatment or from 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 Table 1.

All AEs will be collected from the start of treatment until the Follow-up Visit at 
the time points specified in Table 1.

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 eCRF not the AE section.
 
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
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek 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 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
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 9.2.5), 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 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study 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 board (IRB), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions according to local regulatory requirements and sponsor policy 
and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the IRB, if 
appropriate according to local requirements.
 
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9.2.5.
Adverse Events of Special Interest
Predefined AEs of special interest for this study are cardiovascular (CV) events and 
gastrointestinal events (see Section 3.3.1), which will be identified by a prespecified list 
of coded terms.
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding CV (including 
sudden cardiac death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific CV section of the eCRF within 1 week of receipt of a CV Event 
data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported.
9.2.7.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and through the Follow-up Visit.

If a pregnancy is reported, the investigator should inform GSK/PPD within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 6.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
There is no specific antidote for overdose with a bacterial topoisomerase inhibitor. In the 
event of a suspected overdose, it is recommended that the appropriate supportive clinical 
care should be instituted, as dictated by the participant’s clinical status.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
study treatment can no longer be detected systemically (at least 72 hours).
3. Obtain a plasma sample for PK analysis within 24 hours from the date of the last dose 
of study treatment if requested by the medical monitor (determined on a case-by-case 
basis).
 
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4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in Table 1.
9.4.1.
Physical Examinations

Physical examinations will be performed at the time points indicated in Table 1.

The physical examination will include assessments of the respiratory, CV, 
abdominal, gastrointestinal, neurological, and urogenital systems. Height and 
weight will only be measured and recorded at Baseline.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

Clinically significant changes from baseline or clinically significant new clinical 
signs will be reported as AEs.
9.4.2.
Vital Signs

Vital signs will be measured at the time points indicated in Table 1.

Vital signs will be measured in a semi-supine position and will include 
temperature, systolic and diastolic blood pressure, and pulse rate.

Vital sign measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available.

Vital sign measurements should be obtained before any blood draws scheduled on 
the same assessment day.

Clinically significant changes from baseline will be reported as AEs.
9.4.3.
Electrocardiograms

Triplicate 12-lead ECGs will be performed at Baseline and single 12-lead ECGs 
will be performed at other time points as indicated in Table 1 and Table 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 withdrawal criteria 
and additional QTc readings that may be necessary.

Electrocardiograms will be obtained in semi-supine position.
 
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
Electrocardiograms should be obtained before any vital sign measurements or 
blood draws scheduled on the same assessment day.

For triplicate ECGs, 3 individual ECG tracings should be obtained as closely as 
possible in succession, but no more than 2 minutes apart. The full set of triplicates 
should be completed in less than 4 minutes.

If additional ECGs are performed, clinically significant changes occurring during 
the study will be reported as AEs.

Refer to Section 8.1.2 for QTc withdrawal criteria and additional QTc readings 
that may be necessary.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to 
Table 1 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 participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and Table 1.
9.5.
Pharmacokinetics
9.5.1.
Blood and Urine Samples

Blood and urine samples for PK analysis of gepotidacin will be collected at the 
time points indicated in Table 1 and Table 2. The actual date and time of each 
sample collection will be recorded. The volume of blood required for each PK 
sample is approximately 3 mL. 

During the On-Therapy Visit, when the predose urine PK collection coincides 
with the predose urine bacteriology sample collection, a single urine sample of 
adequate volume may be collected and split into separate samples for PK and 
microbiological purposes. Note:  The date and time of the last dose taken before 
the predose PK collection will be recorded.

If a participant is switched to a different antibiotic before the end of study 
treatment, a final blood and urine PK sample should be collected prior to 
 
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administration of the different antibiotic. The actual date and time of each sample 
collection will be recorded. 

Collection, processing, storage, and shipping procedures for blood and urine PK 
samples are provided in the SRM and/or laboratory manual.

Plasma PK parameters for gepotidacin will include AUC(0-), Cmax, tmax, 
CLss/F, Ro, and C. Urine PK parameters for gepotidacin will include Ae 12h, 
Ae(t1-t2), fe%, CLr, and C.
9.5.2.
Cervical, Rectal, and Pharyngeal Swab Specimens

Cervical, rectal, and pharyngeal swab specimens for PK analysis of gepotidacin 
will be obtained at the time points shown in Table 1. The actual date and time of 
each sample collection will be recorded. Participation is optional. Participants 
who do not wish to participate in the tissue PK assessments may still participate in 
the study.

Specific details to ensure a similar physical site of the pharynx is used for swab 
collection are provided in the SRM and/or laboratory manual.

Collection, processing, storage, and shipping procedures for cervical, rectal, and
pharyngeal swab specimens are provided in the SRM and/or laboratory manual.
9.6.
Pharmacodynamics
9.6.1.
Pharmacokinetics/Pharmacodynamics 
Minimum inhibitory concentration values will be included for PK/PD analyses examining 
the potential relationship between gepotidacin exposure and clinical and microbiological 
outcome and/or response at the On-Therapy, TOC, and Follow-up Visits, if data permit.
9.6.2.
Microbiome Assessments

Stool specimens for potential microbiome assessment will be obtained at the time 
points shown in Table 1. The actual date and time of each sample collection will 
be recorded. Participation is optional. Participants who do not wish to participate 
in this microbiome assessment may still participate in the study.

Vaginal and pharyngeal swab specimens for potential microbiome assessment 
will be obtained at the time points shown in Table 1. The actual date and time of 
each sample collection will be recorded. Participation is optional. Participants 
who do not wish to participate in this microbiome assessment may still participate 
in the study.

Posttreatment stool, vaginal, and pharyngeal microbiome specimens should only 
be collected from participants who had a corresponding baseline specimen 
collected for each specimen type. 

Collection, processing, storage, and shipping procedures for microbiome 
specimens are provided in the SRM and/or laboratory manual.
 
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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.
Details on processes for collection and shipment and destruction of these samples can be 
found in Appendix 7.
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 endpoints are not 
evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
Full details of all data handling conventions and statistical analyses conducted for this 
study will be provided in the reporting and analysis plan (RAP).
Hypothesis
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the PK of gepotidacin in female participants with uncomplicated UTI.
10.1.
Sample Size Determination
The target sample size is approximately 20 participants who complete the study 
assessments through Day 5. The sample size for this study was based on feasibility; 
however, justification has been considered. Gepotidacin 1500 mg BID PK parameter 
estimates are available from a healthy volunteer study with repeat dosing for 14 days. For 
this dose of gepotidacin, the coefficient of variations for AUC(0-) and Cmax were 
21.9% and 40.3%, respectively, after the initial dose, and 29.6% and 31.1%, respectively,
at steady state. The upper limit of the 95% confidence interval for the mean of the PK 
parameters on both Days 1 and 4 for AUC(0-) and Cmax will be approximately within 
15% and 20%, respectively, above the point estimate of the corresponding PK parameter.
 
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10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
PK Population
Participants who receive at least 1 dose of gepotidacin and have 
evaluable plasma, urine, or tissue concentration data for 
gepotidacin. This primary analysis population will be used in the 
assessment and characterization of PK concentrations 
(summary tables and figures).
PK Parameter Population
All participants in the PK Population who received gepotidacin 
1500 mg BID through the completion of all PK collections for 
whom valid and evaluable plasma or urine PK parameters are 
derived for gepotidacin. This primary analysis population will be 
used in the assessment and characterization of PK parameters
(summary and analysis tables and figures).
Intent-to-Treat (ITT) 
Population
All participants assigned to study treatment.
Microbiological ITT 
(micro-ITT) Population
All participants assigned to study treatment who receive at least 
1 dose of gepotidacin have a qualifying baseline uropathogen 
(as defined in Appendix 9) from a quantitative bacteriological 
culture of a pretreatment clean catch midstream urine specimen. 
Safety
All participants who take at least 1 dose of gepotidacin.
10.3.
Statistical Analyses
10.3.1.
Pharmacokinetic Analyses
Endpoint
Statistical Analysis Methods
Primary

The primary endpoints of this study are PK-related. The analysis for the 
primary PK endpoints will be performed for the PK Parameter Population. 
Plasma concentrations of gepotidacin will be subjected to PK analyses using 
noncompartmental methods.

Based on the individual concentration-time data the following plasma 
parameters will be estimated: 
-
Day 1 (first dose): AUC(0-), Cmax, and tmax
-
Day 4 (repeat dose): AUC(0-), Cmax, tmax, CLss/F, and Ro
-
Days 1 through 5 (predose): C

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma
 
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Endpoint
Statistical Analysis Methods
gepotidacin PK parameter values will be summarized by study day, as 
appropriate. The Cwill be summarized and used to assess achievement of 
steady state. Gepotidacin plasma PK parameter estimates will be listed by 
participant and study day. Individual plasma gepotidacin PK parameter 
estimates will be plotted by day on linear scales.
Secondary

The analysis for the secondary PK endpoints will be performed for the PK 
Parameter Population. Urine concentrations of gepotidacin will be subjected 
to PK analyses using noncompartmental methods.

Based on the individual concentration-time data the following urine 
parameters will be estimated:
-
Day 1 (first dose): Ae 12h, Ae(t1-t2), fe%, and CLr 
-
Day 4 (repeat dose): Ae 12h, Ae(t1-t2), fe%, and CLr 
-
Days 1 through 5 (predose): C

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for urine 
gepotidacin PK parameter values will be summarized by study day, as 
appropriate. The Cwill be summarized and used to assess achievement of 
steady state. Gepotidacin urine PK parameter estimates will be listed by 
participant and study day. Individual urine gepotidacin PK parameter 
estimates will be plotted by day on linear scales
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. The severity of AEs and 
SAEs will be determined by the investigator according to the US National Institute of 
Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases 
(DMID) criteria for adult toxicity assessment [DMID, 2007] (Appendix 5). All reported 
AEs will be coded using MedDRA and summarized by system organ class and preferred 
terms. 
Endpoint
Statistical Analysis Methods
Secondary

The number and percentage of treatment-emergent AEs, study 
treatment-related AEs, deaths, SAEs, and AEs leading to study treatment or 
study withdrawal will be provided.

Treatment-emergent AEs will be summarized by severity.

Change from baseline over time in laboratory parameters, vital signs, and 
ECGs will be summarized with descriptive statistics.

The frequency of laboratory abnormality events along with the shift from 
baseline to the worst-case postbaseline value will be provided. Abnormal liver 
chemistry results will be determined using both change from baseline values 
and increases above the upper limit of normal. 
 
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Endpoint
Statistical Analysis Methods

The severity of specified AEs and laboratory abnormalities will be graded 
according to the modified DMID toxicity grading system (Appendix 5). Data 
will be tabulated and reported by absolute grade for Grade 2/4 and shift 
tables, as appropriate.
10.3.3.
Exploratory Analyses
Endpoint
Statistical Analysis Methods
Exploratory

Therapeutic response (number and percentage of participants with 
combined per-participant microbiological and clinical response) will be 
summarized by pathogen at the TOC Visit for the micro-ITT Population.

The microbiological outcome and response (number and percentage of 
participants with microbiological success) will be summarized by pathogen 
group on Days 2 through 5 (outcome only) and at the TOC and Follow-up 
Visits for the micro-ITT Population.

The clinical outcome and response (number and percentage of participants 
with resolution of signs and symptoms) will be summarized by pathogen 
group on Days 2 through 5 (outcome only) and at the TOC and Follow-up 
Visits for the micro-ITT Population.

Therapeutic response (number and percentage of participants with 
combined per-participant microbiological and clinical response) at the 
Follow-up Visit for the micro-ITT Population.

Gram stain, quantitative bacteriology culture, and in vitro antibacterial 
susceptibility testing results for urine specimens will be summarized at the 
Baseline Visit (predose on Day 1), on Days 2 through 5, and at the TOC and 
Follow-up Visits for the micro-ITT Population.

The PK/PD relationship between gepotidacin exposure and microbiological 
and clinical outcome and/or response at the On-Therapy, TOC, and 
Follow-up Visits may be explored, if data permit. This may include 
assessment of gepotidacin exposures correlated with baseline minimum 
inhibitory concentrations and/or decreases in the baseline pathogen 
CFU/mL.

Gepotidacin concentrations in cervical, rectal, and pharyngeal tissues will be 
summarized, if data permit.
The PK/PD exploratory analyses will be described in the RAP and may be presented 
separately from the main clinical study report. 
Stool, vaginal, and pharyngeal microbiome specimens may be analyzed to assess the 
number and proportion of relevant bacterial populations and metabolomics, as data 
permit. This analysis may be presented separately from the main clinical study report.
 
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10.3.4.
Interim Analyses
No interim analyses are planned for this study.
 
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11.
REFERENCES
Abreu AG, Marques SG, Monteiro-Neto V, Gonçalves AG. Extended-spectrum 
-lactamase-producing enterobacteriaceae in community-acquired urinary tract infections 
in Sãn Luís, Brazil. Braz J Microbiol. 2013;44(2):469-7.
Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the 
United States, 2013. https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-
threats-2013-508.pdf. Accessed 10-Mar-2017.
European Association of Urology (EAU). EAU guidelines on urological infections. 
https://uroweb.org/guideline/urological-infections/?type=pocket-guidelines. Accessed 
12-Jun-2017.
European Medicines Agency (EMA). Addendum to the guideline on the evaluation of 
medicinal products indicated for treatment of bacterial infections. CPMP/EWP/558/95 
rev 2. 24-Oct-2013.
Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. 
N Engl J Med. 2003;349(3):259-66.
Flamm RK, Sader HS, Farell DJ, Jones RN. Ceftazidime-avibactam and comparator 
agents tested against urinary tract isolates from a global surveillance program (2011).
Diagn Microbiol Infect Dis. 2014;80(3):233-8.
Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract infection: 
self-reported incidence and associated costs. Ann Epidemiol. 2000;10(8):509-15.
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic 
costs. Am J Med. 2002;113(Suppl 1A):5S-13S.
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 
2010;7(12):653-60.
GlaxoSmithKline. (Collegeville, PA). Gepotidacin investigator’s brochure. 09-Feb-2018. 
Document Number CM2010/00033/05.
GOV.UK. Management and treatment of common infections. Antibiotic guidance for
primary care: for consultation and local adaption – May 2017. 
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/612744/M
anaging_common_infections_summary_tables.pdf. Accessed 12-Jun-2017.
Gupta K, Hooton TM, Miller L; Uncomplicated UTI IDSA Guideline Committee. 
Managing uncomplicated urinary tract infectionmaking sense out of resistance data. 
Clin Infect Dis. 2011a;53(10):1041-2.
Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International 
clinical practice guidelines for the treatment of acute uncomplicated cystitis and 
pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America 
 
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and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 
2011b;52(5):e103-20.
Ho PL, Poon WW, Loke SL, Leung MS, Chow KH, Wong RC, et al; COMBAT study 
group. Community emergence of CTX-M type extended-spectrum -lactamases among 
urinary Escherichia coli from women. J Antimicrob Chemother. 2007;60(1):140-4.
Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med.
2012;366(11):1028-37.
Johnson JR, Nicolas-Chanoine MH, DebRoy C, Castanheira M, Robicsek A, Hansen G, 
et al. Comparison of Escherichia coli ST131 pulsotypes, by epidemiologic traits, 
1967-2009. Emerg Infect Dis. 2012;18(4):598-607.
Lob SH, Nicolle LE. Hoban DJ, Kazmierczak KM, Badal RE, Sahm DF. Susceptibility 
patterns and ESBL rates of Escherichia coli from urinary tract infections in Canada and 
the United States, SMART 2010-2014. Diagn Microbiol Infect Dis. 2016;85(4):459-65.
Nicolas-Chanoine MH, Bertrand X, Madec JY. Escherichia coli ST131, an intriguing 
clonal group. Clin Microbiol Rev. 2014;27(3):543-74.
Oteo J, Bautista V, Lara N, Cuevas O, Arroyo M, Fernández S, et al; Spanish 
ESBL-EARS-Net Study Group. Parallel increase in community use of fosfomycin and 
resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing 
Escherichia coli. J Antimicrob Chemother. 2010;65(11):2459-63.
Peirano G, Richardson D, Nigrin J, McGreer A, Loo V, Toye B, et al. High prevalence of 
ST131 isolates producing CTX-M-15 and CTX-M-14 among extended-spectrum-beta-
lactamase-producing Escherichia coli isolates from Canada. Antimicrob Agents 
Chemother. 2010;54(3):1327-30. 
Sanchez GV, Babiker A, Master RN, Luu T, Mathur A, Bordon J. Antibiotic resistance 
among urinary isolates from female outpatients in the United States in 2003 and 2012. 
Antimicrob Agents Chemother. 2016;60(5):2680-3.
Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of 
urinary Escherichia coli isolates among US outpatients from 2000 to 2010. Antimicrob 
Agents Chemother. 2012;56(4):2181-83.
Schito GC, Naber KG, Botto H, Palou J, Mazzei T, Gualco L, et al. The ARESC study: 
an international survey on the antimicrobial resistance of pathogens involved in 
uncomplicated urinary tract infections. Int J Antimicrob Agents. 2009;34(5):407-13.
Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J 
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Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, et al. Comparison of 
ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute 
uncomplicated pyelonephritis in women: a randomized trial. JAMA. 
2000;283(12):1583-90.
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Draft guidance for 
industry. Uncomplicated urinary tract infections — developing antimicrobial drugs for 
treatment. https://www.fda.gov/ohrms/dockets/98fr/2567dft.pdf. Last updated July 1998. 
Accessed 29-Mar-2017.
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Guidance for industry. 
Complicated urinary tract infections: developing drugs for treatment. 
https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070981.pdf. Last updated 
February 2015. Accessed 29-Mar-2017.
US National Institute for Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases. Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table. Draft. https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf. 
Last updated November 2007. Accessed 10-Mar-2017.
World Health Organization (WHO). Antimicrobial resistance global report on 
surveillance, 2014. 
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29-Mar-2017.
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guide research, discovery, and development of new antibiotics. 2017. 
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ET_NM_WHO.pdf?ua=1. Accessed 12-Apr-2017.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ABSSSI
acute bacterial skin and skin structure infection
AE
adverse event
Ae 12h
amount of drug excreted over 12 hours
Ae(t1-t2)
amount 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 zero 
(predose) over the dosing interval
BID
twice daily
CDC
Centers for Disease Control and Prevention 
CFU
colony-forming units
CLr
renal clearance
CLss/F
apparent steady state clearance
Cmax
maximum plasma concentration
C
predose concentration (trough)
CV
cardiovascular 
CYP3A4
cytochrome P450 enzyme 3A4
DMID
Division of Microbiology and Infectious Diseases
ECG
electrocardiogram
eCRF
electronic case report form 
EMA
European Medicines Agency 
ESBL
extended-spectrum -lactamase
F
Fahrenheit
fAUC/MIC
ratio of the area under the free-drug concentration-time 
curve to minimum inhibitory concentration over 24 hours
FDA
Food and Drug Administration 
fe%
percentage of the given dose of drug excreted in urine
GSK
GlaxoSmithKline 
HIV
human immunodeficiency virus
IB
investigator’s brochure 
ICF
informed consent form 
INR
international normalized ratio
IRB
institutional review board
ITT
Intent-to-Treat 
kg
kilogram
m
meter
MDR
multidrug-resistant
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram
MIC
minimum inhibitory concentration
micro-ITT
Microbiological Intent-to-Treat 
min
minute
 
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mL
milliliter
mm
millimeter
msec
millisecond
P-gp
P-glycoprotein 
PD
pharmacodynamic
PK
pharmacokinetic 
QTc
corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett
QTcF
QT interval corrected for heart rate according to Fridericia 
RAP
reporting and analysis plan 
Ro
accumulation ratio
SAE
serious adverse event
SRM
Study Reference Manual 
ST
sequence type
TdP
torsades de points 
tmax
time of occurrence of Cmax
TOC
Test-of-Cure 
TMP-SXT
trimethoprim-sulfamethoxazole
µg
microgram
ULN
upper limit of normal
UTI
urinary tract infection
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman of childbearing potential 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
MedDRA
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by the designated laboratory.

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 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC Indices:
MCV
MCH
WBC Count with
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical 
Chemistrya
Blood urea 
nitrogen
Potassium
AST/SGOT
Total and direct 
bilirubin
Creatinine
Sodium
ALT/SGPT
Total protein
Glucose 
nonfasting
Calcium
Alkaline 
phosphatase
Albumin
Chloride
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, nitrite, and leukocyte esterase by 
dipstick

Microscopic examination (if blood or protein is abnormal)
 
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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

A serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and 
benzodiazepines)

Serum hCG pregnancy test (as needed for women of childbearing 
potential)b

Serology (HBsAg, hepatitis C virus antibody, and HIV). If serology testing 
was performed within 3 months prior to the first dose of study treatment and 
results were positive, testing at Baseline is not required. If testing was 
performed within 3 months and any result was negative, testing at Baseline 
is required.
The results of each test must be entered into the eCRF.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report form; HBsAg=hepatitis 
B surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=while blood cell.
a.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.1 and Appendix 8. All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as a serious adverse 
event.
b.
For women of childbearing potential, a negative serum pregnancy test is needed for eligibility at Baseline. A urine 
pregnancy test may be performed on Day 5 and at the Test-of-Cure Visit.
 
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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 ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB by the 
investigator and reviewed and approved by the IRB 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 annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC

Notifying the IRB of an SAE or other significant safety findings as 
required by IRB procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, 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 
 
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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB 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.
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 members, and by inspectors from regulatory 
authorities.
Committees Structure
To protect the safety interests of participants, a GlaxoSmithKline (GSK) Safety Review 
Team will review safety data in real time on a regular basis throughout study conduct. 
Data reviews will include but are not limited to the following participants: medical 
monitor, safety team lead, statistician, clinical team lead, and data quality lead. 
Any written documentation regarding key decisions made by the review teams will be 
promptly distributed to participating investigator and IRB.
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 
 
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individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed case report 
form (CRF) or electronic CRF (eCRF) unless transmitted to the sponsor or 
designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered into the eCRF. 

The investigator must permit study-related monitoring, audits, IRB 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 eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

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 
 
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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 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 Study Reference 
Manual.
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 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: 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, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study 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.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
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 
 
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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
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).
An 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
 
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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 
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.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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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 severity of AEs and SAEs will be determined by the investigator according to the 
US National Institute of Allergy and Infectious Diseases Division of Microbiology 
and Infectious Diseases criteria for adult toxicity assessment [DMID, 2007] and 
(Appendix 5).
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 (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
 
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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.

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 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 study site can report this information to the medical monitor 
or SAE coordinator by telephone.

Contacts for SAE reporting can be found in SRM.
 
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12.5.
Appendix 5: Division of Microbiology and Infectious 
Diseases Adult Toxicity Tables for Adverse Event 
Assessment
ESTIMATING SEVERITY GRADE: For abnormalities NOT found elsewhere in the 
Toxicity Tables, use the scale below to estimate grade of severity:
GRADE 1
Mild
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required
GRADE 2
Moderate
Mild to moderate limitation in activity – some assistance 
may be needed; no or minimal medical 
intervention/therapy required
GRADE 3
Severe
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalizations possible
GRADE 4
Life-threatening
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, 
hospitalization or hospice care probable
SERIOUS OR LIFE-THREATENING AEs: ANY clinical event deemed by the 
investigator to be serious or life-threatening should be considered a grade 4 event. 
Clinical events considered to be serious or life-threatening include, but are not limited to: 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, and severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, National Cancer 
Institute’s Common Toxicity Criteria, and World Health Organization) have been 
adapted for use by the Division of Microbiology and Infectious Diseases (DAIDS) 
and modified to better meet the needs of participants in Division of Microbiology and 
Infectious Diseases (DMID) trials.

For parameters not included in the following Toxicity Tables, study sites should refer 
to the “Guide for Estimating Severity Grade” located above.

Criteria are generally grouped by body system.
Some protocols may have additional protocol specific grading criteria, which will 
supersede the use of these tables for specified criteria.
 
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 to 10.5 gm/dL
8.0 to 9.4 gm/dL
6.5 to 7.9 gm/dL
<6.5 gm/dL
Absolute Neutrophil Count
1000 to 1500 /mm3
750 to 999 /mm3`
500 to 749 /mm3
<500 /mm3
Platelets
75,000 to 99,999 /mm3
50,000 to 74,999 /mm3
20,000 to 49,999 /mm3
<20,000 /mm3
White Blood Cells
11,000 to 13,000 /mm3
13,000 to 15,000 /mm3
15,000 to 30,000 /mm3
>30,000 or <1000 /mm3
% Polymorphonuclear Leukocytes + 
Band Cells
>80%
90 to 95%
>95%
N/A
Abnormal Fibrinogen
Low: 100 to 200 mg/dL
High: 400 to 600 mg/dL
Low: <100 mg/dL
High: >600 mg/dL
Low: <50 mg/dL
High: N/A
Fibrinogen associated with gross bleeding or 
with disseminated coagulation
Fibrin Split Product
20 to 40 mcg/mL
41 to 50 mcg/mL
51 to 60 mcg/dL
>60 mcg/dL
Prothrombin Time (PT)
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated Partial Thromboplastin (APTT)
1.01 to 1.66 ULN
1.67 to 2.33 ULN
2.34 to 3 ULN
>3 ULN
Methemoglobin
5.0 to 9.9%
10.0 to 14.9%
15.0 to 19.9%
>20%
N/A=not applicable; ULN=upper limit of normal. 
 
 
 
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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to 135 mEq/L
123 to 129 mEq/L
116 to 122 mEq/L
<116 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypernatremia
146 to 150 mEq/L
151 to 157 mEq/L
158 to 165 mEq/L
>165 mEq/L or abnormal sodium with mental 
status changes or seizures
Hypokalemia
3.0 to 3.4 mEq/L
2.5 to 2.9 mEq/L
2.0 to 2.4 mEq/L or intensive 
replacement therapy of 
hospitalization required
<2.0 mEq/L or abnormal potassium with
paresis, ileus, or life-threatening arrhythmia
Hyperkalemia
5.6 to 6.0 mEq/L
6.1 to 6.5 mEq/L
6.6 to 7.0 mEq/L
>7.0 mEq/L or abnormal potassium with
life-threatening arrhythmia
Hypoglycemia
55 to 64 mg/dL
40 to 54 mg/dL
30 to 39 mg/dL
<30 mg/dL or abnormal glucose with mental 
status changes or coma
Hyperglycemia
(nonfasting and no prior 
diabetes)
116 to 160 mg/dL
161 to 250 mg/dL
251 to 500 mg/dL
>500 mg/dL or abnormal glucose with
ketoacidosis or seizures
Hypocalcemia
(corrected for albumin)
8.4 to 7.8 mg/dL
7.7 to 7.0 mg/dL
6.9 to 6.1 mg/dL
<6.1 mg/dL or abnormal calcium with
life-threatening arrhythmia or tetany
Hypercalcemia
(corrected for albumin)
10.6 to 11.5 mg/dL
11.6 to 12.5 mg/dL
12.6 to 13.5 mg/dL
>13.5 mg/dL or abnormal calcium with
life-threatening arrhythmia
Hypomagnesemia
1.4 to 1.2 mEq/L
1.1 to 0.9 mEq/L
0.8 to 0.6 mEq/L
<0.6 mEq/L or abnormal magnesium with
life-threatening arrhythmia
Hypophosphatemia
2.0 to 2.4 mg/dL
1.5 to 1.9 mg/dL or 
replacement Rx required
1.0 to 1.4 mg/dL
intensive therapy or hospitalization 
required
<1.0 mg/dL or abnormal phosphate with
life-threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any increase in 
other liver function test)
1.1 to <1.25 ULN
1.25 to <1.5 ULN
1.5 to 1.75 ULN
>1.75 ULN
Hyperbilirubinemia (when other 
liver function tests are in the 
normal range)
1.1 to <1.5 ULN
1.5 to <2.0 ULN
2.0 to 3.0 ULN
>3.0 ULN
Blood urea nitrogen 
1.25 to 2.5 ULN
2.6 to 5 ULN
5.1 to 10 ULN
>10 ULN
Hyperuricemia (uric acid)
7.5 to 10.0 mg/dL
10.1 to 12.0 mg/dL
12.1 to 15.0 mg/dL
>15.0 mg/dL
Creatinine
1.1 to 1.5 ULN
1.6 to 3.0 ULN
3.1 to 6.0 ULN
>6 ULN or dialysis required
Rx=therapy; ULN=upper limit of normal.
 
 
 
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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Aspartate aminotransferase (AST)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alanine aminotransferase (ALT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Gamma to glutamyl transferase (GGT)
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Alkaline Phosphatase
1.1 to <2.0 ULN
2.0 to <3.0 ULN
3.0 to 8.0 ULN
>8.0 ULN
Amylase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
Lipase
1.1 to 1.5 ULN
1.6 to 2.0 ULN
2.1 to 5.0 ULN
>5.1 ULN
ULN=upper limit of normal.
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+ or
200 mg to 1 gm loss/day
2 to 3+ or
1 to 2 gm loss/day
4+ or
2 to 3.5 gm loss/day
Nephrotic syndrome or
>3.5 gm loss/day
Hematuria
Microscopic only
<10 RBC/hpf
Gross, no clots
>10 RBC/hpf
Gross, with or without clots,
or red blood cells casts
Obstructive or 
required transfusion
HPF=high powered field; RBC=red blood cells.
 
 
 
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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac rhythm
N/A
Asymptomatic, transient signs, no 
Rx required
Recurrent/persistent; symptomatic 
Rx required
Unstable dysrhythmia; 
hospitalization and treatment 
required
Hypertension
Transient increase >20 mm/Hg;
no treatment 
Recurrent, chronic increase 
>20 mm/Hg;
treatment required 
Acute treatment required; 
outpatient treatment or 
hospitalization possible 
End organ damage or 
hospitalization required 
Hypotension
Transient orthostatic hypotension 
with heart rate increased by 
<20 beat/min or decreased by 
<10 mmHg systolic BP.
No treatment required
Symptoms due to orthostatic 
hypotension or BP decreased by 
<20 mmHg systolic; correctable with 
oral fluid treatment
Requires IV fluids;
no hospitalization required
Mean arterial pressure <60 mmHg 
or end organ damage or shock;
requires hospitalization and 
vasopressor treatment
Pericarditis
Minimal effusion
Mild/moderate asymptomatic 
effusion, no treatment
Symptomatic effusion; pain; EKG 
changes
Tamponade; pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
Microscopic/occult
Mild, no transfusion
Gross blood loss; 
1 to 2 units transfused
Massive blood loss; >3 units 
transfused
BP=blood pressure; IV=intravenous; EKG=electrocardiogram; N/A=not applicable; Rx=therapy.
RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
Transient; no treatment
Persistent cough; treatment responsive
Paroxysmal cough; uncontrolled with treatment
N/A
Bronchospasm, 
Acute
Transient; no treatment; 
FEV1 70 to 80% of peak flow
Requires treatment; normalizes with 
bronchodilator; FEV1 50 to 70% of peak 
flow
No normalization with bronchodilator; FEV1 25 
to 50% of peak flow; or retractions present
Cyanosis: FEV1 <25% of peak 
flow; or intubation necessary
Dyspnea
Dyspnea on exertion
Dyspnea with normal activity
Dyspnea at rest
Dyspnea requiring oxygen 
therapy
FEV1=forced expiratory volume in 1 second; N/A=not applicable.
 
 
 
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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
Mild or transient; maintains 
reasonable intake
Moderate discomfort; intake 
decreased significantly; some 
activity limited
No significant intake; requires IV fluids
Hospitalization required
Vomiting
1 episode in 24 hours
2 to 5 episodes in 24 hours
>6 episodes in 24 hours or needing IV 
fluids
Physiologic consequences requiring 
hospitalization or requiring parenteral nutrition
Constipation
Requiring stool softener or 
dietary modification
Requiring laxatives
Obstipation requiring manual evacuation 
or enema
Obstruction or toxic megacolon
Diarrhea
Mild or transient; 3 to 
4 loose stools/day or mild 
diarrhea lasting <1 week
Moderate or persistent; 5 to 
7 loose stools/day or diarrhea 
lasting >1 week
>7 loose stools/day or bloody diarrhea; or 
orthostatic hypotension or electrolyte 
imbalance or >2L IV fluids required
Hypotensive shock or physiologic 
consequences requiring hospitalization
Oral discomfort/
Dysphagia
Mild discomfort; no difficulty 
swallowing
Some limits on eating/drinking
Eating/talking very limited; unable to 
swallow solid foods
Unable to drink fluids; requires IV fluids
IV=intravenous.
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
Slight incoordination 
dysdiadochokinesis
Intention tremor, dysmetria, slurred 
speech; nystagmus
Locomotor ataxia
Incapacitated
Psychiatric
Mild anxiety or depression
Moderate anxiety or depression; 
therapy required; change in normal 
routine
Severe mood changes requiring therapy; 
or suicidal ideation; or aggressive 
ideation
Acute psychosis requiring 
hospitalization; or suicidal 
gesture/attempt or hallucinations
Muscle strength
Subjective weakness; no objective 
symptoms/signs
Mild objective signs/symptoms; no 
decrease in function
Objective weakness; function limited
Paralysis
Paresthesia
(burning, tingling, etc.)
Mild discomfort; no treatment 
required
Moderate discomfort; non- narcotic 
analgesia required
Severe discomfort; or narcotic analgesia 
required with symptomatic improvement
Incapacitating; or not responsive 
to narcotic analgesia
Neurosensory
Mild impairment in sensation 
(decreased sensation, e.g., 
vibratory, pinprick, hot/cold in great 
toes) in focal area or symmetrical 
distribution; or change in taste, 
smell, vision, and/or hearing
Moderate impairment (moderately 
decreased sensation, e.g., 
vibratory, pinprick, hot/cold to 
ankles) and/or joint position or mild 
impairment that is not symmetrical
Severe impairment (decreased or loss of 
sensation to knees or wrists) or loss of 
sensation of at least moderate degree in 
multiple different body areas (i.e., upper 
and lower extremities)
Sensory loss involves limbs and 
trunk; paralysis; or seizures
 
 
 
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MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia 
(joint pain)
Mild pain not interfering with function
Moderate pain, analgesics and/or pain 
interfering with function but not with ADL
Severe paid; pain and/or analgesics 
interfering with ADL
Disabling pain
Arthritis
Mild pain with inflammation, erythema or 
joint swelling, but not interfering with 
function
Moderate pain with inflammation, erythema or 
joint swelling; interfering with function but not 
with ADL
Severe pain with inflammation, erythema 
or joint swelling, and interfering with ADL
Permanent and/or 
disabling joint 
destruction
Myalgia
Myalgia with no limitation of activity
Muscle tenderness (at other than injection site) 
or with moderate impairment of activity
Severe muscle tenderness with marked 
impairment of activity
Frank myonecrosis
ADL=activities of daily living.
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
Erythema; pruritus
Diffuse, maculo-papular rash, dry 
desquamation
Vesiculation or moist 
desquamation or ulceration
Exfoliative dermatitis, mucous membrane 
involvement or erythema, multiforme or suspected 
Stevens-Johnson or necrosis requiring surgery
Induration
<15 mm
15 to 30 mm
>30 mm
N/A
Erythema
<15 mm
15 to 30 mm
>30 mm
N/A
Edema
<15 mm
15 to 30 mm
>30 mm
N/A
Rash at injection site
<15 mm
15 to 30 mm
>30 mm
N/A
Pruritus
Slight itching at injection site
Moderate itching at injection extremity
Itching over entire body
N/A
N/A=not applicable.
 
 
 
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic reaction
Pruritus without rash
Localized urticarial
Generalized urticarial; angioedema
Anaphylaxis
Headache
Mild, no treatment required
Transient, moderate; treatment 
required
Severe; responds to initial narcotic 
therapy
Intractable; requires repeated 
narcotic therapy
Fever: oral
37.7 to 38.5C or 100.0 to 101.5F
38.6 to 39.5C or 101.6 to 102.9F
39.6 to 40.5C or 103 to 105F
>40C or >105F
Fatigue
Normal activity reduced <48 hours
Normal activity decreased 25 to 50%; 
>48 hours
Normal activity decreased >50%; 
cannot work
Unable to care for self
 
 
 
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12.6.
Appendix 6: 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
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 8 in addition to using a male condom during intercourse. 
 
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Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

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.)
WOCBP=woman of childbearing potential.
a.
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. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the 
treatment period and through the Test-of-Cure (Day 10 to 13) Visit.
 
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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing will be performed on Day 5 and at the Test-of-Cure 
(Day 10 to 13) Visit, 5 to 8 days after the last dose of study treatment and as required 
locally 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 25 mIU/mL, will be performed using the test 
kit provided by the designated laboratory
Collection of Pregnancy Information
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 
GlaxoSmithKline (GSK)/PPD within 24 hours of learning of a participant’s 
pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy 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 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating will discontinue 
study treatment.
 
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12.7.
Appendix 7: 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 
institutional review board allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to gepotidacin or uncomplicated 
urinary tract infections and related diseases. They may also be used to develop 
tests/assays including diagnostic tests) related to and uncomplicated urinary tract 
infections. Genetic research may consist of the analysis of 1 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) or uncomplicated urinary tract infections continues but no longer than 
15 years after the last participant last visit or other period as per local requirements.
 
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12.8.
Appendix 8: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase IIa liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
Phase IIa liver chemistry stopping criteria and required follow-up assessments 
Liver Chemistry Stopping Criteria 
ALT Absolute
ALT 8 x ULN
ALT Increase
ALT 5 x ULN but <8 x ULN persists for 2 weeks
ALT 3 x ULN but <5 x ULN persists for 4 weeks
Bilirubina,b
ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin) 
INRb
ALT 3 x ULN and INR >1.5, if INR measured
Cannot 
Monitor
ALT 5 x ULN but <8 x ULN and cannot be monitored weekly for 2 weeks
ALT 3 x ULN but <5 x ULN and cannot be monitored weekly for 4 weeks
Symptomaticc
ALT 3 x ULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow-up Assessments 
Actions
Follow-up Assessments

Immediately discontinue study treatment 

Report the event to GSK/PPD within 
24 hours

Complete the liver event eCRF and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAEb

Perform liver event follow-up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below)

Do not restart/rechallenge participant with 
study treatment 

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and continue participant in the 

Viral hepatitis serologyd

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen), 
quantitative hepatitis B DNA, and 
hepatitis delta antibodye

Obtain blood sample for PK analysis, 
within 24 hours after last dosef

Serum creatine phosphokinase and 
lactate dehydrogenase

Fractionate bilirubin, if total bilirubin 
 
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study for any protocol-specified follow-up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 hours

Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 
24 to 72 hours 

Monitor participants weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline
2 x 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 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake eCRF page
For bilirubin or INR criteria:

Antinuclear antibody, antismooth muscle 
antibody, type 1 antiliver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and/or liver biopsy to evaluate liver 
disease; complete liver imaging and/or 
liver biopsy eCRFs.
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report 
form; GSK=GlaxoSmithKline; HPLC=high-performance liquid chromatography; IgM=immunoglobulin M; 
INR=international normalized ratio; PK=pharmacokinetic; SAE=serious adverse event; ULN=upper limit of normal.
a.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3 x ULN and bilirubin 2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b.
All events of ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin) or ALT 3 x 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.
 
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c.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).
d.
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.
e.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction of 
hepatitis D RNA virus (where needed) [Le Gal, 2005].
f.
The PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Study Reference Manual. 
Phase III liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5 x ULN and <8 x ULN and
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3 x ULN and <5 x ULN and
bilirubin <2 x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK/PPD medical monitor within 
24 hours of learning of the abnormality to discuss 
participant safety. 

Participant can continue study treatment 

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize, or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5 x ULN and
<8 x ULN to ≥3 x ULN but <5 x ULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3 x ULN and 
bilirubin <2 x ULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; GSK=GlaxoSmithKline; ULN=upper limit of normal.
References
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2009;37:1779-1784.
Le Gal F, Gordien E, Affolabi D, et al. Quantification of hepatitis delta virus RNA in 
serum by consensus real-time PCR indicates different patterns of virological response to 
interferon therapy in chronically infected patients. J Clin Microbiol. 2005;43:2363-2369. 
 
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12.9.
Appendix 9: Algorithm for the Microbiological Intent-to-Treat 
Population
Participants will be included in the Microbiological Intent-to-Treat Population if they 
receive at least 1 dose of gepotidacin and have a qualifying bacterial uropathogen 
(defined in Figure 4) at Baseline (predose on Day 1) from a quantitative bacteriology 
culture of a pretreatment clean-catch midstream urine specimen. 
The algorithm for determining microbiological evaluable participants based on 
microbiology laboratory quantitative culture results is provided in Figure 4.
Figure 4
Baseline Algorithm for the Microbiological Intent-to-Treat Population
CFU=colony-forming units; micro-ITT=Microbiological Intent-to-Treat.
References
McCarter YS, Burd EM, Hall GS, Zervos M. Cumitech 2C, Laboratory diagnosis of 
urinary tract infections. Coordinating ed., Sharp SE. Washington, DC; ASM Press; 
2009.1-26.
Chan WW. Chapter 3.12: Urine cultures. In: Leber AL, editor. Clinical microbiology 
procedures handbook, 4th ed. Vol 1-3. Washington, DC; ASM Press; 2016.
 
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12.10.
Appendix 10: Clinical Signs and Symptoms Scoring for 
Acute Cystitis
Acute cystitis clinical signs and symptoms will be scored as follows:
Clinical Signs 
and Symptoms
None
Participants’ 
normal clinical 
presentation 
prior to current 
infection
Mild
Symptom is 
easily tolerated, 
causing minimal 
discomfort and 
not interfering 
with everyday 
activities
Moderate
Symptom is 
sufficiently 
discomforting to 
interfere with 
normal everyday 
activities
Severe
Symptom 
prevents normal 
everyday 
activities
SCORE 0
SCORE 1
SCORE 2
SCORE 3
Dysuria
Frequency
Urgency
Lower abdominal 
or suprapubic pain
Scores will be recorded by the investigator or a qualified designee. When possible, the 
same scorer will be used at all assessment time points.
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
206899
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase IIa Single-Center, 
Open-Label Study Evaluating the Pharmacokinetics of 
Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult 
Female Participants With Uncomplicated Urinary Tract 
Infection (Acute Cystitis)
Compound Number 
:
GSK2140944
Effective Date 
:
14-NOV-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 206899.

This RAP is intended to describe the full analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
14-NOV-2018
Email
Biostatistician (Early Development Services, 
PPD)
14-NOV-2018
Email
Senior Pharmacokineticist (Biostatistics, PPD)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals:
Approver
Date
Approval Method
29-OCT-2018
Email
Principal Statistician (Infectious Disease, 
Clinical Statistics)
25-OCT-2018
Email
Research Programming (Infectious Disease, 
Clinical Statistics)
24-OCT-2018
Email
SM Executive Medical Director (Infectious 
Disease, RD ID)
26-OCT-2018
Email
Clinical Development Director (Infectious
Disease, RD PCPS Therapy Area Delivery ID)
26-OCT-2018
Email
Director (Clinical Pharmacology)
25-OCT-2018
Email
Director (GCSP Medical SERM US)
26-OCT-2018
Email
Senior Scientific Investigator (Infectious 
Disease, RD ID)
29-OCT-2018
Email
Manager (Clinical Data Management)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
28-OCT-2018
Email
Director (Infectious Disease, Clinical Statistics, 
GSK)
29-OCT-2018
Email
Programming Manager (Infectious Disease, 
Clinical Programming, GSK)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................13
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
7.
PHARMACOKINETIC ANALYSES.........................................................................16
7.1.
Primary Pharmacokinetic Analyses.............................................................16
7.1.1.
Endpoint / Variables.....................................................................16
7.1.1.1.
Drug Concentration Measures....................................16
7.1.1.2.
Derived Pharmacokinetic Parameters.........................16
7.1.2.
Summary Measure ......................................................................17
7.1.3.
Population of Interest...................................................................17
7.1.4.
Statistical Analysis / Methods.......................................................17
7.1.4.1.
Statistical analysis of Pharmacokinetic 
Parameters.................................................................17
7.2.
Secondary Pharmacokinetic Analyses........................................................18
7.2.1.
Endpoint / Variables.....................................................................18
7.2.1.1.
Drug Concentration Measures....................................18
7.2.1.2.
Derived Urine Pharmacokinetic Parameters ...............18
7.2.2.
Summary Measure ......................................................................19
7.2.3.
Population of Interest...................................................................19
7.2.4.
Statistical Analyses / Methods .....................................................19
7.3.
Exploratory Pharmacokinetic Analyses .......................................................19
7.3.1.
Endpoint / Variables.....................................................................19
7.3.1.1.
Drug Concentration Measures....................................19
7.3.1.2.
Derived Pharmacokinetic Parameters.........................19
8.
SAFETY ANALYSES .............................................................................................20
8.1.
Adverse Events Analyses ...........................................................................20
 
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8.2.
Clinical Laboratory Analyses.......................................................................20
8.3.
Other Safety Analyses ................................................................................20
9.
EFFICACY ANALYSES..........................................................................................21
9.1.
Exploratory Efficacy Analyses.....................................................................21
9.1.1.
Endpoint / Variables.....................................................................21
9.1.1.1.
Microbiological Outcome and Response.....................21
9.1.1.2.
Susceptibility ..............................................................24
9.1.1.3.
Clinical Outcome and Response.................................25
9.1.1.4.
Therapeutic Response ...............................................27
9.1.2.
Summary Measure ......................................................................28
9.1.3.
Population of Interest...................................................................28
10. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................29
10.1.
Population of Interest..................................................................................29
11. REFERENCES.......................................................................................................30
12. APPENDICES........................................................................................................31
12.1.
Appendix 1: Schedule of Activities ..............................................................31
12.1.1.
Protocol Defined Schedule of Events...........................................31
12.2.
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................35
12.2.1.
Study Phases ..............................................................................35
12.2.1.1.
Study Phases for Concomitant Medication .................35
12.2.2.
Treatment Emergent Flag for Adverse Events .............................35
12.3.
Appendix 3: Data Display Standards & Handling Conventions....................36
12.3.1.
Reporting Process .......................................................................36
12.3.2.
Reporting Standards....................................................................36
12.3.3.
Reporting Standards for Pharmacokinetic....................................37
12.4.
Appendix 4: Derived and Transformed Data ...............................................38
12.4.1.
General........................................................................................38
12.4.2.
Study Population..........................................................................38
12.4.3.
Safety ..........................................................................................39
12.4.4.
Efficacy........................................................................................40
12.5.
Appendix 5: Reporting Standards for Missing Data.....................................43
12.5.1.
Premature Withdrawals................................................................43
12.5.2.
Handling of Missing Data.............................................................43
12.5.2.1.
Handling of Missing and Partial Dates ........................43
12.6.
Appendix 6: Values of Potential Clinical Importance ...................................45
12.6.1.
ECG.............................................................................................45
12.6.2.
Vital Signs....................................................................................45
12.7.
Appendix 7: Division of Microbiology and Infectious Disease Adult 
Toxicity Tables for Adverse Event Assessment...........................................46
12.7.1.
Laboratory Values........................................................................46
12.8.
Appendix 8: Abbreviations & Trade Marks ..................................................49
12.8.1.
Abbreviations...............................................................................49
12.8.2.
Trademarks .................................................................................50
12.9.
Appendix 9: List of Data Displays ...............................................................51
12.9.1.
Data Display Numbering..............................................................51
12.9.2.
Mock Example Shell Referencing ................................................51
12.9.3.
Deliverables.................................................................................51
 
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12.9.4.
Study Population Tables..............................................................52
12.9.5.
Efficacy Tables ............................................................................53
12.9.6.
Efficacy Figures ...........................................................................55
12.9.7.
Safety Tables...............................................................................56
12.9.8.
Pharmacokinetic Tables...............................................................58
12.9.9.
Pharmacokinetic Figures .............................................................59
12.9.10. Pharmacokinetic / Pharmacodynamic Tables ..............................60
12.9.11. Pharmacokinetic / Pharmacodynamic Figures .............................61
12.9.12. ICH Listings .................................................................................62
12.9.13. Non-ICH Listings..........................................................................66
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 206899.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
This Phase IIa study is designed primarily to evaluate plasma and urine pharmacokinetics 
(PK) of gepotidacin in female participants with clinical signs and symptoms of acute 
cystitis. As this PK study will be conducted in female participants with clinical signs and 
symptoms of acute cystitis, exploratory clinical and microbiological efficacy of 
gepotidacin will also be assessed.
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Clinical outcome will be 
determined by the 
investigator

In addition to 
investigator-determined clinical 
outcome, a sponsor-determined 
clinical outcome will be 
programmatically derived

To solve the potential dilemma 
that a participant with record 
missing or unable-to-determine 
at Test-of-Cure (TOC) visit but 
free of signs and symptoms of 
acute cystitis at Follow-up Visit 
will likely be determined as 
“clinical success” by the 
investigator but falls under 
failure per US Food and Drug 
Administration (FDA) guidance
[DHHS, May 2018; DHHS, 
June 2018].

Clinical outcome will be 
determined at the On-
Therapy (Days 2 
through 5), TOC, and 
Follow-up visits by 
comparing the signs 
and symptoms of acute 
cystitis to those 
present at Baseline. 
Clinical response 
(success or failure) will 
be determined at the 
TOC and Follow-Up 
visits

In addition, clinical cure, a binary 
result of ‘Yes’ or ‘No’ will be 
determined at the On-Therapy 
(Days 2 through 5), TOC, and 
Follow-Up visits. Clinical cure is 
defined as complete resolution of
signs and symptoms of acute 
cystitis present at Baseline, with 
no new signs and symptoms, and 
no use of other antimicrobial 
therapy. Clinical cure at Follow-up 
visit must also meet clinical cure 
at TOC in addition to above 
criteria

To apply a clinical criterion that 
is consistently focusing on 
complete resolution of clinical 
signs and symptoms through 
On-Therapy, TOC, and Follow-
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the plasma PK 
parameters of gepotidacin following 
repeat oral doses of gepotidacin 
(1500 mg [2 × 750-mg tablets] twice 
daily [BID] for 5 days) in adult female 
participants with acute cystitis

Plasma gepotidacin area under the concentration-time 
curve (AUC) from zero (predose) over the dosing interval 
(AUC[0-]), maximum plasma concentration (Cmax), and 
time of occurrence of Cmax (tmax) on Days 1 and 4 and 
apparent steady state clearance (CLss/F) and 
accumulation ratio (Ro) on Day 4

Plasma predose concentration (C) of gepotidacin on 
Days 1 through 5
Secondary Objectives
Secondary Endpoints

To determine the urine PK parameters 
of gepotidacin following repeat oral 
doses of gepotidacin in adult female 
participants with acute cystitis

Urine gepotidacin amount of drug excreted over 12 hours 
(Ae 12h), amount of drug excreted in urine in a time 
interval (Ae[t1-t2]), percentage of the given dose of drug 
excreted in urine (fe%), and renal clearance (CLr) of 
gepotidacin on Days 1 and 4

Urine predose concentration (C) on Days 1 through 5

To assess the safety and tolerability of 
repeat oral doses of gepotidacin in 
adult female participants with acute 
cystitis

Treatment-emergent adverse events (AEs) and serious 
AEs (SAEs) and change from baseline results for vital 
sign measurements, electrocardiograms (ECGs), and 
clinical laboratory tests
Exploratory Objectives
Exploratory Endpoints

To explore the combined clinical and 
microbiological efficacy of gepotidacin 
in adult female participants with acute 
cystitis who have a qualifying baseline 
uropathogen

Therapeutic response (combined per-participant 
microbiological and clinical response) at the TOC Visit

To assess time to eradication of 
uropathogens in adult female 
participants with acute cystitis who 
have a qualifying baseline 
uropathogen

Microbiological outcome on Days 2 through 5; 
Microbiological outcome and response at the TOC and 
Follow-up Visits

To explore time to resolution of signs 
and symptoms in adult female 
participants with acute cystitis

Investigator-determined clinical outcome on Days 2 
through 5, TOC, and Follow-up Visits

Sponsor-determined clinical outcome on Days 2 through 
5; sponsor-determined clinical outcome and response at 
the TOC and Follow-up Visits

To assess the relapse rate 
(microbiological and clinical) of acute 
cystitis after treatment with 
gepotidacin in adult female 
participants with acute cystitis at the 
Follow-up Visit

Therapeutic response (combined per-participant 
microbiological and clinical response) at the Follow-up 
Visit
 
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Objectives
Endpoints

To explore the microbiological and 
antimicrobial susceptibility profile of 
uropathogens recovered from adult 
female participants with acute cystitis, 
including subsets of isolates resistant 
to other antimicrobials

Gram stain, quantitative bacteriology culture, and in vitro 
antimicrobial susceptibility test results at Baseline, Days 2 
through 5, TOC, and Follow-up Visits

To explore gepotidacin plasma 
PK/pharmacodynamic (PD) 
relationships in adult female 
participants with acute cystitis

Relationship between gepotidacin exposure and clinical 
and microbiological response, if data permit

To explore the distribution of 
gepotidacin in cervical, rectal, and 
pharyngeal tissue (swab specimens)

Gepotidacin concentration in cervical, rectal, and 
pharyngeal tissues, if data permit
 
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2.3.
Study Design
Overview of Study Design and Key Features
The study design schematic is shown in Figure 1.
Figure 1
Study Design Schematic
BID=twice daily; PK=pharmacokinetic; TOC=test of cure; WBC=white blood cell.
a.
Serial blood PK sampling will be performed for the first dose of study treatment on Day 1 and for the time-matched 
dose on Day 4. Blood samples will be collected predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose.
b.
Serial urine PK sampling will be performed for the first dose of study treatment on Day 1 and for the time-matched 
dose on Day 4. Urine samples will be collected predose and at intervals of 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 
6 to 8 hours, 8 to 10 hours, and 10 to 12 hours postdose.
c.
Predose PK blood samples will be collected before each time-matched dose on Days 1 through 5. Predose PK 
urine samples will be collected 0 to 2 hours before each time-matched dose on Days 1 through 5. Only 1 sample 
is needed when serial and predose samples overlap.
Participants will check-out of the clinic after all study procedures have been performed, including a predose 
clean-catch midstream urine sample for Gram stain, quantitative bacteriology culture, and antimicrobial susceptibility 
testing, predose PK sample collections, and safety assessments. Participants should remain in the clinic to complete a 
total of 10 doses. Participants will be instructed to return for the TOC (Day 10 to 13) and Follow-up (Day 28±3) Visits
Design
Features

A Phase IIa single-center, open-label, repeat dose PK study.

The study duration is approximately 28 days comprising approximately 5 days of 
confinement at the clinic followed by 2 outpatient visits
o
Clinic Confinement Visits

Baseline (Day -1 to Day 1 predose) Visit

On-Therapy (Day 1 to Day 5) Visit
o
Outpatient Visits

TOC (Day 10 to 13) Visit

Follow-up (Day 28) Visit

Approximately 25 to 30 participants will be enrolled to achieve approximately 20 
participants who complete the study assessments through Day 5 and are evaluable 
for the PK analyses.
 
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Dosing

All participants who meet the study entry criteria and provide informed consent will 
receive oral gepotidacin 1500 mg (2 × 750-mg tablets) BID for 5 days (total of 
10 doses).
Time & 
Events

Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment

This is a nonrandomized, open-label study. Clinic personnel will enroll the participant 
into the study once a participant has met all eligibility requirements.
Interim 
Analysis

No interim analyses are planned for this study.
2.4.
Statistical Hypotheses
A formal hypothesis will not be tested; however, an estimation approach will be taken to 
characterize the PK of gepotidacin in female participants with uncomplicated urinary 
tract infection (UTI).
3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol at Follow-up 
Visit.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Safety

All participants who take at least 1 dose of gepotidacin.

Study Population

Safety
PK

All participants in the Safety Population and have 
evaluable plasma, urine, or tissue concentration data for 
gepotidacin. A subject is considered to have evaluable 
PK data for gepotidacin if the subject has at least 1 
measurable post-dose PK concentration value for 
gepotidacin that was not excluded from the analysis due 
to a protocol deviation. This primary analysis population 
will be used in the assessment and characterization of 
PK concentrations (summary tables, listings, and 
figures)

PK Concentration
PK Parameter

All participants in the PK Population who receive 
gepotidacin 1500 mg BID through the completion of all 
PK collections for whom valid and evaluable plasma or 
urine PK parameters are derived for gepotidacin. This 
primary analysis population will be used in the 
assessment and characterization of PK parameters 
(summary and analysis tables, listings, and figures)

PK Parameter
Intent-To-Treat 
(ITT)

All participants that met all eligibilities and were
assigned to study treatment

Study Population
Microbiological 
ITT (micro-ITT)

All participants in the ITT Population, receive at least 
1 dose of gepotidacin, and have a qualifying baseline 
uropathogen from a quantitative bacteriological culture 
of a pretreatment clean catch midstream urine 
specimen.

The algorithm of the qualifying bacterial uropathogen is 
presented in Appendix 4: Derived and Transformed 
Data, Figure 2
.

Efficacy
PKPD

All participants in both the PK Parameter Population and 
the Micro-ITT Population

PKPD
Refer to Appendix 9: List of Data Displays.
4.1.
Protocol Deviations
Significant protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all significant
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
 
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o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the electronic 
case report form (eCRF).
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Only one treatment, oral gepotidacin 1500 mg BID will be administered in this study as 
the study treatment.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest predose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered as 
Baseline
Baseline Used in Data 
Display
Day -1
Day 1 (Predose)
Efficacy
Acute Cystitis Signs and 
Symptoms
X
Day -1
Gram Stain
X
Day 1 (Predose)
Quantitative Bacteriology 
Culture
X
Day 1 (Predose)
In Vitro Antimicrobial 
Susceptibility Test
X
Day 1 (Predose)
Safety
12-lead Electrocardiogram 
(ECG)
X
X
Day 1 (Predose)[1]
Vital Sign
X
X
Day 1 (Predose)[1]
Hematology
X
Day -1
Clinical Chemistry
X
Day -1
Urinalysis
X
Day -1
1.
Vital sign and ECG assessments at predose on Day 1 will be only performed if the Day -1 assessment is not 
within 4 hours of the first dose of study treatment. If the Day 1 predose assessments are not performed, Day -1 
assessments will be used as baseline in data display. Average of the triplicate ECG assessment at Day -1 will 
be used as the baseline if Day 1 predose assessment is not performed as described in Appendix 4: Derived and 
Transformed Data.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
 
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5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
12.1
Appendix 1: Schedule of Activities
12.2
Appendix 2: Study Phases and Treatment Emergent Adverse Events
12.3
Appendix 3: Data Display Standards & Handling Conventions
12.4
Appendix 4: Derived and Transformed Data
12.5
Appendix 5: Reporting Standards for Missing Data
12.6
Appendix 6: Values of Potential Clinical Importance
12.7
Appendix 7: Division of Microbiology and Infectious Disease Adult Toxicity Tables for 
Adverse Event Assessment
12.8
Appendix 8: Abbreviations & Trade Marks
12.9
Appendix 9: List of Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “ITT” population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards. 
Baseline disease characteristics including baseline uropathogen recovery rate (including 
drug-resistant uropathogens), baseline clinical symptom score, current medication 
conditions, and exposure data will be summarized. History of uncomplicated urinary tract 
infection will be listed.
The details of data displays are presented in Appendix 9: List of Data Displays.
 
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7.
PHARMACOKINETIC ANALYSES
7.1.
Primary Pharmacokinetic Analyses
7.1.1.
Endpoint / Variables
7.1.1.1.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 12.3.3
Reporting Standards for Pharmacokinetic). Only total gepotidacin plasma PK 
concentrations will be measured and reported in the bioanalytical data. Therefore, 
unbound plasma PK concentrations will be derived by multiplying the total plasma PK 
concentrations by 0.67, to correct for the low plasma protein binding of gepotidacin 
(33%) observed in previous studies.
7.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix WinNonlin version 6.4 or higher. All calculations of non-compartmental 
parameters will be based on actual sampling times. Pharmacokinetic parameters listed 
will be determined from the plasma and urine concentration-time data, as data permits.
Table 2 provides the details of derived plasma PK parameters.
Table 2
Derived Plasma Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve (AUC) from time 0 to the 12-hour dosing 
interval, to be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. Calculated 
from Days 1 and 4.
AUC(0-24)
Area under the concentration-time curve (AUC) from time 0 to the 24-hour, 
calculated as:
AUC(0-24) = AUC(0-) × 2
Calculated for Day 4.
Cmax
Maximum observed concentration, determined directly from the concentration-time 
data. Calculated from Days 1 and 4.
Tmax
Time to first occurrence of Cmax. Calculated from Days 1 and 4.
CLss/F
Apparent steady state clearance (Day 4 only), calculated as 
CLss/F = Dose/AUC(0-)
Ro
Accumulation ratio (Day 4 only), calculated as:
Ro = AUC(0-) Day 4/AUC(0-) Day 1
C
Observed predose (nominal time = 0) concentrations on Days 1 through 5
NOTES:

Additional parameters may be included as required.
 
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7.1.2.
Summary Measure
Summary statistics (arithmetic mean, geometric mean, median, standard deviation (SD), 
minimum, maximum, and coefficient of variation [CV]) for plasma gepotidacin PK 
parameter values will be summarized by study day, as appropriate. The Cwill be 
summarized and used to assess achievement of steady state. Gepotidacin plasma PK 
parameter estimates will be listed by participant and study day.
7.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population
and Pharmacokinetic Parameter population, unless otherwise specified.
7.1.4.
Statistical Analysis / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.1.4.1.
Statistical analysis of Pharmacokinetic Parameters
All the derived parameters described in Table 2 will be listed. For each of these 
parameters, except Tmax, the following summary statistics will be calculated for each 
active treatment group: median, maximum, minimum, arithmetic mean, SD, CV on 
arithmetic mean, geometric mean, CV on geometric mean, 95% confidence interval (CI) 
for the geometric mean, and SD of logarithmically transformed data. For tmax, tmin, and 
tlag, median, maximum, minimum, arithmetic mean, and SD will be calculated.
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
Endpoint / Variables

Plasma primary PK endpoints include predose concentrations (C) Day 1 through Day 5
Model Specification

To assess the achievement of steady state, Cconcentrations between Days 1 through 5 for 
each treatment. A linear mixed model using Day as fixed effects and subject as a random 
effect on the ln-transformed pre-dose values will be performed evaluating whether steady state 
was achieved using Helmert transformation approach. The comparison will begin with Day 1 vs 
the average of Days 2, 3, 4 and 5. The ratio of geometric least square means and its 95% CI 
will be presented for the comparison(s). 
Model Results Presentation

Statistical analysis of steady state will be analyzed using Helmert transformation approach.
 
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7.2.
Secondary Pharmacokinetic Analyses
7.2.1.
Endpoint / Variables
7.2.1.1.
Drug Concentration Measures 
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 12.3.3
Reporting Standards for Pharmacokinetic).
7.2.1.2.
Derived Urine Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of SAS 
version 9.3. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the urine
concentration-time data, as data permits.
Table 3
Derived Urine Pharmacokinetic Parameters
Parameter
Parameter Description
Ae 12h
Total unchanged drug excreted over 12 hours (total amount of drug excreted in 
urine), calculated by adding all the fractions of drug collected over all the allotted 
time intervals. Calculated from Days 1 and 4.
Ae(t1-t2)
Amount of drug excreted in urine in time intervals for predose, 0 to 2 hours, 2 to 
4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10, and 10 to 12 hours postdose. Calculated 
from Days 1 and 4.
AUC(0-)
Area under the urine concentration-time curve (AUC) from time 0 to the 12-hour 
dosing interval, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
Calculated from Days 1 and 4.
AUC(0-24)
Area under the urine concentration-time curve (AUC) from time 0 to the 24-hour, 
calculated as:
AUC(0-24) = AUC(0-) × 2
Calculated Day 4.
fe%
Percentage of the given dose of drug excreted in urine, calculated as: 
fe% = (Ae 12h/Dose) × 100
Calculated for Days 1 and 4
CLr
Renal clearance of drug, calculated as: 
CLr = Ae 12h/AUC(0-)
Calculated from Days 1 and 4.
C
Observed predose (nominal time = 0) urine concentrations on Days 1 through 5.
NOTES:

Additional parameters may be included as required.
 
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7.2.2.
Summary Measure
Summary statistics (arithmetic mean, geometric mean, median, SD, minimum, maximum, 
and CV) for urine gepotidacin PK parameter values will be summarized by study day, as 
appropriate. Gepotidacin urine PK parameter estimates will be listed by participant and 
study day.
7.2.3.
Population of Interest 
The secondary PK analyses will be based on the Pharmacokinetic population and 
Pharmacokinetic Parameter population, unless otherwise specified.
7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics and listed.
7.3.
Exploratory Pharmacokinetic Analyses
7.3.1.
Endpoint / Variables
7.3.1.1.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 12.3.3
Reporting Standards for Pharmacokinetic).
7.3.1.2.
Derived Pharmacokinetic Parameters
Cervical, rectal, and pharyngeal swab specimens for PK analysis of gepotidacin will be 
obtained Day 4 at predose and at approximately 2 hours postdose. The actual date and 
time of each sample collection will be recorded. Participation is optional. Participants 
who do not wish to participate in the tissue PK assessments may still participate in the 
study. Specific details to ensure a similar physical site of the pharynx is used for swab 
collection are provided in the Study Reference Manual (SRM) and/or laboratory manual. 
Collection, processing, storage, and shipping procedures for cervical, rectal, and 
pharyngeal swab specimens are provided in the SRM and/or laboratory manual.
Summary statistics (arithmetic mean, geometric mean, median, SD, minimum, maximum, 
and CV) for cervical, rectal, and pharyngeal gepotidacin PK concentration values will be 
summarized by collection time point, as appropriate. Gepotidacin cervical, rectal, and 
pharyngeal concentration estimates will be listed by participant and collection time point.
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of AEs, SAEs and other significant AEs 
will be based on GSK Core Data Standards. All AEs, study drug related AEs, SAEs, and 
AEs leading to discontinuation of study treatment or withdrawal from study will be 
provided in separate listings. The relationship between system organ class (SOC) and 
preferred term (PT) will be listed. Summary tables will be provided for AEs and 
drug-related AEs by SOC, PT, and maximum grade. Number of subjects and occurrences 
with common non-serious AEs will be provided in a summary table by SOC.
In summary tables where are presented by SOC, PT, and maximum grade, SOCs will be 
sorted in descending order of the total incidence then alphabetically, PTs will be sorted in 
descending order of the total incidence then alphabetically within the SOC. 
The details of data displays are presented in Appendix 9: List of Data Displays.
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, and liver function tests will be based on GSK Core Data 
Standards. 
Summaries of change from baseline values for clinical chemistry and hematology tests 
will be provided in separate tables. Shift tables for clinical chemistry and hematology 
results with toxicity grades 2 to 4 will be provided. Urinalysis dipstick results will be 
summarized using categorical statistics. Clinical chemistry, hematology, and urinalysis 
test results with toxicity grade 2 or higher will be listed in separate listings.
The details of data displays are presented in Appendix 9: List of Data Displays.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs, vital signs, and liver 
events will be based on GSK Core Data Standards, unless otherwise specified. 
Summary tables will be provided for ECG findings, ECGs change from baseline values, 
maximum post-baseline QTc values relative to baseline values, and maximum increase in 
post-baseline QTc values relative to baseline values, vital signs change from baseline 
values, and worst post-baseline vital signs results relative to baseline results. 
Listings will be provided for abnormal ECG findings, ECG values of potential clinical 
importance, vital sign values of potential clinical importance, liver events, and 
clostridium difficile results.
The details of data displays are presented in Appendix 9: List of Data Displays.
 
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9.
EFFICACY ANALYSES
9.1.
Exploratory Efficacy Analyses
The details of data displays being presented in Appendix 9: List of Data Displays.
9.1.1.
Endpoint / Variables

Therapeutic response (combined per-participant microbiological and clinical 
response) at the TOC Visit

Microbiological outcome on Days 2 through 5

Microbiological outcome and response at the TOC and Follow-up Visits

Sponsor-determined clinical outcome on Days 2 through 5

Sponsor-determined clinical outcome and response at the TOC and Follow-up Visits

Investigator-determined clinical outcome on Days 2 through 5 and at the TOC and 
Follow-up Visits

Therapeutic response (combined per-participant microbiological and clinical 
response) at the Follow-up Visit

Gram stain results at Baseline, Days 2 through 5, TOC, and Follow-up Visits

Quantitative bacteriology culture results at Baseline, Days 2 through 5, TOC, and 
Follow-up Visits

In vitro antimicrobial susceptibility test results at Baseline, Days 2 through 5, TOC,
and Follow-up Visits
9.1.1.1.
Microbiological Outcome and Response

The microbiological outcome and response to study treatment will be determined by 
prespecified programmed algorithm for each participant/qualifying uropathogen.

The microbiological outcome is determined by comparing the baseline culture results 
to the culture results at each subsequent visit. The corresponding microbiological 
response “by qualifying uropathogen” is then assigned. The criteria of 
microbiological outcome and response are shown in Table 4, Table 5, and Table 6.

Participant level microbiological success refers to participants who have been deemed 
a “microbiological success” for all their “qualifying baseline uropathogen” 
microbiological responses.

All other combinations are deemed failures for participant level microbiological 
response.

Participants who withdraw from the study prior to TOC or Follow-Up Visits will be 
considered not achieving success as the microbiological response. Microbiological 
outcome will be derived and listed at early termination visit.

Microbiological outcome and response along with the 95% Clopper-Pearson CI for 
the percentage of microbiological response will be summarized for qualifying 
uropathogens isolated at baseline using the groups listed below at the On-therapy, 
TOC, and Follow-up visits using counts and percentages. Participant level 
microbiological response and 95% Clopper-Pearson CI will be summarized within the 
same table. The necessity of these categories will depend on the uropathogens that are 
recovered. Any additional uropathogens present in 10 or more participants will be 
 
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summarized separately. Additional uropathogens present in less than 10 participants 
will be grouped into the combined categories (eg, other beta-hemolytic streptococci).
o
Escherichia coli

Quinolone-resistant E. coli

Extended spectrum beta-lactamase (ESBL) producing E. coli

Multidrug-resistant (MDR) E. coli
o
Other gram-negative bacilli
o
Staphylococcus aureus
o
Staphylococcus saprophyticus
o
Coagulase-negative staphylococci
o
Beta-hemolytic streptococci
o
Viridans streptococci
o
Enterococcus spp.
o
Gardnerella vaginalis
o
Aerococcus urinae
o
Other Gram-positive uropathogens

A participant will be counted multiple times under an uropathogen category if 
multiple qualifying uropathogens within that uropathogen category are isolated at 
baseline for the participant.

Urine quantitative bacteriology culture results will be summarized and plotted by visit 
and qualifying uropathogens isolated at baseline
Table 4
Microbiological Outcome by Qualifying Uropathogen at the 
On-Therapy Visit
Defining Criteria
Outcome

Any participant that receives administration of an alternative or additional antibacterial therapy during 
the On-Therapy visit will be assigned a microbiological outcome of “unable to determine” from that day 
onward.

A quantitative urine culture taken during the 
On-Therapy Visit (Days 2 through 5 only) 
shows that the qualifying bacterial 
uropathogen recovered at Baseline is reduced 
to <103 CFU/mL

Microbiological eradication

A quantitative urine culture taken during the 
On-Therapy Visit (Days 2 through 5 only) 
shows that the qualifying bacterial 
uropathogen recovered at Baseline grows 
≥103 CFU/mL

Microbiological persistence

A determination of the baseline qualifying 
bacterial uropathogen microbiological outcome 
cannot be made (e.g., no urine culture taken, 
sample lost, etc.)

Unable to determine

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture during the 
On-Therapy Visit (Days 2 through 5 only) in a 
participant who is a sponsor-determined 
clinical failure or unable to determine

Superinfection
 
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Defining Criteria
Outcome

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the On-Therapy 
Visit (Days 2 through 5 only) in a participant 
who is a sponsor-determined clinical success

Colonization
CFU=colony-forming units
Table 5
Microbiological Outcome and Response by Qualifying Uropathogen 
at the Test-of-Cure Visit
Defining Criteria
Outcome
Response

Any participant that receives administration of an alternative or additional antibacterial therapy before 
the TOC Visit will be assigned a microbiological outcome of “unable to determine” and a response of 
“microbiological failure”.

Participants considered microbiological failures at the TOC Visit will also be considered microbiological 
failures at the Follow-up Visit.

A quantitative urine culture taken at the TOC 
Visit shows reduction of the qualifying bacterial 
uropathogen recovered at Baseline to <103
CFU/mL

Microbiological 
eradication

Microbiological 
success

A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and which 
was also shown to persist at the On-Therapy 
Visit, grows ≥103 CFU/mL

Microbiological 
persistence

Microbiological 
failure

A quantitative urine culture taken at the TOC 
Visit shows that the qualifying bacterial 
uropathogen recovered at Baseline, and which 
was also shown to be eradicated at the On-
Therapy Visit, grows ≥103 CFU/mL

Microbiological 
recurrence

Microbiological 
failure

A determination of the baseline qualifying 
bacterial uropathogen microbiological 
response cannot be made (e.g., no urine 
culture taken, sample lost, etc.)

Unable to determine

Microbiological 
failure

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the TOC Visit in a 
participant who is a sponsor-determined 
clinical failure

New infection

Microbiological 
failure

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the TOC Visit in 
a participant who is a sponsor-determined
clinical success

Colonization

Microbiological 
success
CFU=colony-forming units; TOC=Test-of-Cure.
 
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Table 6
Microbiological Outcome and Response by Qualifying Uropathogen 
at the Follow-Up Visit
Defining Criteria
Outcome
Response

Any participant that receives administration of an alternative or additional antibacterial therapy before 
the Follow-up Visit will be assigned a microbiological outcome of “unable to determine” and a response 
of “microbiological failure”.

Participants considered microbiological failures at the TOC Visit will also be considered microbiological 
failures at the Follow-up Visit.

A quantitative urine culture taken at the Follow-
up Visit shows reduction of the qualifying 
bacterial uropathogen recovered at Baseline to 
<103 CFU/mL

Sustained 
microbiological 
eradication

Microbiological 
success

A quantitative urine culture taken at the 
Follow-up Visit shows that the qualifying 
bacterial uropathogen recovered at Baseline 
grows ≥103 CFU/mL

Microbiological 
recurrence

Microbiological 
failure

A determination of the baseline qualifying 
bacterial uropathogen microbiological 
response cannot be made (e.g., no urine 
culture taken, sample lost, etc.)

Unable to determine

Microbiological 
failure

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who is a sponsor-determined 
clinical failure

New infection

Microbiological 
failure

A new qualifying bacterial uropathogen, not 
identified at Baseline, is documented by 
quantitative urine culture at the Follow-up Visit 
in a participant who is a sponsor-determined 
clinical success

Colonization

Microbiological 
success
CFU=colony-forming units; TOC=Test-of-Cure.
9.1.1.2.
Susceptibility

Results and interpretations of susceptibility testing for all uropathogens against 
gepotidacin and other antimicrobials will be summarized by uropathogen, visit, and 
antimicrobials tested. For summaries, a participant will be counted multiple times 
under an uropathogen category if multiple uropathogens within that uropathogen 
category are isolated at baseline for the participant.

The overall frequency distribution of minimum inhibitory concentrations (MICs) and 
the minimum, maximum, median (MIC50), and 90th percentile (MIC90) MIC will be 
presented. Percent susceptibility (susceptible, intermediate, or resistant) will be 
summarized where available.

Reduction in susceptibility to gepotidacin will be evaluated by comparing the 
baseline gepotidacin MIC value for uropathogens with the value obtained 
post-baseline. Post-baseline uropathogens of the same species and from the same 
participant with a confirmed ≥ 4-fold increase in gepotidacin MIC are considered to 
have developed a reduction in susceptibility to gepotidacin.
 
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
The number and percentage of participants who demonstrate a reduction in 
susceptibility to GSK 2140944 will be summarized by visit and uropathogen.
A participant will be counted multiple times under an uropathogen category if 
multiple uropathogens within that uropathogen category are isolated at baseline for 
the participant.
9.1.1.3.
Clinical Outcome and Response

Clinical signs and symptoms of acute cystitis will be recorded by site staff based on 
participant interview using the scoring system. 

The clinical signs and symptoms include at least dysuria, frequency, urgency, and 
lower abdominal or suprapubic pain. The clinical signs and symptoms will be scored 
from 0 to 3.

At Baseline, the participant must present with at least 2 signs and symptoms and have 
a total cumulative symptom score ≥2. At TOC, success is recorded as normal 
presentation of signs and symptoms with a total cumulative symptom score of zero 
and no new signs and symptoms of the infection under study.

The investigator will determine the clinical outcome by comparing the signs and 
symptoms of acute cystitis at the On-Therapy (Days 2 through 5 only), TOC, and 
Follow-up Visits to those present at Baseline. The clinical response based on 
investigator-determined clinical outcome will be programmatically derived using the 
criteria in Table 7.

The sponsor-determined clinical outcome and response will be programmatically 
determined by comparing the scores of the signs and symptoms of acute cystitis at the 
On-Therapy (Days 2 through 5 only), TOC, and Follow-up Visits to those present at 
Baseline as shown in Table 7.

Participants who withdraw from the study prior to TOC or Follow-Up Visits will be 
considered not achieving success as the clinical response at TOC or Follow-Up 
Visits. The investigator- and sponsor-determined clinical response and outcome at 
Early Termination visit will only be listed.

Clinical response (success or failure) will be determined at TOC or Follow-Up visits 
for each participant. A “success” clinical response is defined as if the clinical 
outcome for all qualifying uropathogens is “clinical success” for the visit, otherwise a 
“failure” clinical response will be assigned.

Clinical cure is defined in Table 8 and will be programmatically derived at the 
On Therapy (Days 2 through 5), TOC, and Follow-up Visits. If a participant does not 
meet clinical cure at TOC visit, the participant will not be considered as clinical cure 
at Follow-up visit.

The investigator- and sponsor-determined clinical outcome and response will be 
summarized for qualifying uropathogens isolated at baseline at the On-therapy, TOC, 
and Follow-up visits using counts and percentages. A participant will be counted 
multiple times under an uropathogen category if multiple qualifying uropathogens 
within that uropathogen category are isolated at baseline for the participant. In 
addition, participant level of clinical outcome will be summarized in the same table.
The 95% Clopper-Pearson CI will be presented for the proportion clinical response at 
each visit.
 
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
Clinical cure will be summarized for qualifying uropathogens isolated at baseline at 
the On-therapy, TOC, and Follow-up visits using counts and percentages. 
A participant will be counted multiple times under an uropathogen category if 
multiple qualifying uropathogens within that uropathogen category are isolated at 
baseline for the participant. The 95% Clopper-Pearson CI will be presented for the 
proportion clinical cure at each visit.

Percent of clinical cure and microbiological eradication over time will be plotted.
A participant with multiple qualifying uropathogens within an uropathogen category 
will be counted multiple times.

The mean clinical symptom scores and boxplots of total score over time will be 
overlaid within one figure for the ITT population.
Table 7
Sponsor-Determined Clinical Outcome and Response
Defining Criteria
Outcome
Response
On-Therapy visit (Days 2 through 5 only)

Resolution of or improvement in signs and 
symptoms of acute cystitis present at Baseline 
(and no new signs and symptoms)

Improvement is based on investigator-
evaluated score and is defined as no increase 
of scores in each sign and symptom of acute 
cystitis present at Baseline and no new signs 
and symptoms of acute cystitis and no use of 
other antimicrobial therapy for the current 
infection

Clinical success

Not applicable

Increase of scores in any of signs and 
symptoms of acute cystitis present at Baseline 
or new signs and symptoms of acute cystitis or 
use of other antimicrobial therapy for the 
current infection

Clinical failure

Not applicable

Refusal to consent to a clinical examination or 
failure to attend the On-Therapy visit (Days 2 
through 5 only)

Unable to Determine

Not applicable
Test-of-Cure Visit

Resolution of signs and symptoms of acute 
cystitis (total cumulative score is zero) present 
at Baseline (and no new signs or symptoms) 
and no use of other antimicrobial therapy

Clinical success

Success

Persistence of signs and symptoms of infection 
(total cumulative score is >0), reappearance of 
signs and symptoms, or use of other 
antimicrobial therapy for the current infection

Clinical failure

Failure

Refusal to consent to a clinical examination of 
failed to attend the TOC Visit

Unable to determine

Failure
 
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Follow-up Visit

Resolution of signs and symptoms of acute 
cystitis demonstrated at the TOC Visit persist 
at the Follow-up Visit (total cumulative score is 
zero) (and no new signs and symptoms) and 
no use of other antimicrobial therapy

Sustained clinical 
success

Success

Resolution of signs and symptoms of acute 
cystitis at the Follow-up Visit (total cumulative 
score is zero) and no use of other antimicrobial 
therapy, but lack of clinical success at the TOC 
Visit

Delayed clinical 
success

Failure

Persistence of signs and symptoms of infection
(total cumulative score is >0), reappearance of 
signs and symptoms, or use of other 
antimicrobial therapy for the current infection

Clinical failure

Failure

Signs and symptoms of acute cystitis absent at 
the TOC Visit re-occur at the Follow-up Visit 
and no use of other antimicrobial therapy

Clinical recurrence

Failure

Refusal to consent to a clinical examination or 
failed to attend the Follow-up Visit

Unable to determine

Failure
TOC=Test-of-Cure.
Table 8
Clinical Cure
Defining Criteria
Clinical Cure (Yes/No)
On-Therapy visit (Days 2 through 5 only), Test-of-Cure visit, and Follow-up visit

Complete resolution of signs and symptoms of 
acute cystitis present at Baseline, with no new 
signs and symptoms, and no use of other 
antimicrobial therapy. Clinical Cure at Follow-
up must also meet Clinical Cure at Test-of-
Cure in addition to above criteria.

Yes
9.1.1.4.
Therapeutic Response

A measure of overall efficacy response, success, or failure.

A therapeutic success refers to participants who have been deemed both a 
‘microbiological success’ (refer to ‘Microbiological Outcome and Response’) and 
a ‘clinical success’ (i.e., ‘responders’) 

All other combinations will be deemed failures for therapeutic response.

Programmatically derived for TOC and Follow-up Visits

Number of participants achieving therapeutic success at the TOC and Follow-up 
visits along with the 95% Clopper-Pearson CI will be summarized by per-participant 
microbiological response and clinical response by qualifying uropathogens isolated at 
baseline. A participant will be counted multiple times under an uropathogen category 
if multiple qualifying uropathogens within that uropathogen category are isolated at 
baseline for the participant.

Percent of clinical success and microbiological eradication over time will be plotted.
 
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9.1.2.
Summary Measure
This study only has one treatment group; thus, treatment comparison is not applicable.
9.1.3.
Population of Interest 
The exploratory efficacy analyses will be based on the “micro-ITT” population, unless 
otherwise specified.
 
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10.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
Relationships between the ratio of Day 4 free plasma and urine PK parameters to baseline 
MIC (free plasma AUC(0-24)/MIC, free plasma Cmax/MIC, urine AUC(0-24)/MIC and 
urine Ctau/MIC) and PD measures (therapeutic response) will be explored in tabular and 
graphical format. 
Summary statistics (arithmetic mean, geometric mean, median, SD, minimum, maximum, 
and CV) for free plasma and urine PK parameters to baseline MIC values will be 
summarized by uropathogen and therapeutic response, as appropriate. Free plasma and 
urine PK parameters to baseline MIC values will be listed by uropathogen and 
therapeutic response for individual participants.
10.1.
Population of Interest
The exploratory analyses will be based on the PKPD population, unless otherwise 
specified.
 
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11.
REFERENCES
GlaxoSmithKline Document Number 2017N317982_00 (Original 10-MAY-2018): A 
Phase IIa Single-Center, Open-Label Study Evaluating the Pharmacokinetics of Repeat 
Oral Doses of Gepotidacin (GSK2140944) in Adult Female Participants With 
Uncomplicated Urinary Tract Infection (Acute Cystitis).
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Draft guidance for 
industry. Uncomplicated urinary tract infections: developing drugs for treatment. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm607095.pdf. Last updated May 2018. Accessed 20-Jun-2018.
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research, Clinical/Antimicrobial. Guidance for industry. 
Complicated urinary tract infections: developing drugs for treatment. 
https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070981.pdf. Last updated June 
2018. Accessed 20-Jun-2018.
US National Institute for Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases. Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table. Draft. https://www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf. 
Last updated November 2007. Accessed 20-Jun-2018.
 
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12.
APPENDICES
12.1.
Appendix 1: Schedule of Activities
12.1.1.
Protocol Defined Schedule of Events
Table 9
Schedule of Activities
Visit
Baseline 
(includes a screening 
window of up to 24 hours 
before the first dose of 
study treatment)
On-Therapy
Test-of-Cure
Follow-up
Study Day
-1
1
2
3
4
5a
10 to 13
283
Procedure
Predose
Postdose
Written informed consent
X
Inclusion and exclusion criteria
X
Admission to clinic
X
Participant demography
X
Physical examination (including height and weight at Baseline only)
X
X
X
Medical/surgical history
X
Diagnosis of presumptive acute cystitisb
X
Bacteriology samplesc
X
X
X
X
X
X
X
Record acute cystitis signs and symptomsd
X
X
X
X
X
X
X
12-lead ECGe
X
Xf
X
X
Vital sign measurementsg
X
Xf
X
X
X
X
X
Hematology, chemistry, and urinalysis
X
X
X
X
Serology (hepatitis B and C and HIV)h
X
Pregnancy testi
X
X
X
Administer study treatmentj
Xj
X
X
X
X
Xj
Blood and urine PK samplingk
X
X
X
X
X
X
Cervical, rectal, and pharyngeal PK sampling (optional)l
X
Genetic sample (optional)
Xm
Stool microbiome collection (optional)n
X
X
X
Vaginal and pharyngeal microbiome collection (optional)n
X
X
X
 
 
 
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Visit
Baseline 
(includes a screening 
window of up to 24 hours 
before the first dose of 
study treatment)
On-Therapy
Test-of-Cure
Follow-up
Serious adverse eventso,p
X
X
X
X
X
X
X
X
X
Adverse eventsp
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Discharge from clinic
Xa,j
Schedule/Reminder for next outpatient visit
Xq
Xr
Xr
ECG=electrocardiogram; HIV=human immunodeficiency virus; PK=pharmacokinetic; TOC=Test-of-Cure; WBC=white blood cell.
a.
If a participant discontinues during the on-treatment confinement period, Day 5 assessments will be completed before the participant is discharged, with the exception of study 
treatment administration.
b.
Based on confirmation of pyuria (≥10 WBC/mm3 or the presence of leukocyte esterase) and/or nitrite from a pretreatment clean-catch midstream urine sample per local laboratory 
procedures. Note: Repeat baseline urine samples are allowed if contamination, defined as ≥10 squamous epithelial cells, is observed under microscopic evaluation.
c.
Participants will provide a clean-catch midstream urine sample pretreatment at Baseline (predose on Day 1), predose on Days 2 through 5 (i.e., before the time-matched dose); and 
at the TOC and Follow-up Visits for Gram stain, quantitative bacteriology culture, and in vitro antimicrobial susceptibility testing.
d.
Site staff will record clinical signs and symptoms of acute cystitis based on participant interview.
e.
Obtain a triplicate 12-lead ECG in semi-supine position at Baseline only. See Table 10 for single 12-lead ECG predose and postdose assessment time points on Days 1 and 4.
f.
Only repeat the ECG and vital sign assessments at predose on Day 1 if the baseline assessment was not within 4 hours of the first dose of study treatment.
g.
Take measurement of temperature, blood pressure, and pulse rate in semi-supine position.
h.
If serology testing was performed within 3 months prior to the first dose of study treatment and results were positive, testing at Baseline is not required. If testing was performed 
within 3 months and any result was negative, testing at Baseline is required.
i.
For women of childbearing potential, a negative serum pregnancy test is needed for eligibility at Baseline. A urine pregnancy test may be performed on Day 5 and at the TOC Visit.
j.
The first dose on Day 1 will only be administered after all baseline procedures have been completed. All doses of study treatment will be administered under site staff supervision 
and all doses will be administered with food (i.e., standardized meals or snacks as applicable). Participants should remain in the clinic to complete a total of 10 doses.
k.
See Table 10 for serial collection time points. Predose PK blood samples will be collected before each time-matched dose on Days 1 through 5. Predose PK urine samples will be 
collected 0 to 2 hours before each time-matched dose on Days 1 through 5. Only 1 sample is needed when serial and predose samples overlap. If a participant is switched to a 
different antibiotic before the end of study treatment, a final blood and urine PK sample should be collected prior to administration of the different antibiotic.
l.
Collection of cervical, rectal, and pharyngeal swab PK specimens is optional. Specimens will be collected on Day 4 at predose and at approximately 2 hours postdose. The 2-hour 
postdose collection should be as close as possible to the 2-hour postdose blood PK draw time on Day 4.
m.
Collect sample only if the participant has a signed consent specific for this purpose. Baseline (predose on Day 1) is the recommended time to collect the sample, but it can be 
collected at any time during the study.
n.
Collection of stool, vaginal, and pharyngeal microbiome specimens is optional. The pretreatment specimens may be collected any time from Day -1 to Day 1 predose. The 
posttreatment specimens on Day 5 and at Follow-up may be collected at any time. Posttreatment stool, vaginal, and pharyngeal microbiome specimens should only be collected 
from participants who had a corresponding baseline specimen collected for each specimen type. 
o.
Record serious adverse events from the time of consent.
 
 
 
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p.
Record adverse events from the time of the first dose of study treatment.
q.
Confirm return day/time for the TOC and Follow-up Visits.
r.
Pre-visit reminder: Site staff will contact the participant 24±4 hours before the scheduled TOC and Follow-up Visits.
Note:
At the discretion of the investigator, for emergency purposes only, participants may temporarily leave the clinic on study days without serial PK collections and only at times that do not 
interfere with required study assessments. Participants will be instructed to follow the protocol restrictions. The investigator will ensure the participant is eligible to continue in the study 
upon return to the clinic. All doses of study treatment will be administered under site staff supervision in the clinic.
The timing and number of planned study assessments, including PK assessments may be altered during 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 institutional review board will be 
informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form.
 
 
 
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Table 10
Blood and Urine Pharmacokinetic Collections and Electrocardiogram Assessments on Days 1 and 4
Time point (hours)
Procedurea
Predose
0
0.5
1
1.5
2
3
4
6
8
10
12
12-lead electrocardiogramb
Xc
X
Administer study treatmentd
X
Xe
Blood collection for pharmacokineticsf
X
X
X
X
X
X
X
X
X
X
Urine collection for pharmacokineticsg
X
X
X
X
X
X
X
a.
Assessments scheduled at the same nominal time should occur in the following order: electrocardiogram, urine collection, blood collection. The timing of the assessments should 
allow the blood draw to occur at the exact nominal time.
b.
Obtain single 12-lead electrocardiogram in semi-supine position at predose and 2 hours postdose on Days 1 and 4. The predose and postdose electrocardiogram time points should 
be the same on both days.
c.
Only repeat the electrocardiogram assessment at predose on Day 1 if it was not performed within 4 hours of the baseline assessment.
d.
Study treatment will be administered under site staff supervision and with food (i.e., standardized meals or snacks as applicable). On Days 1 and 4, for the dose associated with serial 
PK collections, participants should be in a semi-supine position for approximately 3 hours after study treatment administration with only minor exceptions (e.g., urine PK collections).
e.
Collection of the PK samples should occur before this dose is administered.
f.
Blood PK samples will be collected at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose for the first dose of study treatment on Day 1 and for the time-matched dose on 
Day 4.
g.
Urine PK samples will be collected predose and at intervals of 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours postdose for the first dose of 
study treatment on Day 1 and for the time-matched dose on Day 4.
 
 
 
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12.2.
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events
12.2.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and end date of study treatment. 
Study Phase
Definition
Pre-Treatment 
Date and Time ≤ Study Treatment Start Date and Time
On-Treatment
Study Treatment Start Date and Time < Date and Time ≤ Study Treatment Stop Date
and Time
Post-Treatment
Date and Time > Study Treatment Stop Date and Time
12.2.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before participant enrollment
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
12.2.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before the treatment 
stop date + 2 days. 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 2 
days.
NOTES: 

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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12.3.
Appendix 3: Data Display Standards & Handling 
Conventions
12.3.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0)

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for all reporting efforts described in the RAP.
12.3.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings.
 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures except for determining 
baseline or determining the worst-case values.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
12.3.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (xpt format) for the non compartmental analysis will be created 
according to SOP 314000(2.0).
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following plasma PK parameters will be derived by the Programmer: 
     Ro, C
The following urine PK parameters will be derived by the Programmer: 
     Ae 12h, Ae(t1-t2), Fe%, CLr, C
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to [Standards for Handling NQ Impacted PK Parameters].
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
 
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12.4.
Appendix 4: Derived and Transformed Data
12.4.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

The worst finding/interpretation associated with multiple measurements as the finding/interpretation for 
that time point.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.4.2.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any subject with a missing day will have this imputed as day ‘15’.
o
Any subject with a missing day and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / Height (m)2
Micro-ITT Population

Micro-ITT population include participants who receive at least 1 dose of gepotidacin and have 
a qualifying bacterial uropathogen at Baseline from a quantitative bacteriology culture of a pretreatment 
clean-catch midstream urine specimen.

The algorithm of the qualifying bacterial uropathogen is presented in Figure 2. If there’re 2 
uropathogens identified at baseline for a participant, the participant will be included in the micro-ITT 
population if at least 1 of the 2 uropathogens is ≥105 CFU/mL. 
 
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Figure 2
Baseline Algorithm for the Microbiological intent-to-Treat Population
CFU=colony-forming units; micro-ITT=Microbiological Intent-to-Treat.
12.4.3.
Safety
Adverse Events
AE’S of Special Interest

Cardiovascular (CV) events

Gastrointestinal events

A comprehensive list of Medical Dictionary for Regulatory Activities (MedDRA) terms based on clinical 
review will be used to identify each type of event.
Adverse Events with Missing Relationship or Missing Serious Indicator

If the relationship to study treatment is missing for a treatment-emergent AE, it’ll be considered as 
related to the study treatment.

If the serious indicator “Was event serious?” is missing, the AE will be considered as SAE.

Adverse events with missing relationship or missing serious indicator will be presented as it is in 
listings, but will be treated as related AEs or SAEs in summary tables.
 
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12.4.4.
Efficacy
Microbiology Procedures

Microbiology data will be received from two sources

Central laboratory

Excel spreadsheets from the study microbiologist and/or clinical scientist

The central laboratory will analyse the bacteriology urine samples by conducting a Gram stain, 
quantifying and identifying uropathogens and will perform susceptibility testing as listed below.

Broth microdilution results (MIC) on all gram-positive uropathogens for gepotidacin, ampicillin, 
trimethoprim-sulfamethoxazole, trimethoprim, sulfisoxazole, ciprofloxacin, levofloxacin, 
nitrofurantoin and vancomycin.

Broth microdilution results (MIC) on all gram-negative uropathogens for gepotidacin, ampicillin, 
amoxicillin/clavulanic acid, ceftolozatone/tazobactam, ceftazidime/avibactam, 
piperacillin/tazobactam, cefazolin, ceftriaxone, meropenem, amikacin, gentamicin, trimethoprim-
sulfamethoxazole, trimethoprim, sulfisoxazole, ciprofloxacin, levofloxacin, nitrofurantoin and 
vancomycin

Amoxicillin/clavulanic acid is tested in the ratio of 2:1, concentrations for 
amoxicillin/clavulanic acid will be expressed as the amoxicillin concentration. 
Piperacillin/tazobactam and ceftolozane/tazobactam are tested with the concentration of 
tazobactam fixed at 4 mg/L, concentrations for piperacillin/tazobactam and 
ceftolozane/tazobactam will be expressed as the piperacillin and ceftolozane 
concentration, respectively. Ceftazidime/avibactam is tested with the concentration of 
avibactam fixed at 4 mg/L, concentrations for ceftazidime/avibactam will be expressed as 
the ceftazidime concentration. Trimethoprim-sulfamethoxazole is tested in the ratio 1:19, 
concentrations for trimethoprim-sulfamethoxazole will be expressed as the trimethoprim 
concentration.

Gradient diffusion results (MIC) on all gram-negative and gram-positive uropathogens 
for:fosfomycin

All gram-negative uropathogens will be also be tested by broth microdilution (MIC) to determine 
indicate production of extended spectrum beta-lactamases (ESBLs). In accordance with the 
Clinical and Laboratory Standards Institute (CLSI) M100 guidelines (Table3A), ESBL production 
may be indicated by a MIC result of >1 mcg/mL for ceftriaxone ceftazidime, cefotaxime or 
aztreonam for E. coli, K. pneumoniae or K. oxytoca or a MIC result of >1 mcg/mL for ceftazidime, 
cefotaxime or cefpodoxime for P. mirabilis.

The data from the study microbiologist and/or clinical scientist will include clarification of which isolates 
should be labelled as uropathogens and qualifying uropathogens and a determination of whether the 
susceptibility results for identically labelled uropathogens from the same participant at the same visit 
differ enough to classify the uropathogens as separate.
 
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Microbiological Data Procedures

Statistics and Programming will identify all cases within the central laboratory dataset where two or 
more uropathogens of the same genus and species have been identified for the same participant at the 
same visit.

An excel file containing a list of these uropathogens and the associated quantitative bacterial counts 
and MIC results for each isolate will be provided to the microbiologist.

The microbiologist will review the list and determine if the isolates are the same or different strains of 
the identified uropathogen based on the susceptibility data patterns.

If there is a ≥ 4-fold difference in MIC to one member of two or more antibiotic classes, then the 
two isolates will be considered two different strains and both will be used in the analysis.

Otherwise, only one isolate will be kept for analysis based on a pre-defined algorithm.

The microbiologist will add a flag to the list to indicate which of the duplicate records to keep. All 
records will be kept in the SDTM datasets, and those records that are deemed to be duplicates will be 
removed from the final Analysis Data Model (ADaM) dataset.

For participants whom the microbiologist has indicated that both sets of uropathogen records should be 
maintained, Statistics and Programming will provide all central laboratory data from all visits for the
particular uropathogens to the microbiologist.

Should the same uropathogen be presented at additional visits, the microbiologist, with the use of the 
MIC result, will make a determination as to which of the baseline uropathogens has been isolated at 
this new visit.

Statistics and Programming will also provide a list of all distinct isolates (by participant, visit, 
identification, and quantitative bacterial count) from the central laboratory to the microbiologist and 
clinical scientist. 

The microbiologist and clinical scientist will provide an excel spreadsheet containing a list of decoded 
uropathogen codes and a flag to indicate which items within the code list are uropathogens and 
qualifying uropathogens for this protocol. This flag will then be merged into the SDTM dataset.
Fold Change

Fold change will be used to describe how much the MIC for gepotidacin changes between baseline and 
subsequent visits for the same bacterial species from the same participant.

Fold change will be calculated (in doubling dilutions) as the ratio of the MIC at the subsequent visit to 
the MIC at baseline visit.
Susceptibility Interpretations

Susceptibility interpretations will be calculated and reported by the central laboratory and will be based 
on the CLSI M100 guidelines in effect at that time the bacterial isolate is tested. 

Since CLSI breakpoints for certain drug/bug combinations can change in new yearly editions of M100 
guidelines, as GSK and/or the central laboratory become aware of relevant breakpoint changes, the 
central laboratory will identify any reports which would qualify as needing a change in interpretation (e.g. 
a MIC value that was originally reported as susceptible, and would now be considered resistant based 
on the new breakpoint), and will issue amended reports. 

The final clinical database will report interpretations according to the most recent CLSI M100 
interpretations regardless of what the breakpoints were at the time the isolate was initially tested.
 
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Quantitative Bacterial Counts

The central laboratory will quantitatively determine the growth of bacterial uropathogens from culture of 
participant urine samples.

The central laboratory will report the following quantification results
o
If there is no growth on the culture plates for a urine sample: 

No growth (<10^3) 
o
If there is growth on the urine culture plates for a urine sample, each uropathogen will receive an 
associated colony count:

10^3-<10^4

10^4-<10^5

>/-10^5

At subsequent visits, determination of ‘no growth’ for individual uropathogens will need to be derived 
from an overall urine culture result of no growth (meaning there was no growth on the urine culture 
plates) or no identification/quantification being reported for that specific uropathogen (assuming that a 
urine sample was taken and that results were reported).

If the bacterial sample at a subsequent visit is not collected then it’s considered as “unable to 
determine” for the uropathogens identified at baseline.
 
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12.5.
Appendix 5: Reporting Standards for Missing Data
12.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study treatment completion is defined as if the participant has taken all doses 
of the study treatment and completed the TOC Visit. Participants who discontinue study 
treatment will not be considered withdrawn from the study and should attend the TOC 
and Follow-up Visits as applicable.

Subject study completion (i.e. as specified in the protocol) is defined as if the participant 
has completed all study visits including the Follow-up Visit.

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data except for efficacy will be included in summary tables 
and figures, unless otherwise specified.
12.5.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.5.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 3: Study Phases 
and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.

Adverse events with entirely missing or unknown start dates will be assumed to be 
on-treatment for reporting.
Concomitant 
Medications/

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
 
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Element
Reporting Detail
Medical 
History
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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12.6.
Appendix 6: Values of Potential Clinical Importance
12.6.1.
ECG
ECG Parameter
Units
Potential Clinically Important Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450[1]
> 450[2]
≤ 479[2]
≥ 480[2]
≤ 499[2]
≥ 500[2]
Absolute PR Interval
msec
< 110[1]
> 220[1]
Absolute QRS Interval
msec
< 75[1]
> 110[1]
Change from Baseline
Increase from Baseline QTc
msec
> 30[1]
> 30[2]
≤ 59[2]
≥60[2]
NOTES:
1.
Represent standard ECG values of PCI for HV studies.
2.
Represent further subdivisions of ECG values for analysis.
12.6.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Potentially Clinically Important Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
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12.7.
Appendix 7: Division of Microbiology and Infectious Disease Adult Toxicity Tables for Adverse 
Event Assessment
12.7.1.
Laboratory Values
Laboratory abnormalities will be graded according to the modified US National institute of Allergy and Infectious Disease Division of 
Microbiology and Infectious Diseases (DMID) criteria [DMID, 2007]. Laboratory results are converted to use SI units.
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 to 10.5 gm/dL
8.0 to 9.4 gm/dL
6.5 to 7.9 gm/dL
<6.5 gm/dL
Absolute Neutrophil Count
1000 to 1500 /mm3
750 to 999 /mm3`
500 to 749 /mm3
<500 /mm3
Platelets
75,000 to 99,999 /mm3
50,000 to 74,999 /mm3
20,000 to 49,999 /mm3
<20,000 /mm3
White Blood Cells
11,000 to 13,000 /mm3
13,000 to 15,000 /mm3
15,000 to 30,000 /mm3
>30,000 or <1000 /mm3
% Polymorphonuclear Leukocytes + 
Band Cells
>80%
90 to 95%
>95%
N/A
Abnormal Fibrinogen
Low: 100 to 200 mg/dL
High: 400 to 600 mg/dL
Low: <100 mg/dL
High: >600 mg/dL
Low: <50 mg/dL
High: N/A
Fibrinogen associated with gross bleeding or 
with disseminated coagulation
Fibrin Split Product
20 to 40 mcg/mL
41 to 50 mcg/mL
51 to 60 mcg/dL
>60 mcg/dL
Prothrombin Time (PT)
1.01 to 1.25 ULN
1.26 to 1.5 ULN
1.51 to 3.0 ULN
>3 ULN
Activated Partial Thromboplastin (APTT)
1.01 to 1.66 ULN
1.67 to 2.33 ULN
2.34 to 3 ULN
>3 ULN
Methemoglobin
5.0 to 9.9%
10.0 to 14.9%
15.0 to 19.9%
>20%
N/A=not applicable; ULN=upper limit of normal. 
 
 
 
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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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12.8.
Appendix 8: Abbreviations & Trade Marks
12.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
Ae[t1-t2]
Amount of Drug Excreted in Urine in a Time Interval
Ae 12h
Amount of Drug Excreted over 12 Hours
AIC
Akaike's Information Criteria
AUC
Area under the Concentration-Time Curve
AUC(0-)
AUC from Zero over the Dosing Interval
BID
Twice Daily
CDISC
Clinical Data Interchange Standards Consortium
CFU
Colony-Forming Units
CI
Confidence Interval
CLr
Renal Clearance
CLSI
Clinical and Laboratory Standards Institute
CLss/F
Apparent Steady State Clearance
Cmax
Maximum Plasma Concentration
CV
Coefficient of Variation
C
Predose Concentration
DBF
Database Freeze
DBR
Database Release
DMID
Division of Microbiology and Infectious Disease
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FDA
Food and Drug Administration
fe%
Percentage of the Given Dose of Drug Excreted in Urine
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
MIC
Minimum Inhibitory Concentration
PD
Pharmacodynamic
PK
Pharmacokinetic
RAP
Reporting & Analysis Plan
Ro
Accumulation Ratio
SAC
Statistical Analysis Complete
SAE
Serious AE
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
SRM
Study Reference Manual
tmax
Time of Occurrence of Cmax
 
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Abbreviation
Description
TOC
Test-of-Cure
UTI
Urinary Tract Infection
12.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin
 
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12.9.
Appendix 9: List of Data Displays
12.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.9
Efficacy
2.1 to 2.9
2.1 to 2.3
Safety
3.1 to 3.12
Pharmacokinetic
4.1 to 4.6
4.1 to 4.10
Pharmacokinetic / Pharmacodynamic
5.1
5.1
Section
Listings
ICH Listings
1 to 36
Non-ICH Listings
37 to 42
12.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in each tables, listings, and figures shells.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PKPD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.9.3.
Deliverables
Delivery 
Description
DS
During Study
SAC
Final Statistical Analysis Complete
NOTE:

A dry run will be performed during the study (DS).
 
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12.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
Intent-to-
Treat
ES1
Summary of Subject Disposition
DS, SAC
1.2.
Intent-to-
Treat
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
DS, SAC
Protocol Deviation
1.3.
Intent-to-
Treat
DV1
Summary of Significant Protocol Deviations
DS, SAC
Demographic and Baseline Characteristics
1.4.
Intent-to-
Treat
DM1
Summary of Demographic Characteristics
DS, SAC
1.5.
Intent-to-
Treat
DM5
Summary of Race and Racial Combinations
DS, SAC
1.6.
Intent-to-
Treat
DM11
Summary of Age Ranges
DS, SAC
1.7.
Intent-to-
Treat
POP_T1
Summary of Disease Characteristics at Baseline
DS, SAC
1.8.
Intent-to-
Treat
MH4
Summary of Past and Current Medication Conditions
DS, SAC
Exposure
1.9.
Intent-to-
Treat
EX1
Summary of Exposure to Study Treatments
DS, SAC
 
 
 
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12.9.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Bacteriology Assessments and Microbiological Outcome and Response
2.1.
Micro-ITT
EFF_T1
Summary of Microbiological Outcome and Response by Visit 
and Qualifying Uropathogen Isolated at Baseline
DS, SAC
2.2.
Micro-ITT
EFF_T2
Summary of Urine Quantitative Bacteriology Culture Results by 
Qualifying Uropahtogen and Visit
DS, SAC
2.3.
Micro-ITT
EFF_T3
Summary of MIC and Susceptibility Results of Qualifying 
Uropathogens
Summarize only qualifying 
uropathogens (flagged by study 
microbiologist and/or clinical scientist), 
including those no present at baseline 
but emerging later
DS, SAC
2.4.
Micro-ITT
EFF_T4
Distribution of MIC Results of Qualifying Uropathogens by Drug
Summarize only qualifying 
uropathogens (flagged by study 
microbiologist and/or clinical scientist), 
including those no present at baseline 
but emerging later
DS, SAC
2.5.
ITT
EFF_T5
Summary of Reduction in Susceptibility to Gepotidacin
Summarize all uropathogens regardless 
of counts
DS, SAC
Clinical Outcome and Response, Therapeutic Response
2.6.
Intent-to-
Treat
EFF_T6
Summary of Investigator-Determined and Sponsor-Determined 
Clinical Outcome and Response by Uropathogen Isolated at 
Baseline
DS, SAC
2.7.
Micro-ITT
EFF_T7
Summary of Therapeutic Response
DS, SAC
2.8.
ITT
EFF_T8
Summary of Clinical Symptom Score by Visit
DS, SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.9.
ITT
EFF_T9
Summary of Clinical Cure by Qualifying Uropathogen Isolated at 
Baseline
DS, SAC
 
 
 
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12.9.6.
Efficacy Figures
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.1.
Micro-ITT
EFF_F1
Percent of Clinical Cure and Microbiological Eradication Over 
Time by Uropathogen Isolated at Baseline
DS, SAC
2.2.
Micro-ITT
EFF_F2
Quantitative Bacterial Counts (CFU/mL) by Qualifying Baseline 
Uropathogen Over Time
DS, SAC
2.3.
Micro-ITT
EFF_F3
Individual Clinical Symptom Score and Boxplot of Total Score 
Over Time
DS, SAC
 
 
 
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12.9.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1.
Safety
AE5B
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade
DS, SAC
3.2.
Safety
AE5B
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Grade
DS, SAC
3.3.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
DS, SAC
Laboratory 
3.4.
Safety
LB1
Summary of Clinical Chemistry Values Change from Baseline
DS, SAC
3.5.
Safety
LB1
Summary of Hematology Change from Baseline
DS, SAC
3.6.
Safety
UR3
Summary of Urinalysis Dipstick Results
DS, SAC
ECG
3.7.
Safety
EG1
Summary of ECG Findings 
DS, SAC
3.8.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
DS, SAC
3.9.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
DS, SAC
3.10.
Safety
EG2
Summary of Change from Baseline in ECG Values
DS, SAC
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Vital Signs
3.11.
Safety
VS3
Summary of Worst Case Vital Signs Results Relative to 
Potential Clinical Importance Criteria Post-Baseline Relative to 
Baseline
DS, SAC
3.12.
Safety
VS1
Summary of Change from Baseline in Vital Signs
DS, SAC
 
 
 
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12.9.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic Concentrations
4.1.
PK
Concentration
PKCT1
Summary of Gepotidacin Plasma Pharmacokinetic 
Concentration-Time Data (units)
SAC
4.2.
PK
Concentration
PKCT1
Summary of Gepotidacin Urine Pharmacokinetic Concentration-
Time Data (units)
SAC
4.3.
PK
Concentration
PKCT1
Summary of Gepotidacin Cervical, Rectal, and Pharyngeal
Pharmacokinetic Concentration-Time Data (units)
SAC
Pharmacokinetic Parameters
4.4.
PK 
Parameter
PKPT4
Summary Statistics of Derived Gepotidacin Plasma 
Pharmacokinetic Parameters
Free and total PK Parameters include: 
AUC(0-tau) (units), AUC(0-24) (units), 
Cmax (units), Tmax (units), CLss/F 
(units), Ro (units), Ctau (units). Do not 
ln-transform Tmax. Ctau will have 
values for Day 1 through 5
SAC
4.5.
PK 
Parameter
PKPT4
Summary Statistics of Derived Gepotidacin Urine 
Pharmacokinetic Parameters
Parameters include: Ae12h (units), 
A(t1-t2) (units), %fe (units), CLr (units), 
Ctau (units), AUC(0-tau) (units), and 
AUC(0-24) (units) for all subjects; 
Ae(t1-t2) include Ae(0-2) (units), Ae(2-
4) (units), Ae(4-6) units), Ae(6-8) 
(units), Ae(8-10) and Ae(10-12) (units). 
Ctau has values on Day 1 through Day 
5
SAC
4.6.
PK 
Parameter
PK_T1
Statistical Analysis of Gepotidacin Plasma Predose
Ctau values of day 1 through 5
SAC
 
 
 
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12.9.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic Concentrations
4.1.
PK
Concentration
PKCF1P
Individual Gepotidacin Plasma Concentration-Time Plots (Linear 
and Semi-Logarithmic)
SAC
4.2.
PK
Concentration
PKCF1P
Individual Gepotidacin Ctau Plasma Concentration-Time Plots 
(Linear and Semi-Logarithmic)
SAC
4.3.
PK
Concentration
PKCF1P
Individual Gepotidacin Urine Concentration-Time Plots (Linear 
and Semi-Logarithmic)
SAC
4.4.
PK
Concentration
PKCF1P
Individual Gepotidacin Ctau Urine Concentration-Time Plots 
(Linear and Semi-Logarithmic)
SAC
4.5.
PK
Concentration
PKCF2
Mean Gepotidacin Plasma Concentration-Time Plots (Linear 
and Semi-Logarithmic)
SAC
4.6.
PK
Concentration
PKCF2
Mean Gepotidacin Ctau Plasma Concentration-Time Plots 
(Linear and Semi-Logarithmic)
SAC
4.7.
PK
Concentration
PKCF2
Mean Gepotidacin Urine Concentration-Time Plots (Linear and 
Semi-Logarithmic)
SAC
4.8.
PK
Concentration
PKCF2
Median Gepotidacin Plasma Concentration-Time Plots (Linear 
and Semi-Logarithmic)
SAC
4.9.
PK
Concentration
PKCF2
Median Gepotidacin Ctau Plasma Concentration-Time Plots 
(Linear and Semi-Logarithmic)
SAC
4.10.
PK
Concentration
PKCF2
Median Gepotidacin Urine Concentration-Time Plots (Linear and 
Semi-Logarithmic)
SAC
 
 
 
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12.9.10.
Pharmacokinetic / Pharmacodynamic Tables
Pharmacokinetic / Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic/Pharmacodynamic Relationship
5.1.
Micro-ITT
PKPD_T1
Summary of Response by Qualifying Baseline Uropathogen for 
Gepotidacin Free Plasma and Urine PKPD Parameters
Summary of Free plasma AUC/MIC, 
Cmax/MIC and urine AUC(0-24)/MIC
and Ctau/MIC vs clinical, 
microbiological and therapeutic success 
and failure by qualifying baseline 
uropathogen.
SAC
 
 
 
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12.9.11.
Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic/Pharmacodynamic Relationship
5.1.
Micro-ITT
PKPD_F1
Plot of Response by Qualifying Baseline Uropathogen for 
Gepotidacin Free Plasma and Urine PKPD Parameters
Plot of ind free plasma AUC(0-24)/MIC, 
Cmax/MIC and urine AUC(0-24)/MIC, 
Ctau/MIC vs clinical, microbiological 
and therapeutic success and failure by
qualifying baseline uropathogen .
SAC
 
 
 
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12.9.12.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
Intent-to-
Treat
ES2
Listing of Reasons for Study Withdrawal
DS, SAC
2.
Intent-to-
Treat
SD2
Listing of Reasons for Study Treatment Discontinuation
DS, SAC
3.
Intent-to-
Treat
SP3
Listing of Subjects Excluded from Any Population
DS, SAC
Protocol Deviations
4.
Intent-to-
Treat
DV2
Listing of Significant Protocol Deviations
DS, SAC
5.
Intent-to-
Treat
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
DS, SAC
Demographic and Baseline Characteristics
6.
Intent-to-
Treat
DM2
Listing of Demographic Characteristics
DS, SAC
7.
Intent-to-
Treat
DM9
Listing of Race
DS, SAC
8.
Intent-to-
Treat
SAFE_L1
Listing of History of Uncomplicated Urinary Tract Infection
DS, SAC
9.
Intent-to-
Treat
MH2
Listing of Medical Conditions
DS, SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Prior and Concomitant Medications
10.
Intent-to-
Treat
CM3
Listing of Prior and Concomitant Medications
DS, SAC
Exposure and Treatment Compliance
11.
Intent-to-
Treat
EX3
Listing of Exposure Data
DS, SAC
Efficacy
12.
Intent-to-
Treat
EFF_L1
Listing of Clinical Outcome and Response
DS, SAC
13.
ITT
EFF_L2
Listing of Urine Specimen Gram Stain Results
DS, SAC
14.
ITT
EFF_L2
Listing of Urine Quantitative Bacteriology Culture Results
DS, SAC
15.
ITT
EFF_L3
Listing of Susceptibility Results
DS, SAC
16.
Intent-to-
treat
EFF_L4
Listing of Gepotidacin MIC Result, Sponsor-Determined Clinical 
Response, Microbiological Outcome and Response, and 
Therapeutic Response by Uropathogen Isolated at Baseline
Page by participants in micro-ITT 
population and participants not in 
micro-ITT population
DS, SAC
Adverse Events
17.
Safety
AE2
Listing of Relationship Between System Organ Class and 
Verbatim Text
DS, SAC
18.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
DS, SAC
19.
Safety
AE8CP
Listing of All Adverse events
DS, SAC
Serious and Other Significant Adverse Events
20.
Safety
AE8CP
Listing of Study Drug Related Adverse Events
DS, SAC
21.
Safety
SAFE_L2
Listing of Serious Adverse Events (Fatal & Non-Fatal)
DS, SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
22.
Safety
AE8CP
Listing of Adverse Events Leading to Discontinuation of Study 
Treatment or Withdrawal from Study
DS, SAC
All Laboratory
23.
Safety
LB5A
Listing of Clinical Chemistry Toxicities of Grade 2 or Higher
DS, SAC
24.
Safety
LB5A
Listing of All Clinical Chemistry Data for Subjects with Toxicities 
of Grade 2 or Higher
DS, SAC
25.
Safety
LB5A
Listing of Hematology Toxicities of Grade 2 or Higher
DS, SAC
26.
Safety
LB5A
Listing of Hematology Data for Subjects with Toxicities of Grade 
2 or Higher
DS, SAC
27.
Safety
UR2A
Listing of Urinalysis Data
Include all urinalysis data for all 
participants
DS, SAC
ECG
28.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
Flag abnormal ECG findings
DS, SAC
29.
Safety
EG3
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
Flag ECG values of PCI
DS, SAC
Vital Signs
30.
Safety
VS4
Listing of All Vital Signs for Subjects with Potential Clinical 
Importance Values
Flag vital sings of PCI
DS, SAC
Liver Events and Other Safety Endpoints
31.
Safety
SAFE_L3
Listing of Clostridium Difficile Results
DS, SAC
32.
Safety
SU2
Listing of Alcohol Intake at Onset of Liver Event
Conditional Display
DS, SAC
33.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
Conditional Display
DS, SAC
34.
Safety
LIVER6
Listing of Liver Stopping Event Information for RUCAM Score
Conditional Display
DS, SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
35.
Safety
LIVER7
Listing of Liver Biopsy Details
Conditional Display
DS, SAC
36.
Safety
LIVER8
Listing of Liver Imaging Details
Conditional Display
DS, SAC
 
 
 
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12.9.13.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable
Pharmacokinetic Concentrations
37.
PK
PKCL1P
Listing of Gepotidacin Plasma Concentrations (units)
SAC
38.
PK
PKUL1P
Listing of Gepotidacin Urine Concentrations (units)
SAC
39.
PK
PKCL1P
Listing of Gepotidacin Free Plasma, Cervical, Rectal and 
Pharyngeal Concentrations (units)
SAC
Pharmacokinetic Parameters
40.
PK Parameter
PKPL1P
Listing of Gepotidacin Plasma Pharmacokinetic Parameters
Parameters include: AUC(0-tau) (units), 
AUC(0-24) (units), Cmax (units), Tmax 
(units), CLss/F (units), Ro (units), Ctau 
(units). Do not ln-transform Tmax. Ctau 
will have values for Day 1 through 5, 
Total and free PK parameters
SAC
41.
PK Parameter
PKPL1P
Listing of Gepotidacin Urine Pharmacokinetic Parameters
Parameters unclude: Ae12h (units), 
AUC(0-24) (units), A(t1-t2) (units), %fe 
(units), CLr (units), Ctau (units) for all 
subjects; Ae(t1-t2) include Ae(0-2) 
(units), Ae(2-4) (units), Ae(4-6) units), 
Ae(6-8) (units), Ae(8-10) and Ae(10-12) 
(units). Ctau has values on Day 1 
through Day 5
SAC
42.
Micro-ITT
EFF_L5
Listing of Qualifying Baseline Uropathogen for Gepotidacin Free 
Plasma and Urine PKPD Parameters
Free plasma AUC/MIC, Cmax/MIC and 
urine AUC(0-24)/MIC, Ctau/MIC
SAC
 
 
 
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