Clinical trial NCT04488770
Conditions: Urinary Tract Infections
Keywords: SAD MAD FTIH Pharmacokinetics Urinary Tract Infections GSK3882347
Sponsor: GlaxoSmithKline
Start date: 2020-08-24; Completion date: 2021-05-14
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, first time in human (FTIH) study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetics (PK) of GSK3882347 in healthy adult men and Woman of Non Childbearing Potential (WONCBP). Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each participant in the SAD cohort will receive a single dose of GSK3882347 or placebo (PBO) in 3:1 ratio and in Part 2 (MAD), participants will be randomized in a 4:1 ratio to receive active treatment and placebo. Part 1 will consist of two cohorts with a maximum of four-period for each cohort, the food effect evaluation will be conducted in last period (Period 4) in only one of the cohorts based on the observed human pharmacokinetics (PK). Part 2 will consist of maximum of four cohorts for each of the MAD dose or placebo.

Detailed description:

Arms: arm 1: In this single ascending dose phase, participants will receive GSK3882347 50 milligram (mg), 150 mg and 250 mg orally on Day 1 of period 1, 2 and 3 respectively. Period 4 will be conducted to assess food effect based on the observed human PK. arm 2: In this single ascending dose phase, participants will receive matching Placebo orally on Day 1 of period 1, 2 and 3. Period 4 will be conducted to assess food effect based on the observed human PK. arm 3: In this single ascending dose phase, participants will receive GSK3882347 500 mg, 15 mg and 900 mg orally on Day 1 of period 1, 3 and 2 respectively. arm 4: In this single ascending dose phase, participants will receive matching Placebo orally on Day 1 of period 1, 3 and 2. arm 5: In this multiple ascending dose phase, participants will receive GSK3882347 50 mg orally on Day 1 to Day 7 of the study. The dose to be administered may be changed based on clinical safety, tolerability and PK findings in Part 1. arm 6: In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study. arm 7: GSK3882347 150 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 4 will be based on PK/PD results from preceding dosing cohorts. arm 8: In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study. arm 9: GSK3882347 500 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 5 will be based on PK/PD results from preceding dosing cohorts. arm 10: In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study. arm 11: GSK3882347 900 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 6 will be based on PK/PD results from preceding dosing cohorts. arm 12: In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study.
Interventions: intervention 1: GSK3882347 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles. intervention 2: Matching strength placebo capsules will be provided

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Double-Blind Randomized, Placebo-Controlled, Single and Repeated 
Oral Dose Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics
(including food effect) of GSK3882347 in Healthy Participants
Protocol Number: 212148
Compound 
Number:
GSK3882347
Study Phase: Phase 1
Short Title: Safety, tolerability and pharmacokinetic investigation of GSK3882347 in 
healthy participants
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT No. 2020-000680-23
Approval Date: 21-OCT-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


P P D
P P D
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 3
21-Oct-2020
2019N400733_03
Amendment 2
10-Jul-2020
2019N400733_02
Amendment 1
02-Jun-2020
2019N400733_01
Original Protocol
05 -Nov-2019
2019N400733_00
Amendment 3: 21-OCT-2020
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall Rationale for the Amendment: This amendment is to allow for additional 
blood samples to be taken from selected cohorts in order to evaluate an in vitro CYP3A4 
induction flag. Plasma derived from whole blood will be analysed for changes in 4β-
hydroxycholesterol and cholesterol ratio as a potential in vivo marker of CYP3A4 
enzyme activity at baseline and following repeat administration of GSK3882347.


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Section # and Name
Description of Change
Brief Rationale
1.3 SoA (Table 3 and
Table 4)
Addition of 4β-
hydroxycholesterol sampling in 
plasma.
To evaluate CYP3A4 induction within 
Part 2 of the study following repeat 
administration of GSK3882347.
1.3 SoA (Table 4)
Continuous cardiac monitoring 
will be approximately 24 hours 
on Days 1 and 7 (part 2 only) in 
both parts.
A line has been added to the table for 
this activity.
There was an omission of the stop 
time included in Table 4 where a “X” 
should have been marked to 
represent the end of this collection 
period.
1.3 SoA (Table 1 to 
Table 4)
Updated language for stool 
sample 
collections/assessments.
Added timing of collection 
window.
Clarification of stool type assessment 
will be performed on all bowel 
movements while in the clinical unit.
Clarification stool collection can be 
up to 72 hours (3 days) prior to 
required sample.
3 Objectives and 
Endpoints
Addition of exploratory 
objective to assess the 
potential effect of repeat doses 
of GSK3882347 on 
Cytochrome P450 3A4 
(CYP3A4) enzyme activity.
To evaluate CYP3A4 induction within 
Part 2 of the study.
4.2 Scientific 
Rationale for Study 
Design
Addition of rationale to use 
plasma marker to explore 
CYP3A4 induction.
GSK3882347A was shown be a 
moderate inducer of CYP3A4 in vitro
and has the potential to contribute to 
DDIs with CYP3A4 substrates, 
including oral contraceptives.
5.3.1 Meals and 
Dietary Restrictions
Clarification of meals and 
snacks.
Standardized meals/food practices 
including snacks and beverages 
provided by the clinical unit.
6.5.2. Prohibited 
Medications
Added prohibited medications.
Prohibited medications which are 
substrates of CYP3A4 and sensitive 
to induction are not permitted.
8.6 Plasma Sample 
for CYP3A4 Enzyme 
Activity
Addition of 4β-
hydroxycholesterol sample 
collection.
Collection details.


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Section # and Name
Description of Change
Brief Rationale
Appendix 9 COVID-
19 Appendix (Section 
10.9.3)
Additions of Protocol Defined 
Procedures/Visits.
As COVID-19 mitigation strategies.
Appendix 10 Protocol 
Amendment History
Relocation of Amendment 2.
Amendment 2 moved to the 
Amendment History.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY..........................................................................................9
1.1.
Synopsis.......................................................................................................9
1.2.
Schema ......................................................................................................14
1.3.
Schedule of Activities (SoA)........................................................................15
2.
INTRODUCTION....................................................................................................36
2.1.
Study Rationale ..........................................................................................36
2.2.
Background ................................................................................................36
2.3.
Benefit/Risk Assessment ............................................................................38
2.3.1.
Acute Monitoring in FTIH Studies ................................................38
2.3.2.
Risk Assessment .........................................................................39
2.3.3.
Benefit Assessment.....................................................................41
2.3.4.
Overall Benefit: Risk Conclusion..................................................41
3.
OBJECTIVES AND ENDPOINTS...........................................................................41
4.
STUDY DESIGN ....................................................................................................43
4.1.
Overall Design ............................................................................................43
4.2.
Scientific Rationale for Study Design ..........................................................44
4.3.
Justification for Dose ..................................................................................45
4.3.1.
Starting dose ...............................................................................46
4.3.2.
Predicted Efficacious Dose ..........................................................48
4.3.3.
Food Effect ..................................................................................49
4.3.4.
Part 2: Starting Dose and Dose Escalation ..................................49
4.4.
End of Study Definition ...............................................................................49
5.
STUDY POPULATION...........................................................................................50
5.1.
Inclusion Criteria.........................................................................................50
5.2.
Exclusion Criteria........................................................................................51
5.3.
Lifestyle Considerations..............................................................................53
5.3.1.
Meals and Dietary Restrictions ....................................................53
5.3.1.1.
Fasted Conditions ......................................................54
5.3.1.2.
Fed Conditions ...........................................................54
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................54
5.3.3.
Activity .........................................................................................55
5.4.
Screen Failures...........................................................................................55
5.5.
Self-isolation...............................................................................................55
6.
STUDY INTERVENTION........................................................................................56
6.1.
Study Intervention(s) Administered .............................................................56
6.2.
Preparation/Handling/Storage/Accountability..............................................56
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................57
6.4.
Study Intervention Compliance ...................................................................58
6.5.
Concomitant Therapy..................................................................................58
6.5.1.
Permitted Medication and Non-Drug Therapies ...........................59
6.5.2.
Prohibited Medication and Non-Drug Therapies...........................59
6.5.3.
Rescue Medicine .........................................................................59


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6.6.
Dose Modification .......................................................................................59
6.7.
Intervention after the End of the Study........................................................59
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................60
7.1.
Discontinuation of Study Intervention..........................................................60
7.1.1.
Gastrointestinal Events (diarrhea or colitis)..................................60
7.1.2.
Liver Chemistry Stopping Criteria ................................................62
7.1.2.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................62
7.1.3.
QTc Stopping Criteria ..................................................................63
7.1.4.
Individual Stopping Criteria ..........................................................63
7.1.5.
Dose Adjustment/Discontinuation Pharmacokinetic Criteria.........63
7.2.
Study Stopping Criteria...............................................................................64
7.3.
Participant Discontinuation/Withdrawal from the Study ...............................64
7.4.
Lost to Follow Up........................................................................................65
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................65
8.1.
Efficacy Assessments.................................................................................66
8.2.
Safety Assessments ...................................................................................66
8.2.1.
Physical Examinations.................................................................66
8.2.2.
Vital Signs....................................................................................66
8.2.3.
Holter Monitoring .........................................................................67
8.2.4.
Electrocardiograms......................................................................67
8.2.4.1.
12-lead safety ECGs ..................................................67
8.2.4.2.
Cardiodynamic assessment (ECGs extracted 
from Holter recordings)...............................................67
8.2.5.
Clinical Safety Laboratory Assessments ......................................68
8.3.
Adverse Events and Serious Adverse Events.............................................68
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................68
8.3.2.
Method of Detecting AEs and SAEs.............................................69
8.3.3.
Follow-up of AEs and SAEs.........................................................69
8.3.4.
Regulatory Reporting Requirements for SAEs .............................69
8.3.5.
Pregnancy ...................................................................................70
8.4.
Treatment of Overdose...............................................................................70
8.5.
Pharmacokinetics .......................................................................................70
8.5.1.
Blood Sample Collection..............................................................70
8.5.2.
Urine Sample Collection ..............................................................71
8.6.
Plasma Sample for CYP3A4 Enzyme Activity .............................................72
8.7.
Pharmacodynamics ....................................................................................72
8.7.1.
Microbiome Assessments............................................................72
8.8.
Genetics .....................................................................................................72
8.9.
Biomarkers .................................................................................................72
8.10.
Health Economics/Medical Resource Utilization and Health 
Economics..................................................................................................73
9.
STATISTICAL CONSIDERATIONS........................................................................73
9.1.
Statistical Hypotheses.................................................................................73
9.2.
Sample Size Determination ........................................................................73
9.3.
Populations for Analyses ............................................................................75
9.4.
Statistical Analyses.....................................................................................76


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9.4.1.
Safety Analyses...........................................................................76
9.4.2.
Pharmacokinetic Analyses...........................................................77
9.4.3.
Other Analyses ............................................................................77
9.5.
Interim Analyses .........................................................................................78
9.5.1.
Dose Escalation Committee (DEC)..............................................78
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................79
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................79
10.1.1.
Regulatory and Ethical Considerations ........................................79
10.1.2.
Financial Disclosure.....................................................................79
10.1.3.
Informed Consent Process ..........................................................79
10.1.4.
Data Protection............................................................................80
10.1.5.
Committees Structure ..................................................................80
10.1.6.
Publication Policy.........................................................................80
10.1.7.
Dissemination of Clinical Study Data ...........................................81
10.1.8.
Data Quality Assurance ...............................................................81
10.1.9.
Source Documents ......................................................................82
10.1.10. Study and Site Closure ................................................................82
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................84
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................86
10.3.1.
Definition of AE............................................................................86
10.3.2.
Definition of SAE..........................................................................87
10.3.3.
Recording and Follow-Up of AE and SAE....................................88
10.3.4.
Reporting of SAE to GSK.............................................................90
10.4.
Appendix 4: Woman of Nonchildbearing Potential (WONCBP) 
Guidance ....................................................................................................91
10.4.1.
Definition......................................................................................91
10.4.2.
Contraception Guidance: .............................................................92
10.4.3.
Collection of Pregnancy Information: ...........................................93
10.5.
Appendix 5: Genetics..................................................................................94
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................95
10.7.
Appendix 7: Country-specific requirements.................................................97
10.8.
Appendix 8: Abbreviations and Trademarks................................................98
10.9.
Appendix 9: COVID-19 Appendix..............................................................101
10.9.1.
Overall Rationale for this Appendix............................................101
10.9.2.
Study Procedures During COVID-19 Pandemic.........................101
10.9.3.
Protocol Defined Procedures/Visits:...........................................101
10.9.4.
Data Management/Monitoring:...................................................102
10.10. Appendix 10: Protocol Amendment History...............................................103
11. REFERENCES.....................................................................................................110


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Double-Blind Randomized, Placebo-Controlled, Single and Repeated 
Oral Dose Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics 
(including food effect) of GSK3882347 in Healthy Participants
Short Title: Safety, tolerability and pharmacokinetic investigation of GSK3882347 in 
healthy participants
Rationale:
GSK3882347 is a potent and specific competitive antagonist of the Escherichia coli
type 1 pilus adhesin molecule FimH which is being developed as an antibiotic-sparing 
treatment for uncomplicated urinary tract infections. The goal of this study is to evaluate 
the safety, tolerability and pharmacokinetic properties (including food effect) of 
GSK3882347 following oral administration of single and repeat doses in healthy adult 
participants.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the safety and 
tolerability of GSK3882347
following oral administration of 
single and repeat doses in 
healthy adult participants

To evaluate the 
pharmacokinetics of 
GSK3882347 in plasma and 
urine following oral 
administration of single and 
repeat doses in healthy adult 
participants

Occurrence of adverse events (AEs) and 
treatment related AEs

Occurrence of clinically significant changes in 
vital signs, laboratory parameters, and 12-lead 
electrocardiogram (ECG) findings

Single dose (plasma): AUC(0-24), AUC(0-t), 
AUC(0-inf), Cmax, C24h, tmax, tlag and t1/2 of 
GSK3882347, as data permit

Repeat dose (plasma): AUC(0-tau), Cmax, tmax 
and Ctau of GSK3882347, as data permit

Urine concentration at 22-24h collection time-
point

Amount excreted in urine (Ae) of unchanged 
GSK3882347, fraction of the dose excreted in 
urine (fe) and renal clearance (CLr), as data 
permit


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Objectives
Endpoints
Secondary

To further evaluate the 
pharmacokinetics of 
GSK3882347 in plasma

To examine dose proportionality 
of GSK3882347 following oral 
administration of single and 
repeat doses in healthy adult 
participants

To evaluate the extent of 
accumulation, time invariance, 
and achievement of steady-
state of GSK3882347 following 
oral administration of single and 
repeat doses in healthy adult 
participants

Single dose (plasma): AUC(0-12), C12h,CL/F, 
Vd/F and MRT of GSK3882347, as data permit

Repeat dose (plasma): AUC(0-12) and C12h of 
GSK3882347, as data permit

AUC(0-inf) and Cmax for single dose and 
AUC(0-tau) and Cmax for repeat dose, as data 
permit

Ro (accumulation ratio) using AUC(0-tau) for 
repeat dose, as data permit

Time invariance using AUC(0-tau) (repeat dose) 
and AUC(0-inf) (single dose)

Achievement of steady-state (Ctau collected on 
multiple days)
To evaluate the effect of food on 
pharmacokinetics of 
GSK3882347 following oral 
administration of single dose in 
healthy adult participants

AUC(0-24), AUC(0-t), AUC(0-inf), C24h, Cmax, 
tmax and tlag, as data permit
Overall Design:
This is a two-part phase I, first-time-in-human (FTIH), randomized, double-blind, single-
center, placebo-controlled, dose-escalation study to determine the safety, tolerability and 
pharmacokinetic profile of GSK3882347 following oral administration of single (Part 1) 
and repeat doses (Part 2) in healthy adult men and women of non-child bearing potential 
(WONCBP). Part 1 will consist of two cohorts with up to a four-period cross-over. The 
food effect evaluation will be conducted in the last period (Period 4) in only one of the 
cohorts based on the observed human pharmacokinetics.
During Parts 1 and 2, participants who met the criteria for study entry will be assigned to 
the current dose level and randomized to receive GSK3882347 or placebo before 
administration of study intervention on Day 1.
Dose escalation will be conducted only if it is supported by safety, tolerability and 
pharmacokinetic results from the preceding dose level(s). This is the first administration 
of GSK3882347 in humans; therefore, preliminary safety, tolerability and 
pharmacokinetic results will be reviewed internally at GSK in conjunction with the study
site and study design adjustments may be made based on emerging data from each dose 
cohort. The point at which Part 2 is initiated can be modified based on the emerging 
safety, tolerability and pharmacokinetic data from Part 1.


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Study schematic is provided in Figure 1
This is a two-part phase I, first-time-in-human (FTIH), randomized, double-blind, single-
center, placebo-controlled, dose-escalation study to determine the safety, tolerability and 
pharmacokinetic profile of GSK3882347 following oral administration of single (Part 1) 
and repeat doses (Part 2) of GSK3882347 in healthy adult men and WONCBP.
Part 1 is a cross-over design single ascending dose study in 2 cohorts with a maximum of
4 periods per cohort that is participant and investigator blinded. The effect of food on a 
single oral dose of GSK3882347 may be evaluated as period 4 of Part 1. The dose of 
GSK3882347 will be selected based on the review of the ongoing data from the prior 
single ascending doses and predicted to be within the predicted therapeutic range.
Part 2 is a multiple ascending dose study in a maximum of 4 cohorts that is participant 
and investigator blinded.
Number of Participants:
Approximately 56 randomized participants will be enrolled for the entire study.
For Part 1, approximately 16 healthy adult participants will be enrolled with a minimum 
of eight participants each in Cohorts 1 and 2, where each cohort may participate in up to 
four periods. In each cohort, a minimum of six participants will be assigned to active 
treatment and a minimum of two participants will be assigned to placebo according to a 
randomization schedule prepared prior to the start of the study.
For Part 2, approximately 40 healthy adult participants will be enrolled with a minimum 
of ten participants in each of the four planned cohorts. In each cohort, a minimum of 
eight participants will be randomized to receive active treatment and a minimum of 
two participants will be randomized to receive placebo according to a randomization 
schedule prepared prior to the start of the study.
Part 1 is planned to include six dose levels. Up to two additional doses (1 per cohort) may 
be evaluated to further understand the study intervention. Part 2 is planned to include four 
dose levels.
If participants prematurely discontinue the study in Parts 1 and 2, they may be replaced at 
the discretion of the sponsor Medical Monitor in consultation with the Principal 
Investigator. The replacement participants will be assigned to the same treatment 
sequence, starting where the prior participant prematurely discontinued. Previously 
administered doses will not be repeated by replacement participants if dose escalation 
criteria are met.
Sample Size Determination and evaluable subjects are described in Section 9.2.


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Intervention Groups and Duration:
Part 1: Single Dose Escalation and Food Effect in Healthy Adult Participants
Part 1 will consist of a maximum of four periods in a cross-over design conducted in two 
separate cohorts of eight healthy participants. Each of these two cohorts may participate 
in a maximum of four periods and will receive three doses (escalations or reductions) of 
GSK3882347 and a potential assessment of food effect. The food effect evaluation will 
be conducted in only one of the cohorts which will be selected based on the observed 
human pharmacokinetics. The planned starting GSK3882347 dose in Part 1 is 50 mg 
administered as a single oral dose. The dose is planned to increase in subsequent cohorts 
to 150, 250, 500, 750, and 900 mg. In each escalating dose level, six participants will be 
randomized to GSK3882347 and two participants will be randomized to placebo.
Participants who meet the criteria for study entry will be assigned to a cohort and 
randomized to receive GSK3882347 or placebo in a 3:1 ratio before administration of 
study intervention on Day 1 in Part 1. As a safety precaution, cohorts 1 and 2 will be split 
into two sub-cohorts to allow sentinel dosing. At each dose level (Cohort 1 and 2), the 
first two participants will receive either GSK3882347 or placebo (one active and one 
placebo). Dosing of the remaining six participants (five active and one placebo) in that 
cohort will occur at least 24 hours later based on review of the safety data (e.g. vital 
signs, ECGs, clinical laboratory results and adverse events) by the Principal Investigator 
and sponsor Medical Monitor from all sub-cohorts of sentinel participants. Doses are 
planned to escalate in a sequential fashion contingent on the safety, tolerability and 
pharmacokinetic profile of a minimum of four participants who received active treatment 
in the previous cohort. Dose escalations or reductions will progress with modifications 
based on the clinical safety, tolerability and preliminary PK data consideration of the area 
under the concentration-time curve (AUC) from time zero to 24 hours after dosing 
(AUC[0-24]) and maximum plasma concentration (Cmax) exposures based on the no-
observed-adverse-effect-level (NOAEL) from the preceding cohorts.
Holter monitoring will be performed on Day 1 for extraction of ECGs paired with PK 
sampling. Continuous ECG recording will not be performed during the food effect 
periods. In case the cardiodynamic evaluation is undertaken at a later time, please refer to 
Section 8.2.4.2.
In Part 1, participants will remain in the clinical unit from admission on Day-1 until all 
scheduled safety and pharmacokinetic assessments have been completed for that dose 
(approximately 5 days) for each period. The duration of study participation will be  
approximately 3 months (~30 days screening, 5 days in-house assessment for the 
completion of each of the four periods, 2 weeks between each dose escalation and ~14-
day follow-up period) for completion of up to four periods. Part 1 will consist of two 
cohorts with up to a four-period cross-over. The food effect evaluation will be conducted 
in last period (Period 4) in only one of the cohorts based on the observed human 
pharmacokinetics.


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Part 2: Repeat Dose Escalation in Healthy Adult Participants
Part 2 consists of a maximum of four ascending repeat-dose cohorts (Cohorts 3 to 6), 
each with 10 participants who will receive a single oral dose of GSK3882347 or placebo 
for 7 days. The earliest point at which Part 2 of the study will be initiated is once the 
single dose safety and preliminary PK data at an exposure that exceeds the daily exposure 
predicted at steady state for the Part 2 planned starting dose of 50 mg is demonstrated in 
Part 1. The planned starting dose of GSK3882347 in Part 2 is 50 mg administered as once
daily Days 1 to Day 7. The dose is planned to increase in subsequent cohorts to 150, 500 
and 900 mg. The starting dose and maximum dose may be changed based on clinical 
safety, tolerability and PK findings in Part 1 or earlier doses in Part 2 and consideration 
of the area under the concentration-time curve (AUC) from time zero to 24 hours after 
dosing (AUC[0-24]) and maximum plasma concentration (Cmax) exposures based on the 
no-observed-adverse-effect-level (NOAEL). 
Participants who meet the criteria for study entry will be assigned to the current dose 
level and randomized to receive GSK3882347 or placebo in a 4:1 ratio before 
administration of study intervention on Day 1 in Part 2. As a safety precaution, cohorts 
will be split into two sub-cohorts to allow sentinel dosing. At each dose level (Cohorts 3-
6), the first two participants will receive either GSK3882347 or placebo (one active and 
one placebo). Dosing of the remaining eight participants (seven active and one placebo) 
in that cohort will occur at least 120 hours later based on review of the safety data (e.g. 
vital signs, ECGs, clinical laboratory results and adverse events) by the Principal 
Investigator and sponsor Medical Monitor from all sub-cohorts of sentinel participants.
The 120 hour timeframe was selected on the basis of available preclinical data, as 
GSK3882347 is anticipated to have reached steady-state by 120 hours, however this 
duration may be increased or decreased based on emerging PK data.
Doses are planned to escalate in a sequential fashion contingent on the preliminary safety, 
tolerability and pharmacokinetic data from Part 1 and at least 7 days of repeat dosing in a 
minimum of five participants who received active treatment in the previous cohort in 
Part 2. The dosing frequency, duration of dosing, and decision to dose (escalations or 
reductions) in the next dose level may be changed based on the safety, tolerability or 
pharmacokinetic findings in Part 1 or earlier doses in Part 2.
Continuous ECG recording will be performed on Day 1 and Day 7 for extraction of 
ECGs paired with PK sampling.
In Part 2, participants will remain in the clinical unit from admission on Day-1 until after 
all scheduled safety and pharmacokinetic assessments have been completed
(approximately 5 days post the last dose or 5 half-lives, whichever is longer based on the 
emerging data from Part 1). The duration of study participation will be up to 
approximately 8 weeks (~30 days screening, up to 12 days in-house assessment period, 
and ~14-days follow-up period).
Dose Escalation Committee: Yes


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1.2.
Schema
Figure 1
Study Design Schema
Notes

A = active, P = placebo

SAD = single ascending dose; MAD multiple ascending dose

Starting SAD dose (Dose Level 1) = (i.e. 50 mg)

Subsequent dose escalations will be determined based on safety and PK data

Part 2 (MAD) may start in parallel with Part 1 (SAD)

Figure shows illustration of planned dosing strategy, which may be changed or cancelled based on 
preliminary safety, tolerability and PK from preceding doses; and does not represent the 
randomization strategy


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1.3.
Schedule of Activities (SoA)
Table 1
Time and Events Table: Screening and Follow-up Visits; Single and Repeat Dose Escalation (Parts 1 and 2)
Procedure
Screening Period (up to 
30 days before Day 1)
Follow-up Visit
(14 days 3 days after the 
last study intervention)
Notes
Informed consent
X
Inclusion and exclusion criteria
X
Recheck clinical status before randomization and/or 
first dose of study intervention
Demography
X
Medical history (includes substance usage and 
family history of premature cardiovascular disease) 
and medication history
X
Substances: drugs, alcohol, tobacco and caffeine
Full physical examination including height and weight
X
Brief physical examination
X
Additional exams/screens may be performed, or brief 
exams made full exams by the Investigator, as 
deemed necessary (e.g. where safety or laboratory 
findings indicate)
AE Review
X
SAE Review
X
X
Serious AEs will be collected from the signing of 
informed consent
Concomitant medication review
X
X
Vital signs (BP, HR, tympanic temperature, 
respiration rate)
X
X
Single measurements will be obtained
Holter monitoring
X
Approximately 24-hour screening
12-lead safety electrocardiogram
X
X
Single measurements will be obtained
Clinical chemistry (including liver chemistries), 
hematology, and urine tests (including urine 
creatinine)
X
X
Human Immunodeficiency Virus (HIV), Hepatitis B 
surface antigen and hepatitis C screen
X
COVID-19 screening
X
Frequency in accordance with site procedures
Urine Drug, Smoke Breathalyzer and Alcohol Breath 
Tests
X


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Procedure
Screening Period (up to 
30 days before Day 1)
Follow-up Visit
(14 days 3 days after the 
last study intervention)
Notes
b-hCG pregnancy/Estradiol/FSH Tests
X
Pregnancy test as appropriate. Urine Pregnancy Kits 
(HCP Pregnancy Test Strip). Estradiol and FSH
at screening as appropriate.
Only women of non-childbearing potential may 
participate
Stool microbiome collection
X
Participants will be given instructions and collection 
items for specimen collection for the follow up 
visit.
The stool sample can be collected up to 72 hours (3 
days) prior to the visit the stool sample is 
required (Follow-up).
Total of 3 collection time points: Day -1, prior to 
discharge and follow-up. The other sample 
collections can be found in SoA Table 2 for Part 
1 and Table 3 and Table 4 for Part 2.
Out Patient Visit
X
X*
*At least 7 days and no greater than 14 days after 
the last study intervention
Additional follow-up visits may be scheduled if there 
are clinical findings at the follow-up visit
AE = adverse event, -hCG = beta human chorionic gonadotropin, BP = blood pressure, FSH = follicle-stimulating hormone, HR = heart rate, SAE = serious adverse event.

The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority 
(CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require 


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alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by 
the CA and the EC before implementation.
Table 2
Part 1 - Single Dose Escalation and Food Effect
Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
Inclusion and 
exclusion criteria
X
Brief physical 
examination
X
X
X
X
Urine Drug, Smoke 
Breathalyzer/Alcohol 
Breath Tests
X
Additional testing may be 
performed at other timepoints
-hCG pregnancy
test
X
Pregnancy test as appropriate
Admission to clinical 
unit
X
Participants to be admitted to 
the unit the day before dosing 
(Day -1) and remain in house 
until discharge
Randomization
X
Randomization will occur 
before first dose in Period 1
Administration of 
study intervention
X
No minimum time interval is 
required between the 
sentinels at each dose level.  
Approximately 15 minutes will 
be observed between the 
dosing of the remaining 
participants
AE Review
X
--------------------------------------------Continuous review-------------------------------------------------------
SAE Review
-----------------------------------------------------------------------Continuous review------------------------------------------------------------
Serious AEs will be collected 
from the signing of informed 
consent.


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Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
Ad hoc COVID-19 
testing based on 
clinical 
presentations and 
site procedures
----------------------------------------------------------------Continuous review-----------------------------------------------------------
X
Sample collected upon 
discharge
Concomitant 
medication review
X
------------------------------------------Continuous review---------------------------------------------------------
Vital signs (BP, HR, 
tympanic
temperature, 
respiration rate)
X
X*
X
X
X
X
X
X
X
X
X
X
*Triplicate measurements of 
blood pressure and pulse rate 
will be obtained pre-dose and 
averaged.
Single measurements will be 
obtained at all other 
timepoints.
Timings will be reviewed as 
cohorts progress and may be 
adjusted to ensure 
appropriate measurements 
relative to peak drug 
concentrations for subsequent 
cohorts.
12-lead safety 
electrocardiogram
X
X*
X
X
X
X
X
X
X
Triplicate 12-lead safety 
ECGs will be obtained no 
more than 15 minutes apart 
within 1-hour pre-dose and 
single measurements will be 
obtained at all other 
timepoints.


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Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
Continuous cardiac 
monitoring**
X*
--------------------------------Continuous review----------------------------------------
**Participants will be semi-
supine resting for at least 10 
minutes prior to and 5 
minutes after each time point 
for ECG extractions.
*3 time points (-45, -30 and -
15 minutes) prior to dosing.
When ECG extractions 
coincide with safety ECGs, 
vital signs assessment and 
blood draws, procedures 
should occur in that order.
Will not be collected in food 
effect.
Clinical chemistry 
(including liver 
chemistries), 
hematology, and 
urine tests (including 
urine creatinine)
X
X
X
X
X
PK Blood Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Details of PK sample 
collection and storage will be 
provided in the Study 
Reference Manual.
Metabolite Blood 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
No metabolite blood samples 
will be collected in the food 
effect groups


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Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
PK/Metabolite Urine 
Sample
X
See urine collection sampling times*
*Urine collection times (hours)
0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 
12-22, 22-24, 24-26, 26-32, 
32-38, 38-48, 48- 60, 60-72, 
72-84, 84-96 post dosing.
If participant is unable to void 
at a specified timepoint, this 
should be recorded in the
CRF.
Participants will void bladder 
prior to dosing.
Voids from urine will be 
combined into 0-24 hr pool for 
metabolite analysis, after 
aliquots for PK are removed.
Genetic sample 
(optional)
X
Collect the genetic sample 
only if the participant has a 
signed consent specific for 
this purpose. Informed 
consent for optional sub-
studies (e.g., genetics 
research) must be obtained 
before collecting a sample.


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Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
Stool microbiome 
collection/ stool type 
assessment*
X
*Continuous stool type assessment of all bowel movements while in the clinical unit.
X
Participants will be given 
instructions and collection 
items for specimen collection.
The stool sample can be 
collected up to 72 hours (3 
days) prior to the visit the 
stool sample is required (Day 
-1 and Day 5).
A last sample will be collected 
on the day closest to the day 
of discharge (Day 5).
The follow-up sample is 
indicated in SoA Table 1.


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Study Days
Procedure
-1
1
2
3
4
5
Notes
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
24
32
48
72
96
Hours relative to study 
intervention
Meal (post dose)
X
See Notes for meal times
Prior to dosing, participants 
will fast for 8 hrs overnight.
No food is allowed for at least 
4 hrs post-dose; after which 
meals will be permitted as per 
site schedule.
Participants will receive 
standardized meals 
scheduled at the same time in 
each period.
Water is permitted with dosing 
and at all times except 1-hour 
pre-dose through 2-hours 
post-dose.
Test Meal
X
Food Effect (Period 4) Part 1
only, participants will eat a 
high fat meal prior to dosing 
as specified in the Study 
Reference Manual.
Daily fluids 
(intake/output)
X*
See assessment times
X
X
X
X
*Assessed approximately 
over 24 hours
Discharge
X
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event.


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
The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority 
(CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require 
alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by 
the CA and the EC before implementation.


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Table 3
Part 2 – 7-Day Repeat Dose Escalation (Days 1 and 7)
Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
Inclusion and exclusion 
criteria
X
Recheck clinical status before 
randomization and/or 1st dose 
of study treatment
Brief physical 
examination
X
Urine Drug, Smoke 
Breathalyzer/Alcohol 
Breath Tests
X
Additional testing may be 
performed at other timepoints
-hCG pregnancy test
X
Pregnancy test as appropriate
Admission to clinical unit
X
Randomization
X
Randomization will occur 
before first dose on Day 1 
only.
Administration of study 
intervention
X
AE Review
X
----------------------------------------Continuous review-----------------------------------------
SAE Review
-------------------------------------------------------------Continuous review----------------------------------------------------------
Serious AEs will be collected 
from the signing of informed 
consent.
Ad hoc COVID-19 
testing based on clinical 
presentation and site 
procedures
-------------------------------------------------------------Continuous review----------------------------------------------------------
Concomitant medication 
review
X
-----------------------------------------Continuous review----------------------------------------


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Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
Vital signs (BP, HR, 
tympanic temperature, 
respiration rate)
X
X*
X
X
X
X
X
X
Vital signs will be obtained 
within 1 hour of pre-dose and 
at 1, 2, 4, 6, 8, 12 and 24 
hours after study 
administration on Days 1 and 
7.
*Triplicate readings of blood 
pressure and pulse rate will 
be taken pre-dose and 
averaged on Days 1 and 7.
Single measurements will be 
obtained at all other 
timepoints.
Timings will be reviewed as 
cohorts progress and may be 
adjusted to ensure 
appropriate measurements 
relative to peak 
concentrations for 
subsequent cohorts.


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Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
12-lead safety 
electrocardiogram
X
X*
X
X
X
X
X
X
*Triplicate 12-lead safety 
ECGs will be obtained no 
more than 15 minutes apart 
within 1-hour pre-dose on 
Days 1 and 7.
Single 12-lead safety ECGs 
will be obtained at 1, 2, 4, 6, 
8, 12 and 24 hours after study 
administration on Days 1 and 
7.
Continuous cardiac 
monitoring**
X*
---------------------------------------------Continuous review----------------------------------------------
**Participants will be semi-
supine resting for at least 10 
minutes prior to and 5 
minutes after each time point 
for ECG extractions.
*3 time points (-45, -30 and -
15 minutes) prior to dosing on 
Day 1.
When ECG extractions 
coincide with safety ECGs, 
vital signs assessment and 
blood draws, procedures 
should occur in that order.


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Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
Clinical chemistry 
(including liver 
chemistries), 
hematology, and urine 
tests (including urine 
creatinine) 
X
PK Blood Sample
X
X
X
X
X
X
X
X
X
X
X
Details of PK sample 
collection and storage will be 
provided in the Study 
Reference Manual.
4β-hydroxycholesterol 
sampling
X
Sample to be taken pre-dose 
on Day 1 in a fasted state.
Metabolite Blood 
Sample
X
X
X
X
X
X
X
X
X
X
X
PK/Metabolite Urine 
Sample
X
See urine collection times*
*Urine collection times (hours)
0-2, 2-4, 4-6, 6-8, 8-10, 10-
12, 12-22, 22-24 post dosing.
Participants will void bladder 
prior to dosing. 0-24-hr urine 
samples will be collected.
Voids from urine will be 
combined into 0-24 hr pool for 
metabolite analysis, after 
aliquots for PK are removed.


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Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
Genetic sample 
(optional)
X
Collect the genetic sample 
only if the participant has a 
signed consent specific for 
this purpose. 
Informed consent for optional 
sub-studies (e.g., genetics 
research) must be obtained 
before collecting a sample.
Stool microbiome 
collection/ stool type 
assessment*
X
*Continuous stool type assessment of all bowel movements while in the clinical unit.
Participants will be given 
instructions and collection 
items for specimen collection.
The stool sample can be 
collected up to 72 hours (3 
days) prior to the visit the 
stool sample is required (Day 
-1).


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Study Days
Procedure
1 and 7
Notes
-1
Predose
0
0.25
0.5
1
1.5
2
4
6
8
12
16
Hours relative to study 
intervention
Meal (post-dose)
X
See Notes for meal times
Prior to dosing on Days 1 and 
7, participants will fast for 8 
hrs overnight.
No food is allowed for at least 
4 hrs post-dose; after which 
meals will be permitted as per 
site schedule.
Water is permitted with 
dosing and at all times except 
1-hour pre-dose through 2-
hours post-dose.
Participants will receive 
standardized meals 
scheduled at the same time in 
each period.
Daily fluids 
(intake/output)
X*
See assessment times.
*Assessed approximately 
over 24 hours
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event.
24-hour procedures are presented in Table 4.
The 4β-hydroxycholesterol sample may not be available from all Cohorts in Part 2, due to the timing of the amendment when this was added.

The timing and number of planned study assessments, including: safety and pharmacokinetic 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. 


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
Any changes in the timing or addition of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority 
(CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require 
alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by 
the CA and the EC before implementation.


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Table 4
Part 2 – 7-Day Repeat Dose Escalation (Days 2 through 6 and Day 8 to 12)
Study Days
Procedure
2
3
4
5
6
8
9-12
Notes
(24hrs 
post-Day 
1 dose)
0
0
0
0
0
(24 hrs 
post-Day 7 
dose)
0
0
Brief physical examination
X
X
X
X
X
X
X*
*Upon discharge
Administration of study 
intervention
X
X
X
X
X
No minimum time interval 
is required between the 
sentinels at each dose 
level.  Approximately 15 
minutes will be observed 
between the dosing of the 
remaining participants
AE Review
---------------------------------------------------------------------Continuous review----------------------------------------------------------------
SAE Review
---------------------------------------------------------------------Continuous review----------------------------------------------------------------
Ad hoc COVID-19 testing 
based on clinical 
presentation and site 
procedures
---------------------------------------------------------------------Continuous review----------------------------------------------
X*
*Sample collected just 
prior to discharge for 
COVID-19 testing
Concomitant medication 
review
---------------------------------------------------------------------Continuous review----------------------------------------------------------------


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Study Days
Procedure
2
3
4
5
6
8
9-12
Notes
(24hrs 
post-Day 
1 dose)
0
0
0
0
0
(24 hrs 
post-Day 7 
dose)
0
0
Vital signs (BP, HR, 
tympanic temperature, 
respiration rate)
X
X
X
X
X
X
X
Single measurements will 
be obtained within 1-hour 
pre-dose and daily in the
morning on days 9-12 
until discharge.
Timings will be reviewed 
as cohorts progress and 
may be adjusted to 
ensure appropriate 
measurements relative to 
peak concentrations for 
subsequent cohorts.
12-lead safety 
electrocardiogram
X
X
X
X
X
X
X
Single 12-lead safety 
ECGs will be obtained 
within 1 hour before pre-
dose and daily in the 
morning on days 9-12 
until discharge.


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Study Days
Procedure
2
3
4
5
6
8
9-12
Notes
(24hrs 
post-Day 
1 dose)
0
0
0
0
0
(24 hrs 
post-Day 7 
dose)
0
0
Continuous cardiac 
monitoring**
X
X
**Participants will be 
semi-supine resting for at 
least 10 minutes prior to 
and 5 minutes after each 
time point for ECG 
extractions.
When ECG extractions 
coincide with safety 
ECGs, vital signs 
assessment and blood 
draws, procedures should 
occur in that order.
Clinical chemistry 
(including liver and kidney 
chemistries), hematology, 
and urine tests (including 
urine creatinine)
X
X
X
X
X
X
X*
*Just prior to discharge.
PK Blood Sample
X
X*
X*
X*
X*
X
*Trough PK samples
4β-hydroxycholesterol 
sampling
X
Sample to be taken at 
24hr post AM dose on 
Day 7. Sample should be 
in a fasted state.
PK Metabolite Sample
X
X
PK Urine Sample
X
X*
X*
X*
X*
X
*Trough PK samples


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Study Days
Procedure
2
3
4
5
6
8
9-12
Notes
(24hrs 
post-Day 
1 dose)
0
0
0
0
0
(24 hrs 
post-Day 7 
dose)
0
0
Stool microbiome 
collection/ stool type 
assessment*
*Continuous stool type assessment of all bowel movements while in the clinical unit.
X**
A last sample will be 
collected on the day 
closest to the day of 
discharge.
The stool sample can be 
collected up to 72 hours 
(3 days) prior to the visit 
the stool sample is 
required (Days 9-12).
**This includes the last 
sample collected on the 
day closest to the day of 
discharge (Days 9-12) for 
microbiome.
The Day -1 sample is 
indicated in SoA Table 4
and follow-up sample is 
indicated in SoA Table 1.
Meal
X
X
X
X
X
X
X
Participants will receive 
standardized meals 
scheduled at the same 
time in each period.
Daily fluids (intake/output)
X
X


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Study Days
Procedure
2
3
4
5
6
8
9-12
Notes
(24hrs 
post-Day 
1 dose)
0
0
0
0
0
(24 hrs 
post-Day 7 
dose)
0
0
Discharge
X
X
Participants will be 
discharged from the 
clinical unit after the  
assessments are 
completed.
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event.
The 4β-hydroxycholesterol sample may not be available from all Cohorts in Part 2, due to the timing of the amendment when this was added.

The start of Part 2 can be modified from emerging data from Part 1.

The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging pharmacokinetic/pharmacodynamic 
data from this study 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 Competent Authority (CA) and ethics committee (EC) will be informed of any safety issues that constitute a 
substantial amendment and require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be 
approved by the CA and the EC before implementation.


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2.
INTRODUCTION
GSK3882347, a FimH (bacterial adhesin) antagonist, is a potent, novel non-antibiotic that 
is being developed for the treatment of uncomplicated urinary tract infections caused by 
uropathogenic Escherichia coli (UPEC).
2.1.
Study Rationale
The goal of this study is to evaluate the safety, tolerability and pharmacokinetic 
properties (including food effect) of GSK3882347 to enable clinical development of the 
molecule as an antibiotic-sparing treatment for uncomplicated urinary tract infections.
Bacteria possess adhesins, which are cell-surface components or appendages that 
facilitate adhesion or adherence to other cells or to surfaces. GSK3882347 is a potent and 
specific competitive antagonist of the Escherichia coli type 1 pilus adhesin molecule 
FimH, designed to disrupt the interaction between FimH and mammalian mannose-rich 
glycoproteins, such as uroplakin Ia and integrins in the bladder epithelium and other 
epithelia.
GSK3882347 is being developed as an antibiotic-sparing medicine to treat or prevent 
infection of the bladder mucosa, via inhibition of FimH protein function on UPEC, which 
cause approximately 85% of all urinary tract infections. It is anticipated that the use of 
GSK3882347 will help combat the increasing antimicrobial resistance (AMR) to 
traditional antibiotics that threatens to increase greatly the economic burden, morbidity 
and mortality associated with bacterial infections [O’Neill, 2016].
Preclinical data in a murine urinary tract infection (UTI) model supports the use of a 
FimH antagonist in both the treatment and prevention of uncomplicated UTI (uUTI) in 
both infection naïve mice and previously infected mice (a recurrent UTI (rUTI) model). 
In vitro data indicate that GSK3882347 is an effective antagonist of FimH in a broad 
range of clinical UPEC strains. Further, GSK3882347 was effective against a subset of 
these strains representing all the major UPEC FimH alleles in both the murine UTI 
treatment model and in an in situ human bladder tissue binding assay. GSK3882347 
inhibited binding in a concentration-dependent manner by >95% at 30 µM (or less). In 
vivo efficacy studies were also completed using the acute therapeutic model in mice with 
UPEC strain UTI89 to correlate microbiological efficacy and urinary exposure. A 
preliminary PK/PD target for GSK3882347 was determined as the maintenance of a 
trough concentration of ≥5 µM in urine for the duration of the dosing period. Based on 
the studies described above, a target Cmin concentration range of 5-30 µM was defined 
to support dose selection in this study.
2.2.
Background
UTIs 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 


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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 
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].
Due to the increase of more resistant strains, guidelines for acute cystitis now recommend 
first-line antibiotic treatment with nitrofurantoin, trimethoprim-sulfamethoxazole 
(TMP- SMX), fosfomycin, or pivmecillinam, assuming the drug is available and the 
patient does not have a concerning allergy history or tolerance issues [Gupta, 2011b]. 
TMP- SMX should not be used as a first-line treatment if the prevalence of resistance 
exceeds the 20% threshold or if TMP-SMX 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.
Continuous low dose antibiotic is effectively prophylaxis for recurrent urinary tract 
infections (rUTI). Other options include postcoital antibiotic prophylaxis prevention in 
sexually active females, vaginal estrogen in postmenopausal women, other treatments and 
behavioural modifications. With the rise of antibiotic resistance, additional treatment 
strategies and prevention measures for rUTI has led to potential non-antibiotic treatment 
approaches for rUTI.
GSK3882347 will be the first antibiotic-sparing medicine to treat or prevent infection of 
the bladder mucosa, via inhibition of FimH protein function on uropathogenic E. coli
(UPEC), which cause approximately 85% of all UTIs. Use of GSK3882347 will help 
combat the increasing antimicrobial resistance (AMR) to traditional antibiotics that 
threatens to increase greatly the economic burden, morbidity and mortality associated 
with bacterial infections [O’Neill, 2016].
Summaries of the non-clinical safety and pharmacology are included in the 
GSK3882347-Investigator’s Brochure [GlaxoSmithKline Document Number
2019N403317_01, 2020].
In light of the global COVID-19 pandemic, all participants will be screened for COVID-
19 prior to, during and at the end of the study period. Please see further details for risk 
assessment and mitigation strategy below.


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2.3.
Benefit/Risk Assessment
2.3.1.
Acute Monitoring in FTIH Studies
Consistent with GSK standards for early phase studies, the study will be conducted in a 
Phase 1 Clinical Research Unit with previous experience with first-time-in-human trials 
and immediate access to hospital facilities for the treatment of medical emergencies.
GSK3882347 will be administered in an in-patient setting (with sufficient overnight 
facilities) with appropriate monitoring. To minimize the risk of the initial human 
administration of GSK3882347, a sentinel dosing strategy will be utilized at each dose 
level: 1 participant will receive GSK3882347 and 1 participant will receive placebo. 
After the GSK Medical Monitor and Principal Investigator have reviewed the safety data 
through 24 hours post-dose in the Part 1 and at least 120 hours in Part 2, the remaining 
participants from that cohort will be dosed.
Once all assessments through 24 hours post-dose have been completed in a minimum of 
four participants on active treatment in Part 1 and at least 7 days of dosing in a minimum 
of 5 participants on active treatment in Part 2, the GSK team and the investigator will 
review all the available safety and PK data from all participants before proceeding to the 
next dose level. Additional information can be found in the Dose Escalation Plan. More 
detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of GSK3882347 may be found in the GSK3882347 
Investigator’s Brochure [GlaxoSmithKline Document Number 2019N403317_01, 2020].
The following section outlines the risk assessment and mitigation strategy for this 
protocol:


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2.3.2.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK 3882347
Gastrointestinal toxicity
(including body weight loss, decreased 
food consumption and dehydration)
Dogs given ≥300 mg/kg/day had severe 
body weight loss, decreased food 
consumption, dehydration, emesis and 
abnormal feces.  Dogs given 
1000 mg/kg/day were euthanized early due 
to severity of body weight loss.
Pregnant rabbits given ≥300 mg/kg/day had 
severe body weight loss and decreased food 
consumption, which resulted in early 
euthanasia and 1 early death at 
900 mg/kg/day.
These changes in dogs and rabbits resulted 
in early euthanasia or death at the doses 
stated. Nonclinical Risks – concluding 
sections of the Non-Clinical Assessment of 
Safety (NCAS) should provide key 
nonclinical risks associated with the IP.
Dosing for a maximum of 7 days.
Standard clinical monitoring with 
elicitation of clinical symptoms; physical 
examinations and routine safety blood 
haematology and chemistry tests.
Monitoring for AEs.
Monitoring daily fluid balance in 
participants.
Gastrointestinal stopping criteria: 
Participant will continue to dose through 
grade 1 toxicity, interrupt dosing for 
grade 2 toxicity and discontinue drug for 
grade 3-4 toxicity (for the latter, 
consultation with GI experts will occur 
with no plan for drug restart) (see Section
7.1.1)
Monitoring of stool type with the Bristol 
stool chart to identify changes in bowel 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
habit which may represent 
gastrointestinal toxicity.
OTHER
COVID-19
Participation within a hospital environment 
may increase risk of contracting COVID-
19.
Exposure to other participants and staff 
may increase risk of exposure.

Monitoring of clinical presentation 
of COVID-19 signs/symptoms.

Conduct study at sites which have 
appropriate mitigation strategies in 
place.


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2.3.3.
Benefit Assessment
This is a study in healthy participants; no medical benefit will be derived by volunteers’ 
participation. However, participants in this study may be contributing to the development
of new therapies in an area of unmet need.
2.3.4.
Overall Benefit: Risk Conclusion
Given the preclinical profile of GSK3882347, measures taken (careful selection of the 
participants and the extent of safety monitoring incorporated into the study) and the 
planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3882347 are low, evaluable, and manageable.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and 
tolerability of GSK3882347 following 
oral administration of single and 
repeat doses in healthy adult 
participants

To evaluate the pharmacokinetics of 
GSK3882347 in plasma and urine 
following oral administration of 
single and repeat doses in healthy 
adult participants

Occurrence of adverse events (AEs) 
and treatment related AEs

Occurrence of clinically significant 
changes in vital signs, laboratory 
parameters, and 12-lead 
electrocardiogram (ECG) findings

Single dose (plasma): AUC(0-24), 
AUC(0-t), AUC(0-inf), Cmax, C24h, 
tmax, tlag and t1/2 of GSK3882347, 
as data permit

Repeat dose (plasma): AUC(0-tau), 
Cmax, tmax and Ctau of 
GSK3882347, as data permit

Urine concentration at 22-24h 
collection time-point

Amount excreted in urine (Ae) of 
unchanged GSK3882347, fraction of 
the dose excreted in urine (fe) and 
renal clearance (CLr), as data 
permit
Secondary

To further evaluate the 
pharmacokinetics of GSK3882347 in 
plasma

Single dose(plasma): AUC(0-12), 
C12h,CL/F, Vd/F and MRT of 
GSK3882347, as data permit


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Objectives
Endpoints

To examine dose proportionality of 
GSK3882347 following oral 
administration of single and repeat 
doses in healthy adult participants

To evaluate the extent of 
accumulation, time invariance, and 
achievement of steady-state of 
GSK3882347 following oral 
administration of single and repeat 
doses in healthy adult participants

Repeat dose (plasma): AUC(0-12) 
and C12h of GSK3882347, as data 
permit

AUC(0-inf) and Cmax for single 
dose and AUC(0-tau) and Cmax for 
repeat dose, as data permit

Ro (accumulation ratio) using 
AUC(0-tau) for repeat dose, as data 
permit

Time invariance using AUC(0-tau)
(repeat dose) and AUC(0-inf) (single 
dose)

Achievement of steady-state (Ctau 
collected on multiple days)

To evaluate the effect of food on 
pharmacokinetics of GSK3882347 
following oral administration of 
single dose in healthy adult 
participants

AUC(0-24), AUC(0-t), AUC(0-inf), 
C24h, Cmax, tmax and tlag, as data 
permit
Exploratory

To assess ECG effects of GSK3882347, 
including concentration-QTc analysis, 
following single and repeat doses in 
healthy adult participants

Change-from-baseline QTc (∆QTcF)

Change-from-baseline heart rate, PR 
and QRS interval (∆HR, ∆PR and 
∆QRS)

Placebo-corrected ∆QTcF, ∆HR, ∆PR 
and ∆QRS

Treatment emergent T-wave 
abnormalities and presence of U-waves

Categorical outlier analysis for HR, 
QTcF, PR and QRS


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Objectives
Endpoints

To investigate the plasma and urine 
metabolic pathways of GSK3882347 in 
healthy participants

Characterization of the plasma and 
urinary metabolites of GSK3882347, 
estimation of the percentage dose 
eliminated in urine, where possible

To characterize the effect of 
GSK3882347 on intestinal microbiota
following single and repeat doses in 
healthy adult participants

Change in intestinal microbiome over 
time

To assess potential effect of repeat
doses of GSK3882347 on Cytochrome
P450 3A4 (CYP3A4) enzyme activity in 
Part 2

Plasma 4β-hydroxycholesterol to 
cholesterol ratio at pre-treatment and 
following repeat dosing of GSK3882347
Note: The exploratory endpoints may be analyzed as GSK3882347 clinical development 
continues.
4.
STUDY DESIGN
4.1.
Overall Design
This is a two-part phase I, FTIH, randomized, double-blind, single-center, placebo-
controlled, dose-escalation study to determine the safety, tolerability and 
pharmacokinetics of GSK3882347 following oral administration of single (Part 1) and 
repeat doses (Part 2) in healthy adult men and WONCBP. Part 1 will consist of two 
cohorts with a maximum of four-period cross-over. The food effect evaluation will be 
conducted in the last period (Period 4) in only one of the cohorts based on the observed 
human pharmacokinetics.
During Parts 1 and 2, participants who meet the criteria for study entry will be assigned 
to the current dose level and randomized to receive GSK3882347 or placebo before 
administration of study intervention on Day 1.
Dose escalation will be conducted only if it is supported by safety, tolerability and 
pharmacokinetic results from the preceding dose level(s). This is the first administration 
of GSK3882347 in humans; therefore, preliminary safety, tolerability and 
pharmacokinetic results will be reviewed internally at GSK in conjunction with the study 
site and study design adjustments may be made based on emerging data from each dose 
cohort. The repeat dose escalation component (Part 2) of this study will be initiated once 
safety at an exposure that exceeds the daily exposure predicted at steady state for the 
Part 2 planned starting dose of 50 mg has been demonstrated in Part 1. This is predicted 
to occur at the 250 mg single dose. The point at which Part 2 is initiated can be modified 
based on the emerging safety, tolerability and pharmacokinetic data from Part 1.
In Part 1, participants will remain in the clinical unit from admission on Day-1 until all 
scheduled safety and pharmacokinetic assessments have been completed for that dose 
(approximately 5 days) for each period. The duration of study participation will be 
approximately 3 months (~30 days screening, 5 days in-house assessment for the 


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completion of a maximum of the four periods, 2 weeks between each dose escalation and 
~14-day follow-up period) for completion of up to four periods. Part 1 will consist of two 
cohorts with up to a four-period cross-over. The food effect evaluation will be conducted 
in last period (Period 4) in only one of the cohorts based on the observed human 
pharmacokinetics.
In Part 2, participants will remain in the clinical unit from admission on Day-1 until after 
all scheduled safety and pharmacokinetic assessments have been completed
(approximately 5 days post the last dose or 5 half-lives, whichever is longer based on the 
emerging data from Part 1). The duration of study participation will be up to 
approximately 8 weeks (~30 days screening, up to 12 days in-house assessment period, 
and ~14-days follow-up period).
Study schematic is provided in Figure 1.
4.2.
Scientific Rationale for Study Design
The current study has been designed to address regulatory guidance for FTIH studies in 
particular General Considerations for Clinical Trials [The International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E8/ 
Committee For Proprietary Medicinal Products (CPMP)/ICH/291/95] and Guideline on 
Strategies to Identify and Mitigate Risk for First time in -Human Clinical Trials with 
Investigational Medical Products [EMEA/CHMP/SWP/28367/07] including participant 
selection, estimation of starting dose, precautions that are applied within and between 
dosing cohorts, dose escalation scheme, risk mitigation, and stopping rules.
This study represents the first administration of GSK3882347 in humans. The aim of the 
FTIH is to generate human safety, tolerability and pharmacokinetics of GSK3882347 in 
healthy participants. The study will be conducted in healthy adult participants comprising
of healthy adult men and WONCBP.
Scheduled assessments of subjective symptoms, and objective clinical laboratory tests, 
vital signs, and 12-lead safety electrocardiograms (ECGs) will be obtained to monitor 
participant safety.
The single dose assessments in Part 1 will be conducted to determine safety, tolerability 
and pharmacokinetics of the study intervention in individuals before progressing to doses 
explored further in other parts of the study and will allow for any adjustments needed 
based on emerging safety, tolerability and PK data. Part 1 will also include the evaluation 
of the effect of food on GSK3882347.
Part 2 of this study is planned to include 7 days of repeat dosing to provide sufficient 
safety, tolerability, and PK as this is the anticipated dosing duration which will be used in 
females with recurrent UTI (rUTI). The dosing duration may be adjusted depending on 
PK data collected in Part 1 of the study.
Preclinical studies following oral administration as a suspension to rat and mini-pig, 
demonstrated that bioavailability was moderate (~40%) suggesting incomplete absorption 
of compound from the GI tract since first pass hepatic extraction was predicted to be low. 


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Bioavailability in the female rat following IP administration, which bypasses the GI tract, 
but not the liver, was ~75%, further supporting this supposition. The solubility in FeSSIF 
(Fed-state simulated intestinal fluid, pH 6.5) was significantly higher than solubility 
observed in SGF (simulated gastric fluid) and FaSSIF (Fasted-state simulated intestinal 
fluid). The concentration in FaSSIF is 0.4 to 0.5 mg/mL.  The FeSSIF solubility was 
higher than the experimental maximum (1.13 mg/mL); therefore, the maximum solubility 
achievable in GI fluids is not yet known.
Following review of safety, tolerability, and pharmacokinetic data in Part 1, the food 
effect dose of GSK3882347 will be selected based on an assessment of the ongoing data 
from the prior single ascending doses. The formulation used for this study will be a 
capsule of GSK3882347 prepared by extemporaneous compounding. The preliminary 
results will be used to determine whether an effect of food on GSK3882347 can be 
anticipated in future studies which will utilise a tablet formulation and will help to guide 
the pivotal food effect study and commercialization [DHHS, 2019].
Current preclinical data and dose predictions do not indicate any cardiovascular risk. The 
study will evaluate the exposure-response relationship between GSK3882347 and QTcF 
as a possible alternative to conducting a thorough QT/QTC study [Darpo, 2014]. ECG 
wave forms will be collected in both parts and stored for potential analysis, depending on 
observed PK and other project considerations. The food effect in Part 1 will not be part of 
the cardio-dynamic evaluation.
A definitive in vitro study using human hepatocytes revealed that GSK3882347 was 
moderate inducer of CYP3A4. Based on the in vitro data and using preliminary risk 
assessments, GSK3882347A has the potential to perpetrate DDIs when co-dosed with 
CYP3A4 substrates, including oral contraceptives (OCs), resulting in a potential loss of 
efficacy of OCs and other substrates. Therefore, plasma 4β-hydroxycholesterol, a 
potential in vivo marker of CYP3A4 enzyme activity will be measured within Part 2 
(subset - not all cohorts). A comparison will be made between the ratio of 4β-
hydroxycholesterol: cholesterol in plasma at baseline and on Day 8 (i.e. approximately 24 
hours after the Day 7 dose) in order to assess potential changes in CYP3A4 enzyme 
activity following repeat dosing of GSK3882347. This information, combined with 
PBPK modelling, may help to better inform the risk of co-administering GSK3882347 
with OCs in future clinical studies which may include women of childbearing potential.
4.3.
Justification for Dose
Estimated human pharmacokinetics for GSK3882347 were generated using a 
physiologically based pharmacokinetic (PBPK) model that correlates plasma and urine 
exposures incorporating estimates of renal and non-renal clearance derived from single 
species scaling of observed in vivo male rat and dog data. The predicted human clearance 
of GSK3882347 using rat or dog data differed by approximately 10-fold, therefore, two 
separate predictions of likely human pharmacokinetics and exposure for GSK3882347 in 
plasma and urine were established for a 70 kg human.
The highest planned dose in this study is 900 mg, which, for the human exposure 
prediction based on dog PK, provides 1.8-fold coverage to the rat NOAEL, when dosed 


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once-daily repeat doses. The doses in the protocol may be amended based on emerging 
human safety and PK data, however the human exposure will remain below the rat 
NOAEL and ICHQ3 principles will be followed to ensure that any impurities present in 
the drug product remain at acceptable levels if dose levels above 900 mg are used.
4.3.1.
Starting dose
A single dose of 50 mg of GSK3882347 has been selected as the first dose to be 
administered to humans. This starting dose is calculated to have a 48.3-fold NOAEL 
safety margin to the human AUC0-24 predicted based on the dog PK and a 251-fold safety 
margin to the human AUC0-24 predicted based on the rat PK (Table 5 and Table 6). An
81.0-fold NOAEL safety margin to the human Cmax is predicted based on the dog PK 
and a 205-fold safety margin is predicted using the rat PK (Table 5 and Table 6).
Margins to the rat GLP toxicity study NOAEL are presented as the systemic exposure 
was lower in the rat as compared to the dog at the NOAEL (most conservative approach). 
The NOAEL in the 14-day GLP rat toxicity study was the top dose of 450 mg/kg/day and 
was associated with an AUC0-24,SS of 193 μg*h/mL and Cmax of 16.2 μg/mL. As
GSK3882347 does not have a human target, the Minimal Anticipated Biological Effect 
Level (MABEL) in humans for GSK3882347 could not be calculated.
The planned doses for dose escalation in Part 1 after dosing the first cohort with 50 mg 
are 150, 250, 500, 750, and 900 mg. Following each dose, the systemic PK (up to 24h 
post-dose) and safety data will be evaluated. The systemic exposure, Cmax and AUC (up 
to 24h) (where data permits) will be calculated for the current dose and predicted for the 
next dose level assuming linear PK. The predicted Cmax and AUC will be compared 
with the NOAEL from the rat and dog preclinical toxicology studies. The proposed dose 
for the next cohort may be modified if necessary; increments will be no greater than 
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Table 5
Predicted Human AUC0-24 and Cmax Safety Margins Following 
Single and Multiple Dose Administration of GSK3882347 (Predicted 
Human PK Based on Dog PK)
Dose 
(mg)§
Predicted 
human AUC0-24 
(µg*h/mL)#
Safety fold 
cover for 
AUC*
Predicted 
human Cmax 
(µg/mL)
Safety fold 
cover for 
Cmax*
SAD
900
40.5
4.77
1.94
8.34
750
38.0
5.08
1.80
9.00
500
32.0
6.03
1.60
10.1
250
19.0
10.2
0.96
16.9
150
11.8
16.4
0.60
27.0
50
4.00
48.3
0.20
81.0
MAD
900 QD
107
1.80
4.97
3.26
500 QD
80.0
2.41
3.70
4.38
150 QD
26.5
7.29
1.28
12.7
50 QD
8.87
21.8
0.43
37.7
§  Predicted efficacious exposure 50 mg (based on 5 μM target) and 300 mg (based on 30 μM target).
# Predicted AUC0-24 at steady-state (SS) was used for the calculations of the MAD safety margins.
* Safety margins calculated using the NOAEL determined based on the 14-day GLP rat toxicity studies as 
AUC0-24,SS of 193 μg*h/mL and Cmax of 16 μg/mL at the dose of 450 mg/kg/day.


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Table 6
Predicted Human AUC and Cmax Safety Margins Following Single 
and Multiple Dose Administration of GSK3882347 (Predicted Human 
PK Based on Rat PK)
Dose 
(mg) §
Predicted human 
AUC0-24 
(µg*h/mL) #
Safety fold 
cover for 
AUC*
Predicted 
human Cmax 
(µg/mL)
Safety fold 
cover for 
Cmax*
SAD
900
8.61
22.4
0.73
22.3
750
8.12
23.8
0.68
23.8
500
6.64
29.1
0.57
28.3
250
3.76
51.3
0.36
45.1
150
2.29
84.3
0.23
70.1
50
0.77
251 
0.08
205
MAD
900 QD
9.48
20.4
0.81
19.9
500 QD
6.87
28.1
0.60
27.2
150 QD
2.32
83.2
0.23
69.2
50 QD
0.78
248
0.08
203
§  Predicted efficacious exposure 300 mg (based on 5 μM target) and 650 mg (based on 30 μM target).
# Predicted AUC0-24 at steady-state (SS) was used for the calculations of the MAD safety margins.
* Safety margins calculated using the NOAEL determined based on the 14-day GLP rat toxicity studies 
as AUC0-24,SS of 193 μg*h/mL and Cmax of 16.2 μg/mL at the dose of 450 mg/kg/day.
The United States Food and Drug Administration (FDA) guidance suggests calculating a 
human equivalent dose (HED), based on the NOAEL in the most sensitive or most 
relevant preclinical species, utilizing scaling factors that are based on differences in body 
surface area between species. The HED is converted to a maximum recommended 
starting dose (MRSD) in humans by dividing by a safety factor (default = 10). The safety 
factor may be adjusted depending on the pharmacology, toxicology, preclinical 
pharmacokinetics of the drug, or previous experience with compounds in the same 
pharmacologic/structural class. Using the rat NOAEL, the HED was calculated to be 
73 mg/kg. With a safety factor of 10, the estimated MRSD in humans would be 438 mg 
for a 60 kg human. The MRSD dose is ~ 8.8-fold higher than our proposed initial dose of 
50 mg [DHHS, 2005].
4.3.2.
Predicted Efficacious Dose
An in-situ binding assay was used to characterize GSK3882347 mediated inhibition of 
UPEC binding to healthy or inflamed human bladder epithelium. Although there was 
much variation in the level of binding by the strains to human bladder tissue- either 
healthy or inflamed, all strains tested could be inhibited by GSK3882347 and in the clear 
majority of cases tissue binding was inhibited by >95% at 30 µM (or less), relative to 
vehicle controls. In vivo efficacy studies were also completed using the acute therapeutic 
model in mice with UPEC strain UTI89 to correlate microbiological efficacy and urinary 
exposure. A preliminary PK/PD target for GSK3882347 was determined as the 
maintenance of a trough concentration of ≥5 µM in urine for the duration of the dosing 
period. Importantly, achieving this target provided maximal efficacy regardless of dosing 


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regimen (regimens evaluated: QD, BID, and TID). Based on the studies described above, 
a target Cmin concentration range of 5-30 µM was defined to support dose selection in 
this study.
The predicted efficacious doses for humans were calculated using the PBPK model based 
on the target urine Cmin range of 5-30 µM at day 1 and considering the difference in the 
rat and dog pharmacokinetics (see Table 7).
Table 7
Anticipated Therapeutic Dose Range Considering Different Target 
Urine Cmin and Human Predicted Pharmacokinetics Based on Rat 
and Dog Pre-clinical Data
4.3.3.
Food Effect
The dose of GSK3882347 to be administered will be determined from Part 1 to ensure an 
adequate safety margin assuming an arbitrary two-fold increase in exposure to 
GSK3882347 when administered with food.
4.3.4.
Part 2: Starting Dose and Dose Escalation
Four dose levels are planned, with escalation increments no greater than 3.5-fold. The 
lowest dose is expected to be 50 mg. The highest dose will not exceed the top dose tested 
in Part 1. Doses and dosing regimen will be based on findings from Part 1 and emerging 
observations in Part 2.
4.4.
End of Study Definition
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
Predicted Human Therapeutic Dose
Urine target Cmin (μM)
Based on Dog PK
Based on Rat PK
5
50 mg
300 mg
30
300 mg
650 mg


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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1.
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring. A 
participant with a clinical abnormality or laboratory parameter(s) not specifically 
listed in the exclusion or exclusion criteria that is outside the reference range for the 
population being studied may be included only if the investigator, in consultation 
with the Medical Monitor (if required), agree and document that the finding is 
unlikely to introduce additional risk factors and will not interfere with the study 
procedures.
Weight
3.
Body weight at least 50.0 kg (110 lbs.) for males and 45.0 kg (99 lbs.) for females; 
and body mass index (BMI) within the range 18.5 – 32.0 kg/m2 (inclusive).
Sex
4.
Male and female participants
a.
Female Participants: 
A female participant is eligible to participate if she is of non-childbearing potential 
as defined in Appendix 4
b. Male Participants: 
Male participants are eligible to participate if they agree to the following during the 
intervention period for at least five days, corresponding to time needed to eliminate 
study intervention(s) (e.g. 5 terminal half-lives) after the last dose of study 
intervention:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 


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OR

Must agree to use contraception/barrier as detailed below 
o
Agree to use a male condom and should also be advised of the benefit 
for a female partner to use a highly effective method of contraception 
(see Appendix 4) as a condom may break or leak when having sexual 
intercourse with a woman of childbearing potential who is not 
currently pregnant.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory, hepatic, urological, 
gastrointestinal, endocrine, haematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study intervention; or interfering with the 
interpretation of data.
2.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN)
3.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%)
4.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(except for Gilbert's syndrome or asymptomatic gallstones).
5.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
6.
Exclusion criteria for screening ECG:
Males
Females
Heart rate
<45 or >100 bpm
<50 or >100 bpm
PR Interval
<120 or >220 msec
QRS duration
<70 or >120 msec
QTcF interval 
>450 msec
Notes: A heart rate from 100 to 110 bpm can be rechecked by ECG or vitals within 
30 minutes to verify eligibility, and the second reading used if this falls within 
acceptable limits.
The QTc is the QT interval corrected for heart rate according to Fridericia’s 
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7.
Evidence of previous myocardial infarction on ECG (does not include ST segment 
changes associated with re-polarization).
8.
Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome).
9.
Sinus Pauses >3 seconds
10. Any significant arrhythmia which, in the opinion of the Investigator or GSK Medical 
Monitor, will interfere with the safety for the individual participant.
11. Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular ectopic 
beats).
12. Current or history of renal disease, or estimated creatinine clearance 
<90 mL/min/1.73m2 or serum creatinine >ULN at screening.
Prior/Concomitant Therapy
13. Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) before the first dose of study intervention, unless in the opinion of the 
Investigator and  the GSK medical monitor, the medication will not interfere with the 
study procedures or compromise participant safety.
14. Use of a systemic antimicrobial within 30 days of screening.
Prior/Concurrent Clinical Study Experience
15. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 56 days.
16. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
17. Current enrolment or past participation within the last 30 days before signing of 
consent in any other clinical study involving an investigational study intervention or 
any other type of medical research.
Diagnostic assessments
18. Positive human immunodeficiency virus (HIV) antibody test
19. Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention.
20. Positive Hepatitis C antibody test result at screening or within 3 months prior to first 
dose of study intervention.
NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
21. Positive Hepatitis C RNA test result at screening or within 3 months prior to first
dose of study intervention.


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NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.
22. Positive pre-study drug/alcohol screen
23. Any history of substance abuse or a positive test for drugs of abuse at screening or 
admission
24. A positive highly sensitive pregnancy test (urine or serum as required by local 
regulations) at screening.
25. A positive laboratory confirmation of COVID-19 infection, or high clinical index of 
suspicion for COVID-19.
Other Exclusions
26. Part 1 (Food Effect): Participant must have no dietary restrictions (e.g., lactose 
intolerance) or inability to eat a high fat meal.
27. Regular alcohol consumption within 6 months prior to the study defined as:
An average weekly intake of >21 units for males or >14 units for females. One unit is
equivalent to approximately (250 ml) of beer, (100 ml) of wine or (35 ml) measure
of spirits
28. Positive smoke breathalyzer indicative of smoking history at screening and each in-
house admission to the clinical research unit or regular use of tobacco- or nicotine-
containing products (e.g. nicotine patches or vaporizing devices) within 6 months 
prior to screening.
29. Hypersensitivity to any of the study interventions, or components thereof, or drug or 
other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates participation in the study.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Standardized meals will be provided while the participant is confined to the clinical 
unit. At all mealtimes, food will be served only after the completion of protocol 
specific procedures.

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the first dose of the study until after the final dose.

Water is allowed as desired except one hour before and two hours after dosing, 
except for the glass of water needed to administer the study intervention (e.g. 
maximum 240 mL).

Meals will be provided at approximately 4 hours and 10 hours, respectively, after 
dosing. A light snack would be at approximately 13 hours post-dose and is finished 
prior to the overnight 8 hour fast, when fasting is applicable.

Meals on Day-1 will follow the Day 1 schedule.


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5.3.1.1.
Fasted Conditions

In Part 1 (except food effect), participants will fast from food and drink (except 
water) at least 8 hours prior to dose and no food is allowed until 4 hours post-dosing
on Day 1 (Parts 1 and 2) and Day 7 (Part 2 only). Meals at all other times will be 
provided at times that should not interfere with fasting requirements for clinical 
laboratory testing. See the study reference manual (SRM) for additional details.
5.3.1.2.
Fed Conditions

For the Food Effect, participants will be fed a standard FDA high fat/high calorie 
meal after at least 8 hours of fasting and completion of pre-dose assessments (see 
Table 8 for a description of the standard FDA high fat/high calorie meal.). The meal 
will be provided approximately 30 minutes prior to administration of study 
intervention. Study participants must consume the entire meal in 30 minutes or less. 
Noncompliance will be recorded as well as the amount of the meal not eaten.

The high fat/high calorie meal provided in the Food Effect should derive 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively. The caloric breakdown of the test meal will be outlined in the study 
report. Substitutions in this test meal can be made if the meal provides a similar 
number of calories from protein, carbohydrate, and fat and has comparable meal 
volume and viscosity.
Table 8
Standard FDA High Fat, High Calorie Diet
Food
Quantity
Carbohydrate (g)
Protein (g)
Fat (g)
Calories
2 eggs fried in butter
2 eggs / 1 tsp 
butter
1.2
12.6
10 + 7.6
213
Bacon
2 strips
0
8
10
121
Hash brown potatoes
4 oz
20
3
2
125
Whole milk
8 oz
12
8
8
145
Toast
2 slices
30
5
2
180
Pats of butter
2 tsp
0
0
15.2
136
Total
58.2
36.6
53.8
920
These fasting requirements may be removed or modified at the discretion of the sponsor 
in consultation with the investigator
5.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants must abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) sample.

During each dosing session, participants must abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK sample. 

Use of tobacco products is not to be allowed from 6 months prior to screening until 
after the final follow-up visit.


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5.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).

Participants will remain in bed for 4 hours post-dosing on Day 1 (Parts 1 and 2) and 
Day 7 (Part 2 only).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened if the reason for screen failure is an ECG or lab value that, in the 
opinion of the investigator and/or Medical Monitor, is spurious or needs to be 
reconfirmed. Holter monitoring does not need to be repeated for the same participant 
being rescreened within three months of original screening. Rescreened participants 
should be assigned a new participant number.
Individuals who meet the eligibility criteria and are reserve participants who are 
subsequently not required for that cohort, could be used in other groups /later cohorts.

If reserve participants are still within the screening window (30 days) no need to 
rescreen or assign a new subject number.

If reserve participants are outside the screening window the site would reconsent the 
participant and complete the screening assessments (repeat bloods, ECG ,vitals etc).

24-hour Holter Monitor would still be valid if it is completed within 3 months of 
study start and need not be repeated.
5.5.
Self-isolation
Where it is site policy to do so, participants will be asked to attend the Unit a few days 
prior to admittance to receive a COVID-19 test. Once they have had this test they should 
be asked self-isolate at home until their admittance to the Unit for their next dosing 
period.


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6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
6.1.
Study Intervention(s) Administered
Study Intervention
Product name:
GSK3882347
Placebo
Formulation description
Active Pharmaceutical 
Ingredient
Excipient
Dosage form
Capsule
Capsule
Unit dose 
strengths/Dosage levels
Active Pharmaceutical 
Ingredient (API) alone in 
capsule to be prepared by 
extemporaneous compounding 
to required weight. Multiple
Capsules can be used as 
required. Fill weight can span 
from 11mg to 220mg as 
required (equates to 10 -
200mg dose)
To match active
Route of Administration
Oral
Oral
Dosing instructions
Study medication will be 
administered by the study 
personnel during each dosing 
day with approximately 240 mL 
of water
Study medication will be 
administered by the study 
personnel during each dosing 
day with approximately 240 mL 
of water
Physical description
Powder in capsule
Powder in capsule
Sourcing/Compounding
GSK, Addenbrookes Centre for 
Clinical Investigation (ACCI), 
CUC (Clinical Unit Cambridge), 
to provide blinded, labeled, API 
in capsule and Placebo 
capsules via Extemporaneous 
Compounding
GSK, ACCI, CUC (Clinical Unit 
Cambridge), to provide 
blinded, labeled, API in 
Capsule and Placebo capsules 
via Extemporaneous 
Compounding
Packaging and Labelling
Capsules provided in labelled 
HDPE bottles
Capsules provided in labelled 
HDPE bottles
6.2.
Preparation/Handling/Storage/Accountability
Details on storage, handling, and allowable excursions for GSK3882347 investigational 
product (IP) and placebo will be provided in the Technical Terms of Supply (TTS).


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1. A description of the detailed methods and materials required for preparation of 
GSK3882347 capsule and placebo are provided in the Technical Terms of Supply 
(TTS).
2. The capsules will be extemporaneously prepared at GSK, Addenbrookes Centre for 
Clinical Investigation (ACCI), CUC (Clinical Unit Cambridge) as per instructions in the 
Technical Terms of Supply (TTS) that will be reviewed and approved by GSK prior 
to use.
3. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
4. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
5. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
6. Further guidance and information for the final disposition of unused study 
intervention are provided in the Technical Agreement.
7. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.
8. A 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.
Precaution will be taken to avoid direct contact with the study intervention.  A Safety 
Data Sheet describing occupational hazards and recommended handling precautions will 
be provided to the investigator. In the case of unintentional occupational exposure notify 
the monitor, Medical Monitor and/or GSK study contact.
6.3.
Measures to Minimize Bias: Randomization and Blinding
All participants will be randomized, according to the randomization schedule generated 
prior to the study by the Statistics Department at GSK. Each participant will be dispensed 
blinded study intervention, labeled with his/her unique randomization number, 
throughout the study. Each participant scheduled to receive study drug will receive a 
treatment allocation number when randomized. In Part 1(SAD), participants will be 
randomized in a 3:1 ratio and in Part 2 (MAD), participants will be randomized in a 4:1 
ratio to receive study treatment (active drug: placebo). Part 1 will consist of two cohorts 
with up to a four-period for each cohort. Part 2 will consist of four cohorts for each of the 
MAD dose (Figure 1).


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This will be a double-blind study with participants and the site staff blinded. The sponsor 
will be unblinded.  For dose escalation, the Sponsor study team physicians, statistician, 
and clinical pharmacokinetic staff and/or their delegate will have access to unblinded 
data. Other Sponsor staff will remain blinded unless unblinding becomes necessary. The 
blind may be broken if, in the opinion of the investigator, it is in the participant’s best 
interest for the investigator to know the study treatment assignment. The Sponsor study
team must be notified before the blind is broken unless identification of the study
treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the participant’s 
condition. In this case, the Sponsor study team must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and CRF, as applicable.
Unblinded monitors, and in the event of a Quality Assurance audit, the auditor(s), will 
be allowed access to un-blinded study treatment records at the site to verify that
randomization/dispensing has been done accurately.
A participant will be withdrawn if the participant’s treatment code is unblinded by the
investigator or treating physician. The primary reason for discontinuation (the event or
condition which led to the unblinding) will be recorded in the CRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy.
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.

When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention.  Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested.
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates


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
dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1.
Permitted Medication and Non-Drug Therapies
Paracetamol or Acetaminophen, at doses of 2 grams/day, is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Medical Monitor.
6.5.2.
Prohibited Medication and Non-Drug Therapies
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose of the 
study until completion of the follow-up visit, unless, in the opinion of the investigator and 
Medical Monitor, the medication will not interfere with the study. This includes any 
medications which are substrates of CYP3A4 and sensitive to metabolic induction.
Use of a systemic antimicrobial within 30 days of screening.
6.5.3.
Rescue Medicine
It is not anticipated that rescue medication will be required as this is a study in healthy 
participants.
6.6.
Dose Modification
The decision to proceed to the next dose level in both Part 1 (SAD) and Part 2 (MAD) 
will be made by the GSK study team and study investigator based on safety, tolerability, 
and preliminary PK data obtained from the prior dose level(s).
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety, and PK findings at a given dose level or to add cohorts to evaluate up to 
2 additional dose levels. The study procedures for these additional participant(s)/cohort(s) 
will be the same as those described for other study participants/cohorts.
6.7.
Intervention after the End of the Study
Not applicable.


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7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued due to an adverse event, 
the participant will remain in the study to be evaluated for resolution of the event or 
return of labs to acceptable levels. See the SOA for data to be collected at the time of 
discontinuation of study intervention.
If a participant withdraws from the study, he/she must complete a follow-up visit.
7.1.1.
Gastrointestinal Events (diarrhea or colitis)
Grade
Diarrhea
Management
Follow-up
Mild
(Grade 1)
An event that is 
easily tolerated by 
the participant, 
causing minimal 
discomfort and not 
interfering with 
everyday activities
Increase of <4 
stools per day 
over Baseline
Administer 
antidiarrheal and 
symptomatic 
treatment
as appropriate
Discuss participant
continuation in the 
trial with 
Sponsor/Medical 
Monitor
Symptoms resolve to 
baseline within 3 days:
Provide close follow-up 
to evaluate for 
increased severity.
Symptoms ongoing > 3 
days:
Consider following 
algorithm for Grade 2 
events
Moderate
(Grade 2)
An event that 
causes sufficient 
discomfort and 
interferes with 
normal everyday 
activities
Increase of 4 -
6 stools per 
day over 
Baseline
Interrupt study 
drug(s)
Administer 
antidiarrheal and 
symptomatic 
treatment
Investigate etiology; 
consider consulting
GI service
Discuss participant
continuation in the 
trial with 
Sponsor/Medical 
Monitor
Symptoms resolve to ≤ 
Grade 1 or baseline 
within 7 days:
Continue follow-up and 
evaluate for any
increased severity.
Symptoms ongoing > 7 
days, blood or mucus in 
stool, or 
ulceration/bleeding on 
endoscopy:


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Grade
Diarrhea
Management
Follow-up

Consider following 
algorithm for Grade 3 
events
Severe
(Grade 3-4)
An event that 
prevents normal 
everyday activities
Grade 3: 
Increase of ≥7 
stools per day 
over Baseline; 
incontinence; 
hospitalisation 
indicated
Grade 4: life-
threatening 
consequences; 
urgent 
intervention 
indicated
Discontinue study 
drug(s)
Consult GI service
Discuss participant 
continuation in the 
trial with 
Sponsor/Medical 
Monitor
Symptoms ongoing:
Continue follow up of 
participant
Discuss further 
management with GI 
consultant and 
Sponsor/Medical 
Monitor


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7.1.2.
Liver Chemistry Stopping Criteria
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal.
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm
OR

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.
7.1.2.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*


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7.1.3.
QTc Stopping Criteria

The Fridericia QT correction formula (QTcF) 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. 
Safety ECGs and other non-protocol specified ECGs are an exception.

The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 15 minute) recording period.

A participant that meets either bulleted criterion below will be withdrawn from the 
study.

QTcF > 500msec,

Change from baseline: QTcF >60msec
See Section 1.3 for data to be collected at the time of study intervention discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.1.4.
Individual Stopping Criteria

Any participant who experiences an SAE will be withdrawn from the study.

Any participant who experiences an AE of moderate or severe intensity that is 
considered attributable to dosing with GSK3882347 will be withdrawn from the 
study.

If a participant develops COVID-19 like symptoms during the course of the study 
the following actions should be taken:
o
During Part 1 (SAD portion of the study), participants who develop a high 
clinical index of suspicion for COVID-19 disease should be isolated and 
tested for COVID-19 in accordance with site procedures.
o
During Part 2 (MAD portion of the study), study treatment should be 
halted for any participants who develop a high clinical index of suspicion 
for COVID-19 disease; they should be isolated and tested for COVID-19 
in accordance with site procedures.
o
In both cases, assessments should be continued as per the protocol during 
this period; withdrawal of participants from the study will be at the 
discretion of the Principal Investigator, but should first be discussed and 
agreed with the GSK Medical Monitor.
7.1.5.
Dose Adjustment/Discontinuation Pharmacokinetic Criteria
The exposures observed in animal toxicology studies will be used to guide dose 
escalation. Systemic exposures in the human participants in this study may exceed the 
systemic NOAEL animal exposures from 14-day GLP toxicology studies if the doses 
administered in the study are safe and well tolerated.


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For Part 1, the need to dose escalate will be evaluated if no meaningful increase in 
exposure is observed with an increase in dose (i.e., a plateau in exposures is reached).
7.2.
Study Stopping Criteria
In the event of any of the following, ongoing dosing will be halted and no new 
participants will be dosed at this dose level. A safety review will be undertaken; 
following this review an additional cohort may be enrolled at a lower dose level.

An SAE that is related to GSK3882347 in one or more participants on active 
treatment.

Two similar AEs of moderate intensity in 2 or more participants.

Two AEs of severe intensity (but not necessarily similar) in 2 or more 
participants.

Finally, if a sentinel participant receiving GSK3882347 meets any of these 
clinical stopping criteria, the rest of the Period (SAD) or Cohort (MAD) will not 
be dose and further dose escalation will not occur (see Section 7).
Dosing at the current (higher or lower) dose may resume only following approval of a 
substantial amendment by the MHRA as well as the ethics committee.
7.3.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted (assessments in the follow-up visit), as shown in the
SoA in Section 1.3. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.


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7.4.
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 the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

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


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3. Urine specimen collections
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 in 56 days.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

Time window allowances for all study assessments will be followed according to the 
time window allowances as indicated in the SRM.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Vital signs (to be taken before blood collection for laboratory tests) will include 
tympanic-measured temperature, systolic and diastolic blood pressure, pulse and 
respiratory rate.

Blood pressure and pulse measurements will be assessed in a semi-supine 
position with a completely automated device. Manual techniques will be used 
only if an automated device is not available.

Blood pressure and pulse measurements should be assessed after at least 
10 minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones) and for at least 10 minutes prior to and 5 minutes after 
each time point for ECG extractions.


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
Vital signs when measured in triplicate in the SoA blood pressure measurements
and pulse (3 consecutive readings will be recorded at intervals of at least 
1 minute). The average of the 3 readings will be recorded on the CRF.
8.2.3.
Holter Monitoring
Approximately 24-hour screening Holter Monitoring will be collected in all participants 
of the study.  The 24-hour Holter Monitoring will be performed to eliminate participants 
with non-clinically overt cardiac arrhythmias. If necessary, additional or extended 
monitoring (e.g., telemetry or Holter) may be performed at the Investigator or Sponsor’s 
discretion to further characterize any emerging safety signals.
8.2.4.
Electrocardiograms
8.2.4.1.
12-lead safety ECGs
Safety ECGs will be printed and interpreted on-site by the Investigator to ensure 
participant safety. Safety ECGs may be printed from the Global Instrumentation Holter 
device (see below). Refer to Section 7 for QTc withdrawal criteria and additional QTc 
readings that may be necessary (equipment may be used to print out ECG’s for scheduled 
or for AE’s). (if have the capability to print out ECGs, may be done). Holter Monitor
ECG are collected and held for analysis not in real time. Where there are scheduled 
ECGs, collection or an AE that requires ECG collection, if the Holter ECG 
instrumentation allows for a printout of an instantaneous ECG, the Holter equipment may 
be used to collect.
8.2.4.2.
Cardiodynamic assessment (ECGs extracted from Holter recordings)
The frequency of ECG data in the SAD and MAD arises from emerging literature 
suggesting frequent QT evaluation early in development may mitigate the need for a 
formal TQT study [Darpo, 2014]. ECGs will be extracted as shown in the SOA from the 
SAD and the MAD component of the study, not including the extension cohort. Should 
clinical development of GSK3882347 continue, an exploratory objective of this study is 
to assess the exposure-response relationship between GSK3882347 and QTcF following 
single and repeat dose administration.
The 12-lead Holter/ECG equipment will be supplied and supported by ERT. All 
continuous ECG (Holter) data will be collected using a Global Instrumentation (Manlius, 
NY, USA) M12R ECG continuous 12-lead digital recorder. The continuous 12-lead 
digital ECG data will be stored onto SD memory cards. In case the cardiodynamic 
evaluation is undertaken, 12-lead ECGs will be extracted in replicates from the 
continuous ECG recording at pre-determined time points as defined in the SOA and will 
be read centrally by ERT.
The following principles will be followed in ERT’s core laboratory:

ECG analysts are blinded to the participant, visit and treatment allocation

Baseline and on-treatment ECGs for a participant will be over-read on the
same lead and will be analyzed by the same reader.


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
The primary analysis lead is lead II. If lead II is not analyzable in any specific 
participants, then primary lead of analysis will be changed to another lead for the 
entire participant data set.
Additional details can be found in the SRM.
8.2.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and
to the SoA 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 CRF. 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 or within 14 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the informed consent form until 
the follow-up visit at the time points specified in the SoA (Section 1.3).  
However, any SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product will be recorded from the time a subject 
consents to participate in the study.

All AEs will be collected from the start of intervention until [the follow-up visit] 
at the time points specified in the SoA (Section 1.3).


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
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. 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 after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.4). Further information on follow-up procedures is given in 
Appendix 3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority,
Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.


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
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
where conception may have occurred during or up to 5 days after dosing.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Treatment of Overdose
For this study, any dose of GSK3882347 greater than 900 mg within a 24-hour time 
period (1 hour) will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3882347 can no longer be detected systemically (at least 5 days).

Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).

Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.5.
Pharmacokinetics
8.5.1.
Blood Sample Collection

Whole blood samples of approximately 1 mL will be collected for measurement 
of plasma concentrations of GSK3882347 as specified in the SoA. The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring. A maximum of 10 samples may be 
collected at additional time points during the study if warranted and agreed upon 
between the investigator and the sponsor. Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual date 
and time (24-hour clock time) of each sample will be recorded.


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
A 1 mL of whole blood sample will be collected for metabolite profiling on Day 1 
in Part 1 (excluding food effect groups); and 4 mL in Part 2 as specified in the
SoA.

The metabolite profiling of the plasma samples will be conducted under separate 
protocols and results are reported separately according to the IV/IVT DMPK, 
GSK protocols.

Samples will be used to evaluate the PK of GSK3882347. Samples collected for 
analyses of study intervention plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Residual PK Plasma samples may be analyzed for other compound-related 
metabolites and the results reported under a separate IV/IVT, GSK protocols.

Genetic analyses will not be performed on these whole blood samples unless 
consent for this was included in the informed consent. Participant confidentiality 
will be maintained. Participant confidentiality will be maintained. At visits during 
which whole blood samples for the determination of GSK3882347 will be taken, 
one sample of sufficient volume can be used.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Details of blood sample processing, storage and shipping procedures are provided in the 
SRM or equivalent.
8.5.2.
Urine Sample Collection

Urine samples will be collected up to 96 hours from dosing in Part 1 and up to 
24 hours from dosing on Days 1 and 7 in Part 2 MAD (exact times are specified 
in the SoA). The time will be recorded for each urine sample collected, and the 
total urine volume for each subject will be recorded over the collection time 
period.

From each urine PK interval, a 1 mL aliquot of urine will be collected for PK 
analysis and stored at approximately 70ºC or colder. Note: it is highly important 
that the urine sample is thoroughly mixed using several repeat inversions of 
the sample prior to removal of the 1 mL aliquot for PK analysis.

The metabolite profiling of the urine samples will be conducted under separate 
protocols and results are reported separately according to the IV/IVT DMPK, 
GSK protocols.

The timing of urine samples may be altered and/or samples may be obtained at 
additional time points to ensure thorough PK monitoring.
Details of urine sample processing, storage and shipping procedures are provided in the 
SRM.


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8.6.
Plasma Sample for CYP3A4 Enzyme Activity
Plasma derived from 3 mL blood samples in Part 2 (as in the SoA Table, see Section 1.3) 
will be analyzed for 4β-hydroxycholesterol and cholesterol as a potential in vivo marker 
of CYP3A4 enzyme activity.
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM.
Plasma samples collected in the fasted state at Baseline and on Day 8 (i.e. collected 24 
hours post dosing on Day 7) will be analyzed using a validated, specific, and sensitive 
liquid chromatography–mass spectrometry (LC-MS/MS) method to determine 
concentrations of 4β-hydroxycholesterol and total cholesterol. A comparison will be 
made between the ratio of 4β-hydroxycholesterol: cholesterol at baseline and on Day 8 to 
assess potential changes in CYP3A4 enzyme activity following GSK3882347 treatment.
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline.
8.7.
Pharmacodynamics
8.7.1.
Microbiome Assessments
Stool specimens for potential microbiome assessment will be obtained at the time points 
as specified in the SoA. The actual date and time of each sample collection will be 
recorded.
Collection, processing, storage, and shipping procedures for microbiome specimens are 
provided in the Central Laboratory Manual.
8.8.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for Information regarding genetic research. Details on processes for 
collection and shipment can be found in the Central Laboratory Manual and destruction 
of these samples can be found in SRM.
8.9.
Biomarkers
Biomarkers are not evaluated in this study.


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8.10.
Health Economics/Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GlaxoSmithKline.
Reporting of study data will be performed in accordance with applicable GSK and/or 
contract research organization (CRO) standards.
Complete details of the planned statistical analyses will be provided in the Reporting and 
Analysis Plan (RAP).
Any deviations from the planned analyses will be described in a RAP addendum and 
justified in the final integrated clinical study report.
9.1.
Statistical Hypotheses
No formal statistical hypotheses will be tested.
9.2.
Sample Size Determination
Approximately 56 randomized participants will be recruited for the entire study, 
including 16 evaluable participants in the SAD part (Part 1) with 6 active and 2 placebo 
per cohort, and 40 evaluable participants in the MAD part (Part 2) with 8 active and 2 
placebo per cohort. Additional participants may be recruited as replacement for 
withdrawn participants including those for COVID-19.
A preliminary PK/PD target was determined as a trough GSK3882347 urine 
concentrations in the range of 5 to 30 µM, where 5 µM represent the minimum trough 
concentration potentially associated with efficacy in the clinic.
Since this is a first in human study, sample size justification is based on data predicted 
from animal studies. Table 9 and Table 10 contain the predicted human urine trough 
concentration based on dog and rat PK data under 4 dose levels and 3 urine volumes. The 
assumption is the urine trough concentration follows log-normal distribution with mean 
value listed in Table 9 and Table 10.  The probabilities of successfully achieving ≥5 µM 
in urine under each setting are presented in Table 11 and Table 12.


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Table 9
Human Urine Trough Concentration Predicted From Dog PK Data
Dose (mg)
Avg urine vol
Low urine vol
High urine vol
900 QD
93.6
151.6
60.6
500 QD
65.6
106
42.5
150 QD
20.9
33.8
13.5
50 QD
6.94
11.2
4.5
Table 10
Human Urine Trough Concentration Predicted From Rat PK Data
Dose (mg)
Avg urine vol
Low urine vol
High urine vol
900 QD
30.6
49.6
19.8
500 QD
10.7
17.3
6.91
150 QD
1.37
2.22
0.888
50 QD
0.422
0.684
0.274
Table 11
Probability (%) of All 8 Participants (90%) Achieving Urine Trough 
≥5µM PK Based on Dog Data
Dose (mg)
Avg urine vol
Low urine vol
High urine vol
900 QD
98.16
99.59
93.77
500 QD
95.24
98.59
85.14
150 QD
49.86
76.36
22.78
50 QD
2.22
14.44
0.25
*SD of 1.04 from study 206899 is used as the SD of log transformed data.


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Table 12
Probability (%) of All 8 Participants (90%) Achieving Urine Trough 
≥5µM PK Based on Rat Data
Dose (mg)
Avg urine vol
Low urine vol
High urine vol
900 QD
71.8
89.3
46.1
500 QD
11.8
37.1
2.1
150 QD
0
0
0
50 QD
0
0
0
*SD of 1.04 from study 206899 is used as the SD of log transformed data.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Randomized
All participants who passed screening and were randomized into the 
study. 
Note: Screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the Enrolled population as they 
did not enter the study.
Safety
All participants who received at least 1 dose of study intervention. 
Participants will be analyzed according to the treatment they received.
Note: Participants who were not randomized but received at least one 
dose of study intervention should be listed.
Pharmacokinetic 
(PK)
All participants in the Safety population who had at least 1 non-missing 
PK assessment (Non-quantifiable [NQ] values will be considered as non-
missing values).


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9.4.
Statistical Analyses
9.4.1.
Safety Analyses
All safety analyses will be performed on the Safety Population and details will be 
provided in the Reporting and Analysis Plan (RAP).
Endpoint
Statistical Analysis Methods
Adverse events (AEs)
The proportion of participants reporting AEs will be tabulated by 
study intervention and by cohort. AEs will also be tabulated by 
severity and relationship. AEs will be tabulated using MedDRA 
preferred terms. The number and percentage of participants 
experiencing each specific AEs (All AEs, Grade 2 or higher, and 
SAEs) will be tabulated by severity and by relationship to study 
product. For the calculations in these tables, each participant’s AEs 
will be counted once under the maximum severity or the strongest 
relationship to study product. AEs leading to withdrawal will also be 
summarized by study intervention.
Clinical laboratory
Laboratory results will be included in the reporting of this study for 
haematology, clinical chemistry and urinalysis. Based upon 
laboratory normal ranges, the laboratory test results will be 
categorized according to the normal range as low (below the lower 
limit), normal (within the normal range) and high (above the upper 
limit). Summary statistics for change from baseline will also be 
tabulated.
Vital signs assessments
The following Vital Signs measurements will be tabulated: semi-
supine systolic and diastolic blood pressure, pulse rate, respiratory 
rate and tympanic temperature. Summary statistics for change from 
baseline will also be tabulated.


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9.4.2.
Pharmacokinetic Analyses
All pharmacokinetic analyses will be performed on the Pharmacokinetic Population.  For 
the secondary pharmacokinetic (PK) endpoints in this study, no formal hypotheses will 
be tested.
Endpoint
Statistical Analysis Methods
Primary
Plasma GSK3882347 concentration-time data will be analysed by non-
compartmental methods using WinNonlin Professional 5.2 or higher, Phoenix 
(Pharsight Corporation) or comparable software. Calculations will be based on 
the actual sampling times recorded during the study.
From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit:
Part 1 (single dose): AUC(0-24), AUC(0-t), AUC(0-∞), Cmax, C24h, tmax, 
tlag and t1/2 of GSK3882347
Part 2 (repeat dose): AUC(0-tau), Cmax, tmax and Ctau of GSK3882347
Amount excreted in urine (Ae) of unchanged GSK3882347, fraction of the 
dose excreted in urine (fe) and renal clearance (CLr)
Secondary
Part 1 (single dose): Dose proportionality will be assessed by visual 
inspection of dose normalised AUC(0-∞) [or if not available AUC(0-t)] and 
Cmax values versus dose. Analysis of these loge-transformed parameters may 
be carried out, using the power model.
Part 2 (repeat dose): The extent of accumulation after repeat dosing, the 
observed accumulation ratio, may be determined. Accumulation indices for PK 
parameters assessed across first and last doses of multiple dosing, as data 
allow: RAUC(0-tau), RCmax, RCtrough. For repeat dosing, AUC(0-tau), Cmax, 
Ctrough will be analyzed versus dose for the dose-proportionality.
Food Effect: AUC(0-24), AUC(0-t), AUC(0-inf), C24h, Cmax, tmax and tlag 
will be evaluated.
Further details will be included in the RAP.
9.4.3.
Other Analyses
PK and exploratory analyses will be described in the reporting and analysis plan. The 
population PK analysis will be presented separately from the main clinical study report 
(CSR).


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9.5.
Interim Analyses
There will be no formal statistical interim analysis. However, preliminary safety, and PK 
data will be reviewed in-stream by the GSK study team members prior to each dose 
escalation. Data for these reviews will be cumulative and can include individual 
participant data, summaries by study intervention and graphical displays. This is a 
sponsor unblinded trial and GSK staff will be unblinded for these reviews (see Section 
9.5.1).
Preliminary results from available safety data may be reported prior to database freeze for 
the purposes of safety review by GSK, and where required by regulatory bodies. Other 
selected preliminary data may be unblinded and reported prior to database freeze for 
internal decision making.
In each case described above, the study will not be officially unblinded and access to the 
randomization will be restricted.
The dose escalation plan will describe the planned dose escalation analyses in greater 
detail.
9.5.1.
Dose Escalation Committee (DEC)
A Dose Escalation Committee (DEC) will be responsible for ongoing monitoring during 
the study.
A DEC consisting of the following members including but not limited to the Principal 
Investigator, GSK Medical Monitor, GSK Clinical Scientist Lead, GSK Discovery 
Medicine Lead, GSK Pharmacokineticist, GSK Safety and Medical Governance 
Representative, GSK Statistician, GSK Study Delivery Lead and GSK Data Quality Lead 
will review available data from all participants in each cohort; and before initiating each 
new dose level in a minimum of four participants who received active treatment in the 
previous cohort in Part 1 and at least 7 days of repeat dosing in a minimum of five 
participants who received active treatment in the previous cohort in Part 2. Dose 
escalation may occur only after review of the following data:

Part 1: Up to Day 2 (24 hours) post-dose for PK and Day 5 (96 hours) post-dose 
for safety

Part 2: Up to Day 8 (24 hours post-Day 7) for safety and PK
The data may be reviewed in an unblinded fashion by the unblinded members of the DEC 
should a safety concern arise during the blinded review. These unblinded members will 
be defined within the Dose Escalation Plan.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IEC by the 
investigator and reviewed and approved by the IEC before the study is initiated. 

Any amendments to the protocol will require IEC 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 IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IEC

Notifying the IEC of SAE or other significant safety findings as required 
by IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
10.1.2.
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 
study and for 1 year after completion of the study.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.


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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.

Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.

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 IEC members, and by inspectors from regulatory 
authorities.
10.1.5.
Committees Structure
This study will utilize a Dose Escalation Committee (DEC) made up of the at least the 
following members including but not limited to the Principal Investigator, Medical 
Monitor, GSK Study Team Leader, GSK Pharmacokineticist, Safety and Medical 
Governance Representative, GSK Statistician, Operational Study Lead and Data Quality 
Lead. The committee will evaluate data including but not limited to: AEs, vital signs, 
laboratory findings, ECG parameters, and PK data.
Dose escalation decisions will be made as outlined in Section 9.5.1 and in the Dose 
Escalation Plan.
10.1.6.
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.


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
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.1.7.
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 subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding
10.1.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data
documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.


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
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.
10.1.9.
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 source data 
agreement.
10.1.10.
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 IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
subject and should assure appropriate subject therapy and/or follow-up.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 13 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
Table 13
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:

MCV

MCH

%Reticulocytes
and ratio 
(Reticulocyte 
Index [RI])
WBC count with 
Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine3
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
fasting)
Calcium
Alkaline 
phosphatase
Urine 
chemistry
Creatinine from 24-hour urine sample
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick


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Laboratory 
Assessments
Parameters

Microscopy (in the presence of clinically significant amount of blood (e.g. 
> +10 ) by dipstick)

Protein/creatinine ratio (in the presence of clinically significant protein e.g. 
> trace) in urine by dipstick)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Breath alcohol and urine drug screen to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines

Smoke breathalyzer

Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed)2

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C antibody)

COVID-19 testing (performed at additional time noted in the SoA tables 
and as required)
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 6. 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 an SAE 
(excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IEC.
3.
eGFR will be derived from serum creatinine using the Cockroft-Gault formula.
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
Laboratory/analyte results will utilize local standard testing (i.e. serum or plasma) for the 
protocol lab assessments, as appropriate.


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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.


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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
o
Results in death
o
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 


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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.
10.3.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe.
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.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.


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10.3.4.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 72 
hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the Medical Monitor/SAE coordinator by 
telephone.

Contacts for SAE reporting can be found in Study Reference Manual.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames.

Contacts for SAE reporting can be found in Study Reference Manual.


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10.4.
Appendix 4: Woman of Nonchildbearing Potential 
(WONCBP) Guidance
10.4.1.
Definition
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause 
other than the above, (e.g., mullerian agenesis, androgen insensitivity), 
investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history 
interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (>40 IU/L or mIU/mL) is required.


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10.4.2.
Contraception Guidance:

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner

Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc

oral

intravaginal

transdermal

injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable

Sexual abstinence

Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)


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10.4.3.
Collection of Pregnancy Information:
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive GSK3882347.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.

The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.


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10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention 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 IEC allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to GSK3882347 and related diseases. 
They may also be used to develop tests/assays including diagnostic tests) related to
GSK3882347, and recurrent uncomplication urinary tract infection. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data.

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3882347 or study interventions 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 GSK3882347 (or study interventions 
of this class) or recurrent uncomplication urinary tract infection continues but no 
longer than 15 years after the last subject last visit or other period as per local 
requirements.


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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study intervention

Report the event to GSK within 24 hours

Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and 

Viral hepatitis serology3

Obtain international normalized ratio 
(INR) and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 7 days of 
last dose4 

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form


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Liver Chemistry Stopping Criteria 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
If ALT≥3xULN AND bilirubin 2xULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.


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10.7.
Appendix 7: Country-specific requirements
No country-specific requirements exist.


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10.8.
Appendix 8: Abbreviations and Trademarks
Abbreviations
ACCI
Addenbrookes Centre for Clinical Investigation 
AE
adverse event
Ae
amount excreted in urine
ALT
alanine aminotransferase 
API
Active Pharmaceutical Ingredient
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(0-)/ 
AUC(0-inf)
AUC extrapolated from time zero to infinity
AUC(0-)
AUC over the dosing interval 
AUC(0-12) 
AUC from time zero to 12 hours after dosing
AUC(0-24)
AUC from time zero to 24 hours after dosing
AUC(0-t)
AUC from time zero to the last quantifiable concentration after 
dosing
BP
blood pressure
CL
total systemic clearance
CI
confidence interval
CLr
renal clearance
Cmax
maximum plasma concentration
COVID-19
Coronavirus Disease 2019
C24
plasma concentrations at 24 hours after dosing
Ctau
plasma concentrations over the dosing interval 
C
trough concentration
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FaSSIF
Fasted-state simulated intestinal fluid
FDA
Food and Drug Administration
Fe
fraction of drug excreted in urine
FeSSIF
Fed-state simulated intestinal fluid
Feu(t1-t2)
urinary excretion ratio relative to dose
FSH
follicle-stimulating hormone
FTIH
first time in human
GCP
Good Clinical Practice
GRF
Glomerular filtration rate
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
hCG
human chorionic gonadotropin
HED
human equivalent dose
Hgb
Hemoglobin
Hct
Hematocrit


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HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IP
Investigational product
INR
international normalized ratio
Kg
Kilogram
L
Liter
g
Microgram
MABEL
Minimal Anticipated Biological Effect Level
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
MHRA
The Medicines and Healthcare Products Regulatory Agency
mL
Millilitre
mm Hg
millimeters of mercury
MRSD
maximum recommended starting dose
MRT
mean residence time
Msec
Millisecond
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
PBPK
physiologically based pharmacokinetic
PK
Pharmacokinetic
QTc
corrected QT; the measure of time between the start of the Q wave 
and the end of the T wave
QTcF
corrected QT interval using Fridericia’s formula
SAD
single ascending dose
SAE
serious adverse event
SRM
study reference manual
RAP
reporting and analysis plan
RBC
red blood cell
Ro
observed accumulation ratio
rUTI
Recurrent urinary tract infections
t1/2
terminal elimination half-life
tlag
lag time
Tmax
time to Cmax
TTS
Technical Terms of Supply
ULN
upper limit of normal 
UTI
Urinary tract infection
Vd
volume of distribution
Vd/F
Apparent volume of distribution after non-intravenous administration
WBC
white blood cell


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
Phoenix (Pharsight Corporation) 
WinNonlin


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10.9.
Appendix 9: COVID-19 Appendix
10.9.1.
Overall Rationale for this Appendix 
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing.
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity.
These measures will remain in place until study completion.
10.9.2.
Study Procedures During COVID-19 Pandemic
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants.
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants.

Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study 
conduct and duration of those changes and indicate which trial participants were 
impacted and how those trial participants were impacted (as per the current local 
COVID-19 related regulatory guidance).

Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation.
10.9.3.
Protocol Defined Procedures/Visits:

The protocol defined interval for the collection of samples during the follow-up 
visit (see Section 1.3 Schedule of Activities), may be extended up to a maximum 
length of 14 days. 

If visits to a site are not feasible, then the medical evaluation of safety may take 
place by phone calls as a way of communicating with and monitoring the 
participant.


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
The study investigator is responsible for ensuring that the identification, 
management, and reporting of AEs and SAEs are completed in accordance with 
the protocol and applicable regulations. AEs are first reported by participants to 
the investigator/study team or may be identified by the study team during 
interactions with the participants via phone call.

The participant should be informed of the plan and any potential risks associated 
with review of information by site monitors in alternative ways other than during 
in person visits (i.e. phone calls with the site staff or viewing documents remotely 
during secure web or in systems where documents can be uploaded) and sign a 
revised Informed Consent Form if required. IRB/Ethics committee should be 
informed and/or approve of this change in approach and the process documented 
in study files.
10.9.4.
Data Management/Monitoring:

If a situation arises where on-site monitoring is no longer permitted, GSK will 
consider remote Source Data Verification/Source Document Review (SDV/SDR) 
where permitted by the clinical site/institution. Remote SDV/SDR will be proposed 
to study sites to meet a participant and/or critical quality need, e.g., to assess 
participant safety or to ensure data integrity. In case of remote SDV/SDR, GSK will 
work with the site to ensure participant privacy.

eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
PI may sign/re-sign the eCRF from any computer/location by accessing InForm (or 
other eDC platform) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly.

Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK


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10.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 (02-JUN-2020)
Overall Rationale for Amendment 1: This amendment includes revisions to the 
reporting of the primary endpoint, eligibility criteria, including decrease in creatine 
clearance and screening for COVID-19, COVID-19 related activities, removal of PCI for 
extemporaneous compounding, procedural changes in-line with clinical site, minor 
clarifications and consistency corrections, formatting corrections.


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Section # and Name
Description of Change
Brief Rationale
1.1 & 3 Objectives 
and Endpoints
Changed reporting of the 
primary endpoint
To align with new reporting 
guidelines
1.1 Synopsis
4.1 Overall Design
Mentioned in Part 1, that food 
effect evaluation will be 
conducted in last period
Included in these sections for 
completeness
1.3 SoA Tables
2.3.2 Risk 
Assessment
5.2 Exclusion Criteria
5.5 Self Isolation
7.1.4 Individual 
Stopping Criteria
7.3 Withdrawal 
Criteria
9.2 Sample size 
determination
Appendix 10 COVID-
19 Appendix
Addition of COVID-19 to 
eligibility criteria, adjustment of 
age limit, risk and mitigations, 
screening and monitoring to 
SoA tables, additional COVID-
19 testing based on clinical 
presentation during discharge, 
participant stopping criteria, 
withdrawal criteria, 
replacement of participants 
including due to COVID-19 and 
appendix
In light of the COVID-19 pandemic, 
GSK anticipates that many ongoing 
studies will receive cases of 
suspected or confirmed COVID-19 
infections and plans to implement 
procedures within the clinical trials for 
monitoring
1.3 SoA Tables
8.2.2 Vital Signs
Positioning and timing of Vital 
Signs
Consistent positioning throughout to 
avoid any conflicts in timing of 
assessments
1.3 SoA Tables
8.2.2 Vital Signs
Modified method of assessing 
temperature. Changed oral to 
tympanic temperature
Preferred method of assessment of 
temperature for clinical site
1.3 SoA Table
Added Urine Drug, Smoke 
Breathalyzer and Alcohol 
Breath Tests to Screening and 
Day-1
Added Urine Drug, and Alcohol 
and Smoking Breath Tests to 
Day-1
Added β-hCG Pregnancy 
Testing (as appropriate) to 
Day-1
To ensure compliance with protocol 
requirement
Pregnancy testing as appropriate 
since only women of non-
childbearing potential may participate


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Section # and Name
Description of Change
Brief Rationale
1.3 SoA Table
Permissible window included 
for the Follow-up Visit
Protocol omission. A permitted 
3 days window around the Follow-up 
Visit (i.e. 14 days 3 days) should 
have been included
1.3 SoA Table
8.2.3 Holter 
Monitoring
Added 24-hour Holter 
Monitoring at screening
Site specific preference
1.3 SoA Tables
Modified timing of sample 
collection for Genetic analysis
To allow collection of sample at a 
time point when consent is signed, 
and participant qualify on the basis of 
labs and inclusion/exclusion criteria
1.3 SoA Tables
Clarification of stool 
microbiome collection times
Last sample to be collected close to 
the last day of discharge to 
accommodate routine bowel habits
1.3 SoA Tables
2.3.2 Risk 
Assessment
Clarity of stool type 
assessment for all bowel 
movements by Bristol Stool 
chart
Aid with identification of 
gastrointestinal adverse effects
1.3 SoA Tables
5.3.1 Meals and 
Dietary Restrictions
Presentation of meal times 
adjusted in tables
Added meals schedule for 
Day -1
Minor clarifications. Standardized 
meals will be provided per site local 
practices
1.3 SoA Table
IP administration removed from 
Day 8 – Table 4
Minor error. There will be no 
administration of study intervention 
on Day 8 as there is only seven (7) 
days of dosing and the last dose is 
on Day 7
1.3 SoA Table
Urine PK collection times in 
SAD (Part 1) and MAD (Part 2)
Protocol inconsistency. Interval for 
urine PK collection times to be similar
4.3 Dose Justification
Removal of the reference to 
the unqualified impurity 
(RRT1.16)
Specification no longer dose limits up 
to 900mg
5.2 Exclusion Criteria
Changed estimated creatinine 
clearance to 
<60 mL/min/1.73m2
Normal creatinine clearance levels 
may vary (GFR category: Grade 1 
and Grade 2). In the absence of 
kidney disease, neither Grade 1 and 
Grade 2 fulfil the criteria of CKD


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Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
10.2 Clinical 
Laboratory Tests
Change to smoke Breathalyzer 
Test at screening
Removed urine cotinine tests as 
there can be false positives
5.3.3 Activity
Modified abstain from 
strenuous exercise for 48 
hours
Effect of short term strenuous 
exercise on laboratory values was 
extended due to variability in 
parameters returning to baseline
5.4 Screen Failures
Clarification of screen failure 
for reserve participants
Modified to allow reserve participants 
to be rescreened. Reserve 
participants who met eligibility criteria 
are categorized as screen failure if 
not selected for cohort
6 Study Intervention
Removal of PCI
PCI will no longer be responsible for 
extemporaneous compounding and 
replaced with Clinical Unit Cambridge
8.2.4.1 
12-lead safety ECGs
Replaced abbreviations HM = 
Holter Monitor and RT = real 
time
Protocol clarification
8.5.1 Blood Sample 
Collection
Increase blood volume for 
metabolite PK samples, Part 2 
only
Ensure adequate sample in the event 
of reanalysis
8.5.2 Urine Sample 
Collection
Added details on volume of 
urine to be aliquoted and 
storage condition for sample
For clarity
8.7 Genetics
Added details that process for 
genetics samples collection 
and shipping can be found in 
the Central Laboratory Manual
For more clarity
9.5.1 Dose Escalation 
Committee (DEC)
GSK Study Team Leader has 
been replaced by Clinical 
Scientist Lead and GSK 
Discovery Medicine Lead, GSK 
Study Operational Lead has 
been replaced by Study 
Delivery Lead
Revised positions


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Section # and Name
Description of Change
Brief Rationale
10.1.3 Informed 
Consent Process
Removed text on consent form 
Legally Authorized 
Representative
The study is in healthy adult 
participants
10.2 Clinical 
Laboratory 
Assessments
Protein/creatinine ratio to be 
used to investigate proteinuria
For Urinalysis, microscopy will 
be performed by dipstick (in 
presence of clinically significant 
amount of blood [e.g. > +10])
Added reticulocyte index 
(calculated value)
COVID-19 testing
Urinalysis - small amount of protein 
can be found in urine
Urinalysis - small amount of blood 
can be found in urine
Reticulocyte count monitoring to help 
with differential diagnosis
COVID-19 testing for screening
10.4.2 Contraception 
Guidance
Added mandatory use of male 
condoms for contraception to 
footnote
Prior omission from footnote
10.8 Abbreviations
Remove IVRS/IWRS system 
from list of abbreviations
Added TTS
IVRS will no longer be used in study
Details of IP and placebo storage will 
be provided in Technical Terms of 
Supply (TTS)
10.1.9 Source 
Documents
6.2 
Preparation/Handling/
Storage/Accountability
Protocol inconsistencies
Source data definition is normally 
specified in the source data 
agreement, removed reference to 
SRM
Material Safety Data Sheet is now 
Safety Data Sheet
Amendment 2 (10-JUL-2020)
Overall Rationale for the Amendment 2: This amendment is in response to questions 
raised in the MHRA’s Grounds for non-acceptance letter which was received on the 
02/07/2020 and includes revisions to the overall design (in-house stay for Part 2), 
boundaries for dose adjustment, justification of maximum dose, exclusion criteria, 
gastrointestinal events, and individual/study stopping criteria.


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Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis, 1.3 
SoA (Table 4) and 
4.1 Overall Design
Modified in-house stay for 
participants in the clinical unit 
for Part 2
Based on the expected half-life, 
participants will be discharged from 
the clinical unit could be 5 days or 5 
half-lives (whichever is longer based 
on the emerging data from Part 1)
1.3 SoA (Table 4)
Addition of assessments on 
days 9-12 including discharge 
assessments moved from Day 
8 to days 9 through 12. Also 
meal will be provided until 
discharge.
Due to the extending in-house stay 
within clinical unit
2.3.2 Risk 
Assessment
Modified gastrointestinal 
toxicity risk
Impacted by modifying management 
of gastrointestinal toxicity in Section 
7.1.1
4.3 Justification for 
Dose
Added exposure limits
To define the highest permitted dose 
with regards to exposure
1.1 Synopsis, 4.3.1 
Starting Dose
Added boundaries for dose 
adjustments
To clarify boundaries for adjustments
5.2 Exclusion Criteria
Criteria #12 - Changed 
estimated creatinine clearance 
to 90 mL/min/1.73m2 or serum 
creatinine >ULN at screening
To reflect healthy participant 
population
5.2 Exclusion Criteria
Removed Exclusion Criterion 
#29
Already covered under Inclusion 
Criteria #4
7.1.1 Gastrointestinal 
Events (diarrhea or 
colitis)
Defined grading and modified 
the management of 
gastrointestinal toxicity
Severity grading (1-4) required 
defining
7.1.4 Individual 
Stopping Criteria and 
7.2 Study Stopping 
Criteria
Deleted references to CTCAE
Intensity of adverse events are 
assessed using mild, moderate and 
severe terminology is acceptable for 
a healthy participant study
7.2 Study Stopping 
Criteria
Removed requirement for 
adverse events of severe 
intensity to be similar, while 
maintaining two similar 
moderate adverse events
Two severe adverse events in 2 or 
more healthy participant must result 
in the study stopping, regardless of 
the type of reaction


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Section # and Name
Description of Change
Brief Rationale
7.2 Study Stopping 
Criteria
Addition of text of resumption 
of dosing after the study 
stopping criteria have been 
triggered will require approval 
of a substantial amendment by 
the MHRA as well as the ethics 
committee
To align with the Medicines and 
Healthcare Products Regulatory 
Agency (MHRA) guidance for 
substantial amendment
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 2
10-Jul-2020
2019N400733_02
Amendment 1
02-Jun-2020
2019N400733_01
Original Protocol
05 -Nov-2019
2019N400733_00


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11.
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
O’Neill, J., et. al. (2016) The review on antimicrobial resistance. Tackling drug-resistant 
infections globally. Report sponsored by the Wellcome Trust and U.K. Government, 
available at https://amr-review.org/
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.
Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J 
Med. 1993;329(18):1328-34.
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.
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E8/ Committee For Proprietary Medicinal 
Products (CPMP)/ICH/291/95] and Guideline on Strategies to Identify and Mitigate Risk 
for First time in -Human Clinical Trials with Investigational Medical Products 
[EMEA/CHMP/SWP/28367/07.
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Clinical Pharmacology. Draft 
Guidance for Industry. Assessing the Effects of Food on Drugs in INDs and NDAs —
Clinical Pharmacology Considerations. February 2019.

SAP_001.pdf: 
 
 
 
 
Reporting and Analysis Plan 
 
Study ID: 212148 
 
Official Title of Study: Reporting and Analysis Plan for A Double-Blind (Sponsor 
unblinded) Randomized, Placebo-Controlled, Single and Repeated Oral Dose Escalation 
Study to Investigate the Safety, Tolerability, Pharmacokinetics (including food effect) of 
GSK3882347 in Healthy Participants. 
 
Date of Document: 24-MAY-2021 
 
 


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 2 1 4 8  
 
1  
 
Di visi o n  
: W orl d wi de  De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
 
Title  
: Re p orti n g a n d A nal ysis Pla n f or A D o u ble -Bli n d  ( S p o ns or 
u n bli n de d) Ra n d o mize d, Place b o -C o ntr olle d, Si n gle a n d 
Re peate d  Oral D ose Es calati o n St u d y t o I n v esti gate t he 
Safet y, T olera bilit y, P har mac o ki netics  (i ncl u di n g f o o d 
effect) of G S K 3 8 8 2 3 4 7 i n Healt h y Partici pa nts . 
C o m p o u n d N u m ber  : G S K 3 8 8 2 3 4 7  
Cli nic al St u d y 
I de ntifier 
: 2 1 2 1 4 8  
Effecti ve D ate  
: [ Refer t o D oc u me nt Dat e] 
 
•  
Descri pti o n : 
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 1 2 1 4 8 A me n d me nt 3  
•  
T his R A P is i nte n de d t o descri be t he s afet y, t olera bilit y, p h ar mac o ki n etics 
(i ncl u di n g f o o d effect) a n d B i o mar ker a nal ys es re q uire d f or t he st u d y.  
•  
T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of 
t he 2 1 2 1 4 8 Statistical A nal ysis C o m plete ( S A C) deli vera ble.  
 
R A P A ut h or(s):  
A ut h or(s):  
A ut h or  
Le a d  
  
 St u d y Statisticia n ( Lea d Statisticia n, Bi ostatistics)  
C o -A ut h or  
 Statisticia n (J u ni or Statisticia n, Bi ostatistics)  
C o -A ut h or  
 
  
 St u d y P har mac o ki neticist ( 
 Cli nical P har mac ol o g y C P M S)  
 
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.
 
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 2 1 4 8  
 
2  
 
R A P Te a m  R e vie w C o nfir m ati o ns:  
( Met h o d: E-m ail)  
Re vie wer  
D ate  
 
O perati o nal St u d y Lea d ( Gl o bal Cli nical De vel o p me nt  
Ma na ger, R & D G C S D)  
2 4 -Ma y -2 0 2 1  
  
Asset  Lea d 
( Fi m H 
Asset 
Lea d, 
Gl o bal 
Cli nical 
De vel o p me nt  
 G C S D Cli nical P har mac ol o g y)  
1 5 -Ma y -2 0 2 1  
 
St u d y Pr o gra m mer ( Pri nci pal Pr o gra m mer/ A nal yst, De v 
Bi ostats Pr o g D e v)  
1 9 -Ma y -2 0 2 1  
 
St u d y D ata Ma na ger ( 
, Cli nical Data Ma na ge m e nt, 
Data Strate g y & Ma n a ge me nt)  
1 3 -Ma y -2 0 2 1  
  
Cli nical Scie nce Lea d ( Disc o ver y M e dici ne Gr o u p Lea d er)  
1 3 -Ma y -2 0 2 1  
  
 St u d y  
P har mac o ki neticist  
( 
  
Cli nical 
P har mac ol o g y C P M S)  
 
1 4 -Ma y -2 0 2 1  
 
Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als : 
( Met h o d: Vee v a V a ult e T M F e Si g n at ure) 
A p pr o ver  
 ( Pr o gra m mi n g Lea der (I D, Cli nical Pr o gra m mi n g))  
O n be half of 
  
Li ne Ma na ger (I D Cli nical Pr o gra m mi n g)  
 (Pr oject Statisticia n ( Statistics Lea der, Bi ostatistics) ) 
O n be half of 
 (Bi ostatistics Ma na ger ) 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objectives and Estimands / Endpoints ................................................ 7 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Analyses ..................................................................................... 13 
3. 
PLANNED ANALYSES .......................................................................................... 14 
3.1. 
Interim Analyses ......................................................................................... 14 
3.2. 
Final Analyses ............................................................................................ 14 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Baseline Definitions .................................................................................... 17 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 18 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
7. 
SAFETY ANALYSES ............................................................................................. 20 
7.1. 
Adverse Events Analyses ........................................................................... 20 
7.2. 
Clinical Laboratory Analyses ....................................................................... 20 
7.3. 
Other Safety Analyses ................................................................................ 20 
7.4. 
Exploratory Safety Analyses ....................................................................... 20 
8. 
PHARMACOKINETIC ANALYSES ......................................................................... 21 
8.1. 
Pharmacokinetic Parameter Analyses and Summaries ............................... 21 
8.1.1. 
Endpoint / Variables ..................................................................... 21 
8.1.1.1. 
Drug Concentration Measures .................................... 21 
8.1.1.2. 
Derived Pharmacokinetic Parameters......................... 21 
8.1.2. 
Summary Measure ...................................................................... 23 
8.1.3. 
Population of Interest ................................................................... 24 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 24 
8.1.5. 
Statistical Analyses / Methods ..................................................... 24 
8.1.5.1. 
Statistical Methodology Specification .......................... 24 
8.2. 
Statistical Analysis of Derived PK Parameters ............................................ 25 
8.2.1. 
Endpoint / Variables ..................................................................... 25 
8.2.2. 
Summary Measure ...................................................................... 25 
8.2.3. 
Population of Interest ................................................................... 25 
8.2.4. 
Strategy for Intercurrent Events ................................................... 25 
8.2.5. 
Statistical Analyses / Methods ..................................................... 25 
8.2.5.1. 
Statistical Methodology Specification .......................... 26 
8.3. 
Exploratory Pharmacokinetic Analyses ....................................................... 31 


 
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8.4. 
Microbiome analysis ................................................................................... 31 
9. 
POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 32 
10. BIOMARKER ANALYSES ...................................................................................... 33 
10.1. 
Exploratory Biomarker Analyses ................................................................. 33 
10.1.1. 
Endpoint / Variables ..................................................................... 33 
10.1.2. 
Summary Measure ...................................................................... 33 
10.1.3. 
Population of Interest ................................................................... 33 
10.1.4. 
Statistical Analyses / Methods ..................................................... 33 
11. REFERENCES ....................................................................................................... 34 
12. APPENDICES ........................................................................................................ 36 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 36 
12.2. 
Appendix 2: Schedule of Activities .............................................................. 37 
12.2.1. 
Protocol Defined Schedule of Events ........................................... 37 
12.3. 
Appendix 3: Assessment Windows ............................................................. 54 
12.4. 
Appendix 4: Study Phases .......................................................................... 55 
12.4.1. 
Study Phases for Concomitant Medication ................................... 55 
12.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 56 
12.5.1. 
Reporting Process ....................................................................... 56 
12.5.2. 
Reporting Standards .................................................................... 56 
12.5.3. 
Reporting Standards for Pharmacokinetic .................................... 57 
12.6. 
Appendix 6: Derived and Transformed Data ............................................... 58 
12.6.1. 
General ........................................................................................ 58 
12.6.2. 
Safety .......................................................................................... 59 
12.6.3. 
Pharmacokinetic .......................................................................... 59 
12.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 60 
12.7.1. 
Premature Withdrawals ................................................................ 60 
12.7.2. 
Handling of Missing Data ............................................................. 60 
12.7.2.1. Handling of Missing and Partial Dates ........................ 60 
12.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 62 
12.8.1. 
Laboratory Values ........................................................................ 62 
12.8.2. 
ECG ............................................................................................. 63 
12.8.3. 
Vital Signs .................................................................................... 63 
12.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 64 
12.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 65 
12.11. Appendix 11: Abbreviations & Trade Marks ................................................ 66 
12.11.1. Abbreviations ............................................................................... 66 
12.11.2. Trademarks ................................................................................. 67 
12.12. Appendix 12: List of Data Displays.............................................................. 68 
12.12.1. Data Display Numbering .............................................................. 68 
12.12.2. Mock Example Shell Referencing ................................................ 68 
12.12.3. Deliverables ................................................................................. 68 
12.12.4. Study Population Tables .............................................................. 69 
12.12.5. Safety Tables ............................................................................... 70 
12.12.6. Safety Figures ............................................................................. 73 
12.12.7. Pharmacokinetic Tables ............................................................... 73 
12.12.8. Pharmacokinetic Figures ............................................................. 77 
12.12.9. Biomarker Tables ......................................................................... 79 


 
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12.12.10. Biomarker Figures ....................................................................... 79 
12.12.11. ICH Listings ................................................................................. 80 
12.12.12. Non-ICH Listings .......................................................................... 85 
12.12.13. Covid-19 Listings ......................................................................... 86 
12.12.14. Conditional Listings ...................................................................... 87 
12.13. Appendix 13: Example Mock Shells for Data Displays ................................ 88 
 


 
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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 212148: 
Revision Chronology: 
2019N40073_00 
05 -Nov-2019 
Original 
2019N40073_01 
02-Jun-2020 
This amendment includes revisions to the reporting of 
the primary endpoint, eligibility criteria, including 
decrease in creatine clearance and screening for 
COVID-19, COVID-19 related activities, removal of PCI 
for extemporaneous compounding, procedural changes 
in-line with clinical site, minor clarifications and 
consistency corrections, formatting corrections. 
2019N40073_02 
10-Jul-2020 
This amendment is in response to questions raised in 
the MHRA’s Grounds for non-acceptance letter which 
was received on the 02/07/2020 and includes revisions 
to the overall design (in-house stay for Part 2), 
boundaries for dose adjustment, justification of 
maximum dose, exclusion criteria, gastrointestinal 
events, and individual/study stopping criteria. 
2019N400733_03 
21-Oct-2020 
This amendment is to allow for additional 
blood samples to be taken from selected cohorts in 
order to evaluate an in vitro CYP3A4 
induction flag. Plasma derived from whole blood will be 
analysed for changes in 4βhydroxycholesterol and 
cholesterol ratio as a potential in vivo marker of 
CYP3A4 enzyme activity at baseline and following 
repeat administration of GSK3882347. 


 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
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 
• 
Dose proportionality analysis 
of Amount excreted in urine 
(Ae) was not included in the 
statistical analysis section of 
protocol 
• 
Dose proportionality 
analysis of Ae has been 
added in Statistical 
analysis section of RAP 
• 
Since plasma PK may be used 
as surrogate marker for urine 
PK an assessment of dose 
proportionality in both plasma 
and urine is being explored 
• 
No Biomarker endpoint is 
evaluated 
• 
Biomarker population is not 
defined in Population for 
analyses section 
• 
4β-hydroxycholesterol 
and cholesterol data 
included as per 
amendment 3 is 
considered under 
Biomarker endpoint  
• 
Biomarker population 
has been added to the 
list of analysis 
populations 
• 
The objective ‘To assess 
potential effect of repeat doses 
of GSK3882347 on 
Cytochrome P450 3A4 
(CYP3A4) enzyme activity in 
Part 2’, to evaluate the 
biomarker endpoint plasma 4β-
hydroxycholesterol to 
cholesterol ratio has been 
added in protocol amendment 
3. Since this is a biomarker end 
point, the population definition 
has been included  
 
2.2. 
Study Objectives and Estimands / Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and 
tolerability of GSK3882347 
following oral administration 
of single and repeat doses in 
healthy adult participants 
 
 
• To evaluate the 
pharmacokinetics of 
GSK3882347 in plasma and 
urine following oral 
administration of single and 
repeat doses in healthy adult 
participants 
• Occurrence of adverse events (AEs) 
and treatment related AEs 
• Occurrence of clinically significant 
changes in vital signs, laboratory 
parameters, and 12-lead 
electrocardiogram (ECG) findings 
 
• Single dose (plasma): AUC(0-24), 
AUC(0-t), AUC(0-∞), Cmax, C24h, 
tmax, tlag and t1/2 of GSK3882347, as 
data permit 
 
• Repeat dose (plasma): AUC(0-tau), 
Cmax, tmax and Ctau of 
GSK3882347, as data permit 


 
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Objectives 
Endpoints 
 
• Urine concentration at 22-24h 
collection time-point 
 
• Amount excreted in urine (Ae) of 
unchanged GSK3882347, fraction of 
the dose excreted in urine (fe) and 
renal clearance (CLr), as data permit 
Secondary 
• To further evaluate the 
pharmacokinetics of 
GSK3882347 in plasma 
 
 
 
 
• To examine dose 
proportionality of 
GSK3882347 following oral 
administration of single and 
repeat doses in healthy adult 
participants 
 
• To evaluate the extent of 
accumulation, time invariance, 
and achievement of steady-state 
of GSK3882347 following oral 
administration of single and 
repeat doses in healthy adult 
participants 
• Single dose(plasma): AUC(0-12), 
C12h, CL/F, Vd/F and MRT of 
GSK3882347, as data permit 
 
• Repeat dose (plasma): AUC(0-12) 
and C12h of GSK3882347, as data 
permit 
 
• AUC(0-inf) and Cmax for single dose 
and AUC(0-tau) and Cmax for repeat 
dose, as data permit 
 
• Ro (accumulation ratio) using 
AUC(0-tau) for repeat dose, as data 
permit 
 
• Time invariance using AUC(0-tau) 
(repeat dose) and AUC(0-inf) (single 
dose) 
 
• Achievement of steady-state (Ctau 
collected on multiple days) 
• To evaluate the effect of food 
on pharmacokinetics of 
GSK3882347 following oral 
administration of single dose in 
healthy adult participants 
• AUC(0-24), AUC(0-t), AUC(0-inf), 
C24h, Cmax, tmax and tlag, as data 
permit 
Exploratory 
• To assess ECG effects of 
GSK3882347, including 
concentration-QTc analysis, 
following single and repeat doses 
in healthy adult participants 
• 
Change-from-baseline QTc (∆QTcF) 
• 
Change-from-baseline heart rate, PR and 
QRS interval (∆HR, ∆PR and ∆QRS) 
• 
Placebo-corrected ∆QTcF, ∆HR, ∆PR 
and ∆QRS 


 
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Objectives 
Endpoints 
• 
Treatment emergent T-wave 
abnormalities and presence of U-waves 
• 
Categorical outlier analysis for HR, 
QTcF, PR and QRS 
• To investigate the plasma and urine 
metabolic pathways of 
GSK3882347 in healthy 
participants 
• 
Characterization of the plasma and 
urinary metabolites of GSK3882347, 
estimation of the percentage dose 
eliminated in urine, where possible 
• To characterize the effect of 
GSK3882347 on intestinal 
microbiota following single and 
repeat doses in healthy adult 
participants 
• Change in intestinal microbiome over 
time 
• To assess potential effect of repeat 
doses of GSK3882347 on 
Cytochrome P450 3A4 (CYP3A4) 
enzyme activity in Part 2  
• Plasma 4β-hydroxycholesterol to 
cholesterol ratio at pre-treatment and 
following repeat dosing of GSK3882347  
Note: The exploratory endpoints may be analyzed as GSK3882347 clinical development 
continues  
Safety Estimand 
The primary objective is to determine the safety, tolerability and pharmacokinetic profile 
of GSK3882347 following oral administration of single (Part 1) and repeat doses (Part 2) 
of GSK3882347 in healthy adult men and women. 
 
The safety estimand is described by the following attributes: 
• 
Population: Healthy adult men and women of non-child bearing potential 
(WONCBP). 
• 
Treatment condition: In part 1, ascending single oral dose of GSK3882347 or 
placebo and a food effect.  In part 2, four ascending repeat-dose cohorts (Cohorts 3 
to 6), who will receive a single oral dose of GSK3882347 or placebo for 
7 consecutive days.  
• 
Variable: Occurrence of adverse events (AEs) and treatment related AEs, 
Occurrence of clinically significant changes in vital signs, laboratory parameters, 
and 12-lead electrocardiogram (ECG) findings. 
• 
Summary measure: Descriptive statistics (percentage in each category in each arm 
separately (as no direct comparison between treatment groups will be made) and 
summary statistics (appropriate for each type of endpoint) in each arm separately. 
• 
Intercurrent events (ICE): Study treatment discontinuation (due to any reason) – the 
occurrence of the ICE is considered irrelevant in defining the treatment effect of 
interest.  All safety data will be included up to the end of the period or up to the end 
of the follow-up (FU) (for the last period) in the analysis irrespective of the 


 
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occurrence of this ICE and the event/assessment will be assigned to the last 
treatment before ICE occurred. 
 
Rationale for Estimand: 
This attempts to estimate safety effects likely to be attributable to the drug irrespective of 
whether the participant completed the treatment.   
  
Pharmacokinetic Estimand 
The pharmacokinetic estimand is described by the following attributes: 
• 
Population: Healthy adult men and women of non-child bearing potential 
(WONCBP). 
• 
Treatment condition: In part 1, ascending single oral dose of GSK3882347 or 
placebo and a food effect.  In part 2, four ascending repeat-dose cohorts (Cohorts 3 
to 6), who will receive a single oral dose of GSK3882347 or placebo for 
7 consecutive days.  
• 
Variable: AUCs, Cmax, C12h, C24h, CL/F, Vd/F, tmax, tlag, t1/2, MRT, C22-
24,U, CLr, Ae, fe (See Section 8.1.1) 
• 
Summary measure: Descriptive statistics, treatment ratios, slope of loge(dose), least 
squares geometric mean, Ro, RCmax, Rctrough, Rss 
• 
Intercurrent events (ICE):  
• 
Study treatment discontinuation (due to any reason) - while on treatment 
strategy (treatment effect is only considered before the ICE occurs) 
• 
Received incorrect dose or meal consume less than 99% of the meal (in 
fed participants) - hypothetical strategy (the data from a period in which 
ICE occurs would be considered missing at random and excluded from 
analyses) 
Rationale for Estimands: 
The objective of the while on treatment strategy is to estimate the PK parameters when 
participants have actually taken the dose/treatment condition as per protocol. 
  
The hypothetical strategy attempts to estimate treatment effects had the intercurrent event 
not occurred. 


 
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2.3. 
 Study Design 
Overview of Study Design and Key Features 
This is a two-part Phase I, first-time-in-human (FTIH), randomized, double-blind, 
single-centre, placebo-controlled, dose-escalation study to determine the safety, 
tolerability and pharmacokinetic profile of GSK3882347 following oral administration 
of single (Part 1) and repeat doses (Part 2) of GSK3882347 in healthy adult men and 
women of non-child bearing potential (WONCBP). Part 1 will consist of two cohorts 
with up to a four-period cross-over. The food effect evaluation will be conducted in last 
period (Period 4) in only one of the cohorts based on the observed human 
pharmacokinetics. During Parts 1 and 2, participants who meet the criteria for study entry 
will be assigned to the current dose level and randomized to receive GSK3882347 or 
placebo before administration of study intervention on Day1. 
Dose escalation will be conducted only if it is supported by safety, tolerability and 
pharmacokinetic results from the preceding dose level(s). This is the first administration 
of GSK3882347 in humans; therefore, preliminary safety, tolerability and 
pharmacokinetic results will be reviewed internally at GSK in conjunction with the study 
site and study design adjustments may be made based on emerging data from each dose 
cohort. The repeat dose escalation component (Part 2) of this study will be initiated once 
safety at an exposure that exceeds the daily exposure predicted at steady state for the 
Part 2 planned starting dose of 50 mg has been demonstrated in Part 1. This is predicted 
to occur at the 250 mg single dose. The point at which Part 2 is initiated can be modified 
based on the emerging safety, tolerability and pharmacokinetic data from Part 1. 
Notes 
• A = active, P = placebo 
• SAD = single ascending dose; MAD multiple ascending dose 
• Starting SAD dose level = 50mg  
• Subsequent dose escalations will be determined based on safety and PK data 
• Part 2 (MAD) may start in parallel with Part 1 (SAD) 
Figure shows illustration of planned dosing strategy, which may be changed or cancelled 


 
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Overview of Study Design and Key Features 
based on preliminary safety, tolerability and PK from preceding doses; and does not 
represent the randomization strategy. 
Design 
Features 
• This is a two-part Phase I, double-blind (sponsor-unblinded), 
randomized, placebo-controlled, single and multiple-ascending-
dose study in healthy volunteers. 
• For Part 1, approximately 16 healthy adult participants will be 
enrolled with a minimum of 8 participants in each cohort, where 
each cohort may participate in up to 4 periods.   
• 
In each cohort of Part 1, each participant will receive three doses 
(escalations or reductions) of GSK3882347. In the fourth period, one 
cohort will potentially assess food effect and the other cohort will 
potentially receive a fourth dose (escalated or reduced) of 
GSK3882347. 
• In Part 2, enough healthy adults will be screened to provide 
approximately 10 participants for randomization within each of the 
4 MAD dosing cohorts.  
• Preliminary safety, tolerability and pharmacokinetic results will be 
reviewed internally at GSK in conjunction with the study site and 
study design adjustments may be made based on emerging data from 
each dose cohort before dose escalation.  
Dosing 
• Part 1 will consist of 2 separate cohorts of 8 healthy participants 
each. The planned starting GSK3882347 dose in Part 1 is 50 mg 
administered as a single oral dose. The dose is planned to increase 
in subsequent cohorts to 150, 250, 500, 750 and 900 mg. 
• Part 2 consists of approximately four ascending repeat-dose cohorts 
(Cohorts 3 to 6), each with 10 participants who will receive a single 
oral dose of GSK3882347 or placebo for 7 consecutive days.  
The planned starting dose of GSK3882347 in Part 2 is 50 mg 
administered as a single dose on Days 1 through 7. The dose is 
planned to increase in subsequent cohorts to 150, 500 and 900 mg.   
Time 
& 
Events 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
Approximately 56 randomized participants will be recruited for the 
entire study, including 16 evaluable participants in the SAD part (Part 
1) with 6 active and 2 placebo in each of the two cohorts, and 40 
evaluable participants in the MAD part (Part 2) with 8 active and 2 
placebo in each of the four cohorts. Additional participants may be 
recruited as replacement for withdrawn participants. 
Interim 
Analysis 
• No formal interim analyses (IA) are planned for this study. 
• However, preliminary safety, tolerability and PK data will be 
reviewed prior to each dose escalation in Part 1 (single dose) and 
Part 2 (repeat dose). 
• Data for these reviews will be cumulative and can include individual 
participant data, summaries by study intervention and graphical 


 
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Overview of Study Design and Key Features 
displays. This is a sponsor unblinded trial and select roles within the 
GSK study team (detailed in Section  9.5.1 of the protocol) will be 
unblinded for these reviews 
  
2.4. 
Statistical Analyses 
The main purpose of this study is to assess the safety, tolerability, and pharmacokinetic 
attributes of oral doses of GSK3882347 in healthy participants. Results for the primary 
analyses will be descriptive in nature. Statistical modelling on select pharmacokinetic 
parameters will be performed to test for dose proportionality, dose accumulation, time 
invariance, achievement of steady state and food effects. Point estimates along with 90% 
confidence intervals will be reported for all secondary endpoints, where appropriate. 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
There will be no formal interim analysis. However, preliminary safety, and PK data will 
be reviewed in-stream by the GSK study team members prior to each dose escalation in 
Part 1 (SAD), Part 2 (MAD) and before the food effect in Part 1. Data for these reviews 
will be cumulative and can include individual participant data, summaries by study 
intervention and graphical displays. This is a sponsor unblinded trial and select roles within 
the GSK study team will be unblinded for these reviews. Dose escalation can only occur 
after the safety, PK profiles are found supportive to proceed with the evaluation of the next 
higher dose level. The details of internal review process to support dose-escalation are 
included in the dose escalation plan charter document. 
Preliminary results from available safety data may be reported prior to database freeze for 
the purposes of safety review by GSK, and where required by regulatory bodies. Other 
selected preliminary data may be unblinded and reported prior to database freeze for 
internal decision making. 
In each case described above, the study will not be officially unblinded and access to the 
randomization will be restricted to the unblinded site pharmacist. For dose escalation the 
Sponsor study team physicians, statistician, and clinical pharmacokinetic staff and/or their 
delegate will have access to unblinded data if required.  
After each cohort, the data will be reviewed – the data consists of the PK and safety data.  
Non-compartmental analysis (NCA) PK analysis will be performed to obtain PK 
parameters.  
3.2. 
Final Analyses 
The final planned primary, secondary and exploratory analyses will be performed after 
the completion of the following sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release (DBR), source data lock (SDL), and database freeze (DBF) has been declared 
by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• All participants who were screened for 
eligibility  
• Study 
Population  
Enrolled 
 
• All participants who had passed screening 
and entered the study.  
Note: Screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the 
Enrolled population as they did not enter the 
study. 
• Study 
Population  
Randomized 
• All 
enrolled 
participants 
who 
were 
randomized into the study irrespective of 
whether they receive any treatment.  
Note: This population will be based on the 
treatment the participant was randomized to. 
 
• Study 
Population  
Safety 
• All participants who received at least 1 dose 
of study intervention. Participants will be 
analysed according to the treatment they 
received. 
• Study 
Population 
• Safety  
Pharmacokinetic 
(PK) 
• All participants in the Safety population 
who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• PK 
Biomarker  
• All participants in the Safety population 
who had at least 1 non-missing Biomarker 
assessment 
• Biomarker 
 
4.1. 
Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. Data will be reviewed prior 
to freezing the database to ensure all important deviations are captured and categorised on 
the protocol deviations dataset. 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 eCRF. 
 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Header 
Order in 
TLF  
PART 1 
 
P/PS 
Placebo/Placebo Sentinel 
Placebo SD 
SD PBO 
1 
D1/D1S 
GSK3882347 Dose Level 1/ GSK3882347 
Dose Level 1 sentinel 
GSK3882347 50 mg 
SD 
SD 50mg 
3 
D2/D2S 
GSK3882347 Dose Level 2/ GSK3882347 
Dose Level 2 sentinel 
GSK3882347 150 mg 
SD 
SD 150 
mg 
4 
D3/D3S 
GSK3882347 Dose Level 3/ GSK3882347 
Dose Level 3 sentinel 
GSK3882347 250 mg 
SD 
SD 250 
mg 
5 
D7/D7S 
GSK3882347 Dose Level 7 fed/ 
GSK3882347 Dose Level 7 fed sentinel 
GSK3882347 250 mg 
SD Fed 
SD 250 
mg Fed 
6 
D4/D4S 
GSK3882347 Dose Level 4/ GSK3882347 
Dose Level 4 sentinel 
GSK3882347500 mg 
SD 
SD 500 
mg 
7 
D5/D5S 
GSK3882347 Dose Level 5/ GSK3882347 
Dose Level 5 sentinel 
GSK3882347 900 mg 
SD 
SD 900 
mg 
8 
D6/D6S 
GSK3882347 Dose Level 6/ GSK3882347 
Dose Level 6 sentinel 
GSK3882347 15 mg 
SD 
SD 15 mg 
2 
D8/D8S 
GSK3882347 Dose Level 8/ GSK3882347 
Dose Level 7 sentinel 
This Treatment group not utilized in the study  
 
PART 2 
RP/RPS 
Placebo Repeated/Placebo Repeated 
Sentinel 
Placebo RD 
RD PBO 
1 
R1/R1S 
GSK3882347 Repeat Dose Level 1/ 
GSK3882347 Repeat Dose Level 1 sentinel 
GSK3882347 50 mg 
RD 
RD 50mg 
2 
R2/R2S 
GSK3882347 Repeat Dose Level 2/ 
GSK3882347 Repeat Dose Level 2 sentinel 
GSK3882347 150 mg 
RD 
RD 150 
mg 
3 
R3/R3S 
GSK3882347 Repeat Dose Level 3/ 
GSK3882347 Repeat Dose Level 3 sentinel 
GSK3882347 500 mg 
RD 
RD 500 
mg 
4 
R4/R4S 
GSK3882347 Repeat Dose Level 4/ 
GSK3882347 Repeat Dose Level 4 sentinel 
GSK3882347 900 mg 
RD 
RD 900 
mg 
5 
 
NOTES: 
• 
Order represents treatments being presented in TFL, as appropriate. Dose levels will be updated 
after database freeze based on the actual number of dose levels and cohorts.  
• 
Doses will be listed in the increasing order in all summaries.  
• 
Placebo will be pooled by part 
• 
Descriptions and headers will be updated with actual doses after database freeze.  


 
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• 
Doses mentioned in code D1/ D1S, D2/ D2S, D3/D3S and D7/D7S (optional) in Part I shall be 
for cohort 1. Dose level in code D4/D4S, D5/D5S, D6/D6S and D8/D8S (optional) in Part 1 
shall be for cohort 2. Each cohort will have 2 participants on Placebo in each period.  
• 
Each of the four doses in Part 2 will be administered in cohorts 3, 4, 5 and 6.  
• 
Dose Levels 7 and 8 are reserved for testing the food effect. Dose Level 8 was not utilised in 
the study. 
 
5.2. 
Baseline Definitions 
For all endpoints the baseline value will be the latest pre-dose assessment (at each period 
for part 1) 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. The mean will be considered for triplicate measurements taken at the latest pre-
dose assessment. 
If the latest pre-dose assessment is missing, then the previous assessment time point would 
be considered as baseline where possible (i.e. if Day 1 (Pre-dose) is missing the Day -1 
will be used).  
Baseline Definitions – Part 1 
Parameter 
Screening 
Day -1 
Day 1 (Pre-
Dose) 
Baseline 
Used in Data 
Display 
12-lead 
Electrocardiogram (ECG)  
Vital signs (BP, HR, tympanic 
temperature, respiration rate) 
 
 
X 
 
 
X 
 
 
X 
 
 
Day 1 
Clinical chemistry (including 
liver chemistries), hematology 
and urine tests (including 
urine creatinine) 
 
 
X 
 
 
Day -1 
 
Baseline Definitions – Part 2 
Parameter 
Screening 
Day -1 
Day 1 (Pre-
Dose) 
Baseline Used 
in Data 
Display 
12-lead Electrocardiogram 
(ECG), Vital signs (BP, HR, 
Tympanic temperature, 
respiration rate) 
 
 
X 
 
 
X 
 
 
X 
 
 
Day 1 
Clinical chemistry (including 
liver chemistries), 
hematology, and urine tests 
(including 
 
X 
 
Day -1 


 
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Parameter 
Screening 
Day -1 
Day 1 (Pre-
Dose) 
Baseline Used 
in Data 
Display 
urine creatinine) 
4β-hydroxycholesterol 
Sampling 
 
 
X 
Day 1  
 
 
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 
12.3 
Appendix 3: Assessment Windows 
12.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.6 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Reporting Standards for Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
 


 
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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 Safety population, unless otherwise 
specified. 
Study population analyses including analyses of participant’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. 
Details of the planned displays are presented in Appendix 12: List of Data Displays. 


 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
Outputs will be presented separately for the two parts (Parts 1 and 2).  
All safety data displays will be split by actual treatment received, except where specified 
below. 
Details on the safety estimand are given in Section 2.2.  
7.1. 
Adverse Events Analyses 
Adverse Events (AE) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary. Adverse events analyses will be based on GSK Core 
Data Standards. The following displays for Adverse events shall be generated: All Adverse 
Events by System Order Class and Preferred Term, Adverse Events by maximum 
grade/intensity, Common Serious and Non-Serious Adverse Events, Serious Adverse 
Events, Drug-related Adverse Events. 
COVID-19 events will be listed based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 12: List of Data Displays. 
7.2. 
Clinical Laboratory Analyses 
Laboratory results will be included in the reporting of this study for haematology, clinical 
chemistry and urinalysis. Based upon laboratory normal ranges, the laboratory test results 
will be categorized according to the normal range as low (below the lower limit), normal 
(within the normal range) and high (above the upper limit). Summary statistics for change 
from baseline will also be tabulated. Laboratory evaluations will be based on GSK Core 
Data Standards. The details of the planned displays are in Appendix 12: List of Data 
Displays. 
7.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
7.4. 
Exploratory Safety Analyses 
All ECG-related analyses listed in the exploratory objectives/endpoints will be conducted 
and reported separately. 


 
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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
Pharmacokinetic Parameter Analyses and Summaries 
The derived PK parameters (AUC, Cmax) of partially completed participants will be 
computed if data permits (see Section 8.1.1.2). In the food effect period, derived PK 
parameters of participants who consume less than 99% of the meal (in fed participants) 
will be computed. 
 
If feasible, participants who withdraw from study will be replaced until the desired 
sample size is attained. PK data from withdrawn participants and their replacement will 
be included in PK analyses. If a participant discontinues from study treatment, they will 
proceed to follow up and no further PK data will be collected. 
Details on the pharmacokinetic estimand are given in Section 2.2.  
8.1.1. 
 Endpoint / Variables 
Part 1 (Single dose):  
• Plasma: AUC(0-12), AUC(0-24), AUC(0-t), AUC(0-inf), Cmax, C12h, C24h, 
CL/F, Vd/F (log-transformed and untransformed), tmax, tlag, t1/2, and MRT 
(untransformed) 
• Urine: C22-24,U: concentration at 22-24h collection, CLr (loge-transformed and 
untransformed), Ae, fe (untransformed), ∑Ae 
 
Part 2 (Repeat dose):  
 
• Plasma: AUC(0-12), AUC(0-tau), Cmax, Ctau, C12h (log-transformed and 
untransformed), tmax for Days 1 and 7, and Ro (untransformed) 
 
Urine: C22-24,U: concentration at 22-24h collection, CLr (loge-transformed and 
untransformed), Ae, fe (untransformed), ∑Ae for Days 1 and 7 
 
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Plasma pharmacokinetic parameters will be calculated by standard non-compartmental 
methods according to current CPMS working practices and using the currently supported 
version of WinNonlin (Currently version 8.0.) 
Calculations of pharmacokinetic parameters for the final analysis will be based on actual 
sampling times. Pharmacokinetic parameters listed below in Table 4 will be determined 
from the plasma and urine concentration-time data, as data permits. If parameters cannot 
be determined, a ‘Not done’ or ‘Not calculable’ flag will be present in the data. 


 
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Urine pharmacokinetic parameters will be calculated as follows: 
 
• Ae (amount excreted in urine) = urine concentrations x weight of urine sample 
• ∑Ae (cumulative amount excreted in urine) = sum of Ae per individual profile 
• CLr (renal clearance) = ∑Ae / plasma AUC(0-t) 
• fe (fraction of dose eliminated in urine) = ∑Ae / dose administered  
 
Table 2 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration (C(t)) will be 
calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental 
trapezoid. 
AUC(0-inf) or  
AUC(0-∞) 
 
Area under the concentration-time curve extrapolated to infinity 
calculated as:  
AUC(0-inf) = AUC(0-t) + C(t) / λz 
AUC(0-12) 
Area under the concentration-time curve from time zero to 12 
hours post-dose 
AUC(0-24) 
Area under the concentration-time curve from time zero to 24 
hours post-dose 
AUC(0-) or  
AUC(0-tau) 
AUC from time zero during a dosing interval of duration “” 
(tau) 
Ro 
Observed accumulation ratio (Ro) for AUC will be calculated as 
follows:  
Day 7 AUC(0-24)/ Day 1 AUC(0-24) 
Ae 
Amount of GSK3882347 in urine  
C22:24;U 
Urine concentration between 22-24 hours after dosing  
C12h 
Plasma concentrations at 12 hours after dosing 
C24h 
Plasma concentrations at 24 hours after dosing 
Cmax 
Maximum observed blood concentration, determined directly 
from the concentration-time data. 


 
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Ctau 
Plasma concentrations over the dosing interval  (tau) 
Ctrough 
Trough concentration   
CLr 
Renal clearance 
CL/F 
Apparent total clearance of the drug from plasma after oral 
administration 
fe 
Fraction of the dose excreted in the urine 
λz 
The first order rate constant associated with the terminal (log-
linear) portion of the concentration-time curve. 
MRT 
Mean residence time 
Rss 
Steady state ratio (Rss) will be calculated as follows:  
Day 7 AUC(0-τ)/ Day 1 AUC(0-inf) 
RoCmax 
Observed accumulation ratio for Cmax (RoCmax) will be 
calculated as follows:  
RoCmax = Day 7 Cmax/ Day 1 Cmax 
Tmax 
Time to reach Cmax, determined directly from the 
concentration-time data. 
t½ 
Apparent terminal phase half-life will be calculated as:  
t½ = ln2 / λz 
tlag 
Lag time 
Vd/F 
Apparent volume of distribution after oral administration 
∑Ae  
Cumulative amount excreted in urine 
NOTES: Additional parameters may be included as required. 
 
8.1.2. 
Summary Measure 
Parameters will be summarised according to the method defined in Section 8.1.1. 
Endpoints/Variables and described below. They will be calculated and tabulated by dose 
level for study Part 1 and Part 2 separately. 


 
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Untransformed Data 
N, n, arithmetic mean, 90% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum 
Loge-transformed Data 
Geometric mean, 90% CI for the geometric mean, SD of loge-
transformed data and %CVb (percent coefficient of variation 
between groups) 
 
8.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the PK population, unless 
otherwise specified. 
8.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
There are three kinds of intercurrent events (ICE): 
• 
Study treatment discontinuation (due to any reason) - while on treatment strategy 
(treatment effect is only considered before the ICE occurs) 
• 
Received incorrect dose or meal or did not consume at least 90% of the meal (in 
fed participants) - hypothetical strategy (the data from a period in which ICE 
occurs would be considered missing at random and excluded from analyses) 
 
8.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
8.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• (Part 1) Single dose plasma: AUC(0-12), AUC(0-24), AUC(0-t), AUC(0-inf), Cmax, C12h, 
C24h, CL/F, Vd/F (log-transformed and untransformed), tmax, tlag, t1/2 and MRT 
(untransformed) 
• (Part 2) Repeat dose plasma: AUC(0-12), AUC(0-tau), Cmax, Ctau, C12h (log-transformed 
and untransformed), tmax (untransformed) 
• (Part 1 and Part 2) Single and repeat dose urine C22-24,U, CLr (log-transformed and 
untransformed) Ae, fe (untransformed)  
 Results Presentation 
• Separate outputs will be produced for Part 1 and Part 2 
• Geometric LS means for each treatment and associated 90% CIs for each parameter. 
• Estimates of within-participant variability (%CVw) for AUC and Cmax (%CVw represents a 
pooled measure of within-participant variability across treatments). 
• Comparative plots of individual plasma PK parameters by treatment on linear and semi-
logarithmic scales. 
 


 
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8.2. 
Statistical Analysis of Derived PK Parameters 
The following statistical analyses will only be performed if PK concentration levels 
exceed the lower level of Quantification (LLQ) for the data to be available.  
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modelling and Simulation Department, (CPMS) and Statistical analyses of the 
pharmacokinetic parameters will be the responsibility of the Biostatistics Department. 
8.2.1. 
 Endpoint / Variables 
• Dose proportionality AUC, Cmax, Ctrough, Ae 
• Accumulation ratio Ro  
• Time invariance using AUC, C22-24,U (repeat dose)  
• Steady state (Ctau) 
• Food effect AUC, C24h, Cmax, tmax and tlag 
8.2.2. 
Summary Measure 
PK of GSK3882347 after single dose. 
• Dose proportionality (Day 1)  
• Food effect (equivalent dose comparisons fed vs fasted) 
 
PK of GSK3882347 after repeat dose. 
 
• Dose proportionality (on Day 1 and Day 7)  
• Accumulation (Day 7/ Day 1 for each dose) 
• Time invariance (Day 7/ Day 1 for each dose) 
• Steady state (Day 7/ Day 1 for each dose) 
 
8.2.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the pharmacokinetic 
population  
8.2.4. 
Strategy for Intercurrent Events 
For details of the estimand strategy for intercurrent events see Section 2.2 and Section 
8.1.4 
8.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 


 
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Unless otherwise specified, endpoints/variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
8.2.5.1. 
Statistical Methodology Specification 
Assessment of dose proportionality will be done on Day 1 in Part 1 (single dose) and Day 
1 and 7 in Part 2 (repeat dose). The following PK analyses will only be performed if 
sufficient data is available (i.e. if participants have well defined plasma profiles). 
1. Pharmacokinetic Statistical Analyses (Dose Proportionality - Single and Repeat 
Dose Study Phases) 
Endpoint(s) 
• Single Dose: AUC(0-24), AUC(0-t), AUC(0-inf), Cmax, Ae(Urine) 
• Repeat Dose: AUC(0-τ), Cmax, Ctrough 
Model Specification 
• Will be statistically analyzed using the power model 
y = exp(1+ ri+)·  dose2 
where y denotes the PK parameter being analyzed and r the random subject effect. The 
s, s=1,2, in the power model will be estimated by linear regression of the loge-
transformed PK parameters on loge dose levels. 
log(yij) = 1 + 2· log(dij) + ri + ij    (1) 
where 
• 𝑦𝑖𝑗  is the observed or predicted PK variable of the j-th dose dij administered to the 
i-th participant. In particular, it is an AUC  or a Cmax, as applicable. 
• 𝜃1,𝜃2 are population intercept and slope, respectively. 
• ri is the random effect associated with participants, it has mean zero and variance s2 
• 𝜖𝑖𝑗 is a random error term, with mean zero and variance 𝜎2. 
• The covariance structure of the G matrix will be specified as unstructured. 
 
Note, for part 2, participants will not receive more than one dose, therefore the random 
subject effect (ri) will not be included in that model.  
• If the power model (and attempts at fitting the power model with simplified 
covariance structures fail to converge) does not indicate dose proportionality, the 
ANOVA model will be performed: 
o On Day 1 and 7, dose proportionality will also be assessed using the Analysis of 
Variance (ANOVA) method. Following a loge transformation, dose-normalized 
AUC (0--), AUC(0-t) and Cmax will be analyzed separately using a mixed 
effects model. Dose (categorical variable), day and a day by dose interaction will 
be fitted as a fixed effect, and repeated day/subject=subject type=’UN’ will be 
fitted. 
o All doses will be compared to the chosen planned dose which will be decided 
by the kineticist. To calculate the dose normalized parameters, the derived 
parameter for each dose will be divided by the relevant dose and multiplied 
by the chosen planned dose. 


 
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Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable 
Model Results Presentation 
• Estimates of the slope of loge(parameter) vs loge (dose) will be reported along with 
corresponding 90% confidence intervals (slope≈1 implies dose proportionality). 
• If the ANOVA model is used, adjusted geometric means for each dose will be 
presented along with the standard errors (SE) of the logged data and the 90% CIs. 
Estimated treatment ratios and corresponding 90% confidence intervals will also be 
presented. 
 
2. Pharmacokinetic Statistical Analyses - Dose Accumulation for Repeat Dose 
Endpoint / Variables 
AUC(0-tau), Cmax, Ctrough, and C22-24(Urine) 
Model Specification 
• loge-transformed values of endpoints will be statistically analyzed using a Mixed 
Model with the following effects: 
o Fixed effect:               
 Main: day, dose 
                   Interaction: day*dose. 
o Random Effect: Subject  
Data will be analyzed for all participants in the repeat dosing part.  
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure for the G matrix will be used. 
o If this model fails to converge, alternative covariance structures may be 
considered such as VC or CS etc.  
o Akaike's Information Criteria (AIC) will be used to assist with the selection 
of covariance structure. 
Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 


 
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assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable.  
Model Results Presentation 
Day 7 will be compared to Day 1 in order to estimate the accumulation ratio.  
Point estimates and 90% confidence intervals for the differences “Day 7- Day 1” will be 
constructed using the appropriate error term. The point estimates and associated 90% 
confidence intervals will then be exponentially back-transformed to provide point and 
90% confidence interval estimates for the ratios “Day 7: Day 1” for each active dose. If 
both the dose and day by dose interaction terms are not significant, a single point estimate 
and confidence interval pooled across all doses will also be constructed. 
 
3. Pharmacokinetic Statistical Analyses – Time Invariance in Repeat Dose 
Endpoint / Variables 
Time Invariance Ratio: AUC (0-tau) on Day 7 to AUC (0-inf) on Day 1,  
                                        C22-24,u on Day 7 to C 22-24,u on Day 1 
  Note: Day 1 AUC(0-t) to be used if Day 1 AUC(0-inf) is not available  
Model Specification 
• loge-transformed values of endpoints will be statistically analyzed using Mixed 
Model ANOVA  
o Fixed effect:               
 Main: day, dose 
                   Interaction: day*dose. 
o Random Effect: Subject  
• Data will be analyzed for all participants in the repeat dosing part of the study. 
• AUC(0-inf) on Day 1 will be the reference phase in the analysis, while AUC(0- tau) 
on Day 7 (both collected at repeat dosing) will be the test phase, using log-
transformed AUC.  
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure for the G matrix will be used.  
o In the event that this model fails to converge, alternative covariance 
structures may be considered such as VC or CS.  
o Akaike's Information Criteria (AIC) will be used to assist with the selection 
of covariance structure. 
Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 


 
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Model Results Presentation 
The time invariance ratio of GSK3882347 will be estimated by calculating the ratio of 
the generalized least square means of AUC (0- ) on Day 7 to AUC (0-inf) on Day 1, 
along with the corresponding 90% CI at each dose level. Point estimates and 90% CIs 
will be presented by exponentiating the difference in least squares means of AUC (0-) 
Day 7 and AUC (0-inf) Day 1 along with the associated CI limits.  
 
4. Pharmacokinetic Statistical Analyses – Steady state for Repeat Dose  
Endpoint / Variables 
Trough plasma concentration at end of dosing (Ctau) 
Note : Include Day 3 to Day6  Pre dose concentration 
Model Specification 
The loge-transformed endpoint will be statistically analyzed using a mixed model (MM) 
using log-transformed dose data. 
• Fixed effects: day(continuous variable) 
• Random effect: Subject 
Note: day as continuous variable 
The analysis is done separately for each treatment 
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure for the G matrix will be used.  
o If this model fails to converge, alternative covariance structures may be 
considered such as VC or CS. Akaike's Information Criteria (AIC) will be used 
to assist with the selection of covariance structure. 
Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable.  
• If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared or square root of data, will be explored 
Model Results Presentation 
The coefficients of the slopes for the day effect on log scale for each dose, along with 
corresponding 90% confidence intervals, will be used to determine whether steady state 
was achieved. If the day-by-dose interaction were not significant, then the point 
estimates and 90% CIs for the individual dose levels will also be pooled across all doses 
for a single D7/D1 ratio. 


 
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Steady-state will be assessed visually by plotting trough concentration levels, Cτ, 
collected pre-morning dose versus collection day by dose. 
 
5. Pharmacokinetic Statistical Analyses - Food Effect for Single Dose 
Endpoint(s) 
AUC(0-24), AUC(0-t), AUC(0-inf), C24h, Cmax 
Model Specification 
• Will be statistically analyzed using a mixed model (MM) using loge transformed data  
• Terms fitted in the mixed effect ANOVA model will include: 
o Fixed effect: fed/fasted 
o Random Effect: Subject 
• Only data from the same dose level as the fed dose group will be included in this 
analysis, all other dose level data will be excluded.  
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure for the G matrix will be used.  
o If this model fails to converge, alternative covariance structures may be 
considered such as VC or CS.  
o Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure. 
Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 
Model Results Presentation 
Point estimates and corresponding 90% confidence intervals will be constructed for the 
comparisons of interest of GSK3882347 fed – GSK3882347 fasted, using the residual 
variance. These will then be back-transformed to provide point estimates and 
corresponding 90% confidence intervals for the geometric mean ratios fed: fasted. 
Non-parametric Analysis 
Endpoint(s) 
tmax and tlag 
Note: These endpoints will not be log transformed for analysis 
Model Specification 
Wilcoxon matched pair test  
Only data from the same dose level as the fed dose group will be included in this analysis, 
all other dose level data will be excluded. 


 
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Model Results Presentation 
Point estimate and corresponding 90% CI for the median difference (fed-fasted) will be 
presented 
 
8.3. 
Exploratory Pharmacokinetic Analyses 
The analyses for characterization of the plasma and urinary metabolites of GSK3882347, 
estimation of the percentage dose eliminated in urine (where possible) will be reported 
separately by DMPK. 
8.4. 
Microbiome analysis 
Change in intestinal microbiome over time will be analysed by Diversigen and reported 
separately. 
 


 
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9. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Population pharmacokinetic analyses will be performed under a separate CPMS RAP and 
reported separately. 
 


 
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10. 
BIOMARKER ANALYSES 
10.1. 
Exploratory Biomarker Analyses 
10.1.1. 
Endpoint / Variables 
Part 2 (Repeat dose): Plasma 4β-hydroxycholesterol to cholesterol ratio 
Plasma 4β-hydroxycholesterol and cholesterol will be provided in the Biomarker data set 
(provided by Covance) and the below described ratios will be derived for this endpoint  
• Ratio of Plasma 4β-hydroxycholesterol to Cholesterol at each visit 
• Ratio to baseline (ratio post/ratio pre-dose) of Plasma 4B-hydroxycholesterol to 
Cholesterol ratios. 
• Ratio of Plasma 4β-hydroxycholesterol at Post-baseline to Baseline visit  
10.1.2. 
Summary Measure 
Derived Ratios of Plasma 4B-hydroxycholesterol to Cholesterol is summarized. 
10.1.3. 
Population of Interest 
The biomarker analyses will be based on the Biomarker population, unless otherwise 
specified. 
10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Endpoints / variables defined in Section 10.1.1 will be summarised using descriptive 
statistics, graphically presented and listed. 
 
 
 
 
 
 
 
 


 
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11. 
REFERENCES 
Darpo B., Garnett C., Benson C.T., Keirns J., Leishman D., et. al.  Cardiac safety 
research consortium: Can the thorough QT/QTc study be replaced by early QT 
assessment in routine clinical pharmacology studies? Scientific update and a research 
proposal for a path forward. Am Heart J 2014; 168:262-72. 
US Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER). Guidance for Industry. Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers. July 2005.. Available from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM078932.pdf 
European Medicines Agency. Guideline on Strategies to Identify and Mitigate Risks for 
First-In-Human and Early Clinical Trials With Investigational Medicinal Products 
(EMEA/CHMP/SWP/28367/07 Rev. 1). Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002988.pdf 
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 Document Number 2019N403317_01. Investigator’s Brochure for 
GSK3882347, June 2020. 
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 
and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 
2011b;52(5):e103-20. 


 
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Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 
2012;366(11):1028-37. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
O’Neill, J., et. al. (2016) The review on antimicrobial resistance. Tackling drug-resistant 
infections globally.  Report sponsored by the Wellcome Trust and U.K. Government, 
available at https://amr-review.org/ 
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. 
Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J 
Med. 1993;329(18):1328-34. 
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. 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E8. General Considerations for Clinical Trials 
(CPMP/ICH/291/95).  
US Department of Health and Human Services, DHHS, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Clinical Pharmacology. Draft 
Guidance for Industry. Assessing the Effects of Food on Drugs in INDs and NDAs — 
Clinical Pharmacology Considerations. February 2019. Available from: 
https://www.fda.gov/media/121313/download. 
 
 


 
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12. 
APPENDICES 
12.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
• 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 unblinding and freezing the database to ensure 
all important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations.  
•  A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.  
 


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12.2. 
Appendix 2: Schedule of Activities  
12.2.1. 
Protocol Defined Schedule of Events  
Table 3 
Time and Events Table: Screening and Follow-up Visits; Single and Repeat Dose Escalation (Parts 1 and 2) 
Procedure 
Screening Period (up to 
30 days before Day 1) 
Follow-up Visit 
(14 days  3 days after 
the last study 
intervention) 
Notes 
Informed consent 
X 
 
 
Inclusion and exclusion criteria 
X 
 
Recheck clinical status before randomization and/or first dose of study 
intervention 
Demography 
X 
 
 
Medical history (includes substance usage and 
family history of premature cardiovascular 
disease) and medication history 
X 
 
Substances: drugs, alcohol, tobacco and caffeine 
Full physical examination including height and 
weight 
X 
 
 
Brief physical examination 
 
X 
Additional exams/screens may be performed, or brief exams made full exams by 
the Investigator, as deemed necessary (e.g. where safety or laboratory findings 
indicate) 
AE Review 
 
X 
 
SAE Review 
X 
X 
Serious AEs will be collected from the signing of informed consent 
Concomitant medication review 
X 
X 
 
Vital signs (BP, HR, tympanic temperature, 
respiration rate) 
X 
X 
Single measurements will be obtained 
Holter monitoring 
X 
 
Approximately 24 hour screening 
12-lead safety electrocardiogram 
X 
X 
Single measurements will be obtained 
Clinical chemistry (including liver chemistries), 
hematology, and urine tests (including urine 
creatinine) 
X 
X 
 
Human Immunodeficiency Virus (HIV), 
Hepatitis B surface antigen and hepatitis C 
screen 
X 
 
 
COVID-19 screening 
X 
 
Frequency in accordance with site procedures 


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Procedure 
Screening Period (up to 
30 days before Day 1) 
Follow-up Visit 
(14 days  3 days after 
the last study 
intervention) 
Notes 
Urine Drug, Smoke Breathalyzer and Alcohol 
Breath Tests 
X 
 
 
b-hCG pregnancy/Estradiol/FSH Tests 
X 
 
Pregnancy test as appropriate. Urine Pregnancy Kits (HCP Pregnancy Test 
Strip). Estradiol and FSH at screening as appropriate. 
 
Only women of non-childbearing potential may participate 
Stool microbiome collection/stool type 
assessment 
 
X 
Participants will be given instructions and collection items for specimen 
collection for the follow up visit. 
 
Total of 3 collection time points: Day -1, prior to discharge and follow-up. The 
other sample collections can be found in SoA Table 4 for Part 1 and Table 
5 and Table 6 for Part 2.  
Out Patient Visit 
X 
X* 
*At least 7 days and no greater than 14 days after the last study intervention 
 
Additional follow-up visits may be scheduled if there are clinical findings at the 
follow-up visit 
AE = adverse event, -hCG = beta human chorionic gonadotropin, BP = blood pressure, FSH = follicle-stimulating hormone, HR = heart rate, SAE = serious adverse event. 
• The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority (CA) 
and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of 
the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the 
EC before implementation. 


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Table 4 
Part 1 - Single Dose Escalation and Food Effect 
 
Study Days 
 
Procedure 
-1 
1 
2 
3 
4 
5 
Notes 
 
 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
24 
32 
48 
72 
96 
Hours relative to study 
intervention 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Urine Drug, Smoke 
Breathalyzer/Alcohol 
Breath Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional testing may be 
performed at other timepoints 
-hCG pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test as appropriate 
Admission to clinical 
unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants to be admitted to 
the unit the day before dosing 
(Day -1) and remain in house 
until discharge 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization will occur 
before first dose in Period 1 
Administration of 
study intervention 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No minimum time interval is 
required between the 
sentinels at each dose level.  
Approximately 15 minutes will 
be observed between the 
dosing of the remaining 
participants 
AE Review 
 
 
X 
----------------------------------------------------Continuous review---------------------------------------------------
-------------→ 
 
SAE Review 
-----------------------------------------------------------------------Continuous review----------------------------------------------------------------
-------→ 
Serious AEs will be collected 
from the signing of informed 
consent. 
 


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Ad hoc COVID-19 
testing based on 
clinical 
presentations and 
site procedures 
-----------------------------------------------------------------------Continuous review-------------------------------------------------------
--------------→ 
X 
Sample collected upon 
discharge 
Concomitant 
medication review 
 
 
X 
----------------------------------------------------Continuous review---------------------------------------------------
-------------→ 
 
Vital signs (BP, HR, 
tympanic 
temperature, 
respiration rate) 
X 
X* 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
*Triplicate measurements of 
blood pressure and pulse rate 
will be obtained pre-dose and 
averaged. 
 
Single measurements will be 
obtained at all other 
timepoints. 
 
Timings will be reviewed as 
cohorts progress and may be 
adjusted to ensure 
appropriate measurements 
relative to peak drug 
concentrations for subsequent 
cohorts. 
12-lead safety 
electrocardiogram 
X 
X* 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Triplicate 12-lead safety 
ECGs will be obtained no 
more than 15 minutes apart 
within 1-hour pre-dose and 
single measurements will be 
obtained at all other 
timepoints. 


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Continuous cardiac 
monitoring** 
 
X* 
--------------------------------------Continuous review--------------------------------------
---------→ 
 
 
 
 
**Participants will be semi-
supine resting for at least 10 
minutes prior to and 5 
minutes after each time point 
for ECG extractions. 
 
*3 time points (-45, -30 and -
15 minutes) prior to dosing. 
 
When ECG extractions 
coincide with safety ECGs, 
vital signs assessment and 
blood draws, procedures 
should occur in that order. 
 
Will not be collected in food 
effect. 
Clinical chemistry 
(including liver 
chemistries), 
hematology, and 
urine tests (including 
urine creatinine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
PK Blood Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Details of PK sample 
collection and storage will be 
provided in the Study 
Reference Manual. 
Metabolite Blood 
Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
No metabolite blood samples 
will be collected in the food 
effect groups 


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PK/Metabolite Urine 
Sample 
 
X 
See urine collection sampling times* 
*Urine collection times (hours) 
0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 
12-22, 22-24, 24-26, 26-32, 
32-38, 38-48, 48- 60, 60-72, 
72-84, 84-96 post dosing. 
 
If participant is unable to void 
at a specified timepoint, this 
should be recorded in the 
CRF. 
 
Participants will void bladder 
prior to dosing. 
 
Voids from urine will be 
combined into 0-24 hr pool for 
metabolite analysis, after 
aliquots for PK are removed. 
Genetic sample 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect the genetic sample 
only if the participant has a 
signed consent specific for 
this purpose. Informed 
consent for optional sub-
studies (e.g., genetics 
research) must be obtained 
before collecting a sample. 
Stool microbiome 
collection/stool type 
assessment 
X 
Continuous stool type assessment of all bowel movements 
X 
Participants will be given 
instructions and collection 
items for specimen collection. 
 
A last sample will be collected 
on the day closest to the day 
of discharge (Day 5). 
 
The follow-up sample is 
indicated in SoA Table 3. 


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Meal (post dose) 
X 
See Notes for meal times 
Prior to dosing, participants 
will fast for 8 hrs overnight. 
 
No food is allowed for at least 
4 hrs post-dose; after which 
meals will be permitted as per 
site schedule. 
 
Participants will receive 
standardized meals 
scheduled at the same time in 
each period. 
 
Water is permitted with dosing 
and at all times except 1-hour 
pre-dose through 2-hours 
post-dose. 
Test Meal 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Food Effect (Period 4) Part 1 
only, participants will eat a 
high fat meal prior to dosing 
as specified in the Study 
Reference Manual. 
Daily fluids 
(intake/output) 
 
X* 
See assessment times 
X 
 
X 
X 
X 
*Assessed approximately 
over 24 hours 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event. 
• 
The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation. 


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Table 5 
Part 2 – 7-Day Repeat Dose Escalation (Days 1 and 7) 
 
Study Days 
 
Procedure 
1 and 7 
Notes 
 
-1 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
Hours relative to study 
intervention 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status before 
randomization and/or 1st dose 
of study treatment 
Brief physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug, Smoke 
Breathalyzer/Alcohol 
Breath Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Additional testing may be 
performed at other timepoints 
-hCG pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test as appropriate 
Admission to clinical unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization will occur 
before first dose on Day 1 
only. 
Administration of study 
intervention 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AE Review 
 
 
X 
----------------------------------------Continuous review-----------------------------------------→ 
 
SAE Review 
-------------------------------------------------------------Continuous review----------------------------------------------------------→ 
Serious AEs will be collected 
from the signing of informed 
consent. 
Ad hoc COVID-19 
testing based on clinical 
presentation and site 
procedures 
-------------------------------------------------------------Continuous review----------------------------------------------------------→ 
 
Concomitant medication 
review 
 
 
X 
-----------------------------------------Continuous review----------------------------------------→ 
 


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Study Days 
 
Procedure 
1 and 7 
Notes 
 
-1 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
Hours relative to study 
intervention 
Vital signs (BP, HR, 
tympanic temperature, 
respiration rate) 
X 
X* 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Vital signs will be obtained 
within 1 hour of pre-dose and 
at 1, 2, 4, 6, 8, 12 and 24 
hours after study 
administration on Days 1 and 
7. 
 
*Triplicate readings of blood 
pressure and pulse rate will 
be taken pre-dose and 
averaged on Days 1 and 7. 
 
Single measurements will be 
obtained at all other 
timepoints. 
 
Timings will be reviewed as 
cohorts progress and may be 
adjusted to ensure 
appropriate measurements 
relative to peak 
concentrations for 
subsequent cohorts. 


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Study Days 
 
Procedure 
1 and 7 
Notes 
 
-1 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
Hours relative to study 
intervention 
12-lead safety 
electrocardiogram 
X 
X* 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
*Triplicate 12-lead safety 
ECGs will be obtained no 
more than 15 minutes apart 
within 1-hour pre-dose on 
Days 1 and 7. 
 
Single 12-lead safety ECGs 
will be obtained at 1, 2, 4, 6, 
8, 12 and 24 hours after study 
administration on Days 1 and 
7. 
Continuous cardiac 
monitoring** 
 
X* 
---------------------------------------------Continuous review----------------------------------------------→ 
**Participants will be semi-
supine resting for at least 10 
minutes prior to and 5 
minutes after each time point 
for ECG extractions. 
 
*3 time points (-45, -30 and -
15 minutes) prior to dosing on 
Day 1. 
 
When ECG extractions 
coincide with safety ECGs, 
vital signs assessment and 
blood draws, procedures 
should occur in that order. 
Clinical chemistry 
(including liver 
chemistries), 
hematology, and urine 
tests (including urine 
creatinine)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Days 
 
Procedure 
1 and 7 
Notes 
 
-1 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
Hours relative to study 
intervention 
PK Blood Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Details of PK sample 
collection and storage will be 
provided in the Study 
Reference Manual. 
4β-hydroxycholesterol 
sampling 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Sample to be taken pre-dose 
on Day 1 in a fasted state. 
Metabolite Blood 
Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK/Metabolite Urine 
Sample 
 
X 
See urine collection times* 
*Urine collection times (hours) 
0-2, 2-4, 4-6, 6-8, 8-10, 10-
12, 12-22, 22-24 post dosing. 
 
Participants will void bladder 
prior to dosing. 0-24-hr urine 
samples will be collected. 
 
Voids from urine will be 
combined into 0-24 hr pool for 
metabolite analysis, after 
aliquots for PK are removed. 
Genetic sample 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Collect the genetic sample 
only if the participant has a 
signed consent specific for 
this purpose.  
Informed consent for optional 
sub-studies (e.g., genetics 
research) must be obtained 
before collecting a sample. 


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Study Days 
 
Procedure 
1 and 7 
Notes 
 
-1 
Predose 
0 
0.25 
0.5 
1 
1.5 
2 
4 
6 
8 
12 
16 
Hours relative to study 
intervention 
Stool microbiome 
collection/stool type 
assessment 
X 
*Continuous stool type assessment of all bowel movements while in the clinical unit. 
 
Participants will be given  
instructions and collection 
items for specimen collection. 
The stool sample can be 
collected up to 72 hours (3 
days) prior to the visit the 
stool sample is required (Day 
-1). 
Meal (post-dose) 
X 
See Notes for meal times 
Prior to dosing on Days 1 and 
7, participants will fast for 8 
hrs overnight. 
 
No food is allowed for at least 
4 hrs post-dose; after which 
meals will be permitted as per 
site schedule. 
 
Water is permitted with 
dosing and at all times except 
1-hour pre-dose through 2-
hours post-dose. 
 
Participants will receive 
standardized meals 
scheduled at the same time in 
each period. 
Daily fluids 
(intake/output) 
 
X* 
See assessment times. 
*Assessed approximately 
over 24 hours 
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event. 
24-hour procedures are presented in Table 4. 
The 4β-hydroxycholesterol sample may not be available from all Cohorts in Part 2, due to the timing of the amendment when this was added. 


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• 
The timing and number of planned study assessments, including: safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority (CA) and 
ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the 
safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by the CA and the EC 
before implementation. 
 


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Table 6 
Part 2 – 7-Day Repeat Dose Escalation (Days 2 through 6 and Day 8 to 12) 
 
Study Days 
 
Procedure 
2 
3 
4 
5 
6 
8 
9-12 
Notes 
 
(24hrs 
post-Day 
1 dose) 
0 
0 
0 
0 
0 
(24 hrs 
post-Day 7 
dose) 
0 
0 
 
Brief physical examination 
 
X 
X 
X 
X 
X 
 
X 
X* 
*Upon discharge 
Administration of study 
intervention 
 
X 
X 
X 
X 
X 
 
 
 
No minimum time 
interval is required 
between the sentinels at 
each dose level.  
Approximately 15 
minutes will be observed 
between the dosing of 
the remaining 
participants 
AE Review 
---------------------------------------------------------------------Continuous review---------------------------------------------------------------
-→ 
 
SAE Review 
---------------------------------------------------------------------Continuous review---------------------------------------------------------------
-→ 
 
Ad hoc COVID-19 testing 
based on clinical 
presentation and site 
procedures 
---------------------------------------------------------------------Continuous review----------------------------------------------
→ 
X* 
*Sample collected just 
prior to discharge for 
COVID-19 testing 
Concomitant medication 
review 
---------------------------------------------------------------------Continuous review---------------------------------------------------------------
-→ 
 
 


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Vital signs (BP, HR, 
tympanic temperature, 
respiration rate) 
X 
 
X 
X 
X 
X 
X 
 
X 
Single measurements 
will be obtained within 1-
hour pre-dose and daily 
in the morning on days 
9-12 until discharge. 
 
Timings will be reviewed 
as cohorts progress and 
may be adjusted to 
ensure appropriate 
measurements relative 
to peak concentrations 
for subsequent cohorts. 
12-lead safety 
electrocardiogram 
X 
 
X 
X 
X 
X 
X 
 
X 
Single 12-lead safety 
ECGs will be obtained 
within 1 hour before pre-
dose and daily in the 
morning on days 9-12 
until discharge. 
Continuous cardiac 
monitoring** 
X 
 
 
 
 
 
X 
 
 
**Participants will be 
semi-supine resting for 
at least 10 minutes prior 
to and 5 minutes after 
each time point for ECG 
extractions. 
 
When ECG extractions 
coincide with safety 
ECGs, vital signs 
assessment and blood 
draws, procedures 
should occur in that 
order. 


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Clinical chemistry (including 
liver and kidney 
chemistries), hematology, 
and urine tests (including 
urine creatinine) 
 
X 
X 
X 
X 
X 
 
X 
X* 
*Just prior to discharge. 
PK Blood Sample 
X 
 
X* 
X* 
X* 
X* 
X 
 
 
*Trough PK samples 
4β-hydroxycholesterol 
sampling 
 
 
 
 
 
 
X 
 
 
Sample to be taken at 
24hr post AM dose on 
Day 7. Sample should 
be in a fasted state. 
PK Metabolite Sample 
X 
 
 
 
 
 
X 
 
 
 
PK Urine Sample 
X 
 
X* 
X* 
X* 
X* 
X 
 
 
*Trough PK samples 
Stool microbiome collection/ 
stool type assessment 
*Continuous stool type assessment of all bowel movements while in the clinical unit. 
X** 
A last sample will be 
collected on the day 
closest to the day of 
discharge. 
The stool sample can be 
collected up to 72 hours 
(3 days) prior to the visit 
the stool sample is 
required (Days 9-12). 
 
**This includes the last 
sample collected on the 
day closest to the day of 
discharge (Days 9-12) 
for microbiome. 
 
The Day -1 sample is 
indicated in SoA Table 4 
and follow-up sample is 
indicated in SoA Table 
3.. 


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Meal 
 
X 
X 
X 
X 
X 
 
X 
X 
Participants will receive 
standardized meals 
scheduled at the same 
time in each period. 
Daily fluids (intake/output) 
X 
 
 
 
 
 
X 
 
 
 
Discharge 
 
 
 
 
 
 
 
X 
X 
Participants will be 
discharged from the 
clinical unit after the  
assessments are 
completed. 
AE = adverse event, BP = blood pressure, HR = heart rate, PK = Pharmacokinetic, SAE = serious adverse event. 
The 4β-hydroxycholesterol sample may not be available from all Cohorts in Part 2, due to the timing of the amendment when this was added. 
• 
 
• 
The start of Part 2 can be modified from emerging data from Part 1. 
• 
The timing and number of planned study assessments, including safety and pharmacokinetic 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 as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study 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 Competent Authority 
(CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment and require 
alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved by 
the CA and the EC before implementation. 
 


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12.3. 
Appendix 3: Assessment Windows 
• Actual times will be used in the derivation of PK parameters and in the individual 
concentration-time plots. Planned times will be used in the descriptive summaries and 
in mean and median plots 
• PK concentration listings shall have both the planned and actual times  
• Planned time will be used for all other analysis Appendix 4: Study Phases and 
Treatment Emergent Adverse Events 


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12.4. 
Appendix 4: Study Phases 
In Part 1 the study phase and study period for adverse events and concomitant medication 
as follows: 
Study Phase 
Definition 
Pre-Treatment  
Date and time of event < Date and time of First dose in Period 1 
Treatment 
Date and time of event ≥ Date and time of first dose in Period 1 
 
Study Period 
Definition 
Period 1 
Date and time of First dose in Period 1 ≤ Date and time of event < Date and 
time of first dose in Period 2 or last visit of study if participant did not take a 
dose in Period 2 
Period 2 
Date and time of first dose in Period 2 ≤ Date and time of event < Date and time 
of first dose in Period 3 or last visit of study if participant did not take a dose in 
Period 3 
Period 3 
Date and time of first dose in Period 3 ≤ Date and time of event < Date and time 
of first dose in Period 4 or last visit of study if participant did not take a dose in 
Period 4 
Period 4 
Date and time of event ≥ Date and time of first dose in Period 4 
 
For Part 2 Cohorts 3, 4, 5 and 6, assessments and events will be classified according to 
the following: 
 
Study Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date of each Cohort 
Treatment 
Study Treatment Start Date and time ≤ Date and time ≤ Date of Unit discharge, 
in each cohort 
Post-Treatment 
Date > Date of unit discharge, in each cohort 
 
12.4.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: 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. 
 


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12.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
12.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Compound 
: GSK3882347 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1].. 
Generation of RTF Files 
• 
RTF files will be generated for SAC. 
12.5.2. 
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.  
• 
Display all numeric variables with the same number of decimal places as the collected precision.  
• 
Display minimum and maximum values with the same number of decimal places as the collected 
precision.  
• 
Display the mean and percentiles (e.g. median, Q1, and Q3) with one additional decimal place.  
• 
Display the standard deviation and standard error with two additional decimal places.  
• 
Within a column, align all data values or summary statistics along the decimal point.  
• 
The reported precision for PK concentration data will be 1 decimal place but may be altered by 
parameter depending on the significant digits.  
 
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses:  
o Planned time relative to dosing will be used in figures, summaries, statistical analyses 
and calculation of any derived parameters, unless otherwise stated.  


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o 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: 
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).  
o Unscheduled or unplanned readings will be presented within the participant’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and figures (except for situations where 
worse case post-baseline is summarised) 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. 
12.5.3. 
Reporting Standards for Pharmacokinetic 
 Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[SOP_514512]. 
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 
• 
Ae (amount excreted in urine) = urine concentrations x weight (volume) of 
urine sample 
• 
Ʃ(Ae) (cumulative amount excreted in urine) = sum of Ae per individual 
profile 
• 
CLr (renal clearance) = Ʃ (Ae) / plasma AUC(0-t) 
• 
fe (fraction of dose eliminated in urine) = Ʃ (Ae) / dose administered 
Note: Urine sample volume needs to be merged with PK concentration data set 
to derive urine PK parameters 
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. 
 
loge-transformed data: N, n, geometric mean, 90% CI of geometric mean, standard 
deviation (SD) of loge transformed data and the coefficient of variation CVb in % 
will be reported. Here 
CVb (%) = √𝑒𝑆𝐷2 −1 × 100,  
where SD2  = variance of loge transformed data. 
Parameters Not Being loge-transformed: tmax, t1/2, tlag, Ae, fe, and MRT. 


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12.6. 
Appendix 6: Derived and Transformed Data 
12.6.1. 
 General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but 
when listed, all data will be presented. 
• 
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 
• 
In Part 1 for each period: Period Study day is calculated as the number of days from First Dose Date 
in the period for each participant as follows: 
o Ref Date = Missing              → Period Study Day = Missing  
o Ref Date < First Dose Date in the period → Period Study Day = Ref Date – Period 
First Dose Date 
o Ref Data ≥ First Dose Date in the period → Period Study Day = Ref Date – (Period 
First Dose Date) + 1     
• 
In Part 1 and 2: Study day is calculated as the number of days from First Dose Date in each cohort 
for each participant as follows: 
o Ref Date = Missing              → Study Day = Missing  
o Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
o Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 


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12.6.2. 
Safety 
LAB Parameter 
Reticulocyte Index 
Reticulocyte Index (RI) = Reticulocyte count (%) X [Measured haematocrit / Normal haematocrit] * 0.5 
ECG Parameters 
RR Interval 
• 
IF RR interval (msec) is not provided directly, then RR can be derived as: 
[1] If QTcB is machine read & QTcF is not provided, then: 
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐵)
2
] ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅= [( 𝑄𝑇
𝑄𝑇𝑐𝐹)
3
] ∗1000 
• 
If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.  
Corrected QT Intervals 
• 
When not entered directly in the eCRF (ClinBase), corrected QT intervals using the Bazett’s (QTcB) 
and Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements. 
• 
IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 
  
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
                           𝑄𝑇𝑐𝐹= 
𝑄𝑇
3√𝑅𝑅
1000
 
 
12.6.3. 
Pharmacokinetic 
  
PK parameters 
• 
The PK Population will include all participants who undergo PK sampling and have evaluable PK assay 
results. 
• 
See Section 8.1.1.2 for derived Pharmacokinetic parameters  
 
 
 


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12.7. 
Appendix 7: Reporting Standards for Missing Data 
12.7.1. 
 Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion - . A participant is considered to have completed the 
study if he/she has completed all phases of the study including the last visit 
• 
Withdrawn participants 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 will be included in summary tables and figures, unless 
otherwise specified 
12.7.2. 
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: 
• 
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.  
• 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
• 
Missing safety data (labs, ECG, Vitals) will not be imputed 
• 
 
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. 
12.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse Events 
• 
The Database 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 4: Study Phases  
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. 
Concomitant 
Medications/Medical 
History 
• 
Partial dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention: 
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 


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Element 
Reporting Detail 
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.  
• 
For assigning periods: 
If only the start date is completely missing, we assume that the medication has 
been taken from the beginning of the study for the patient  
If only the stop date is missing, assume that the medication has been taken till 
the end of the compete study for the patient  
• 
If both start and end date is missing, we assume that the medication has 
been taken for the duration of the study for the patient. 
 


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12.8. 
Appendix 8: Values of Potential Clinical Importance 
12.8.1. 
 Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Haematocrit  
Ratio of 1 
Male 
0.39 
0.54 
Female 
0.36 
0.54 
∆ from BL 
↓0.075 
 
Haemoglobin  
g/L 
 
Male 
124 
180 
Female 
10.7 
180 
∆ from BL 
↓25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
While Blood Cell Count (WBC) 
x109/ L 
 
3 
20 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin 
mmol/L 
 
30 
 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
µmol/L 
∆ from BL 
 
↑44.2 
Glucose 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
≥ 2x ULN 
AST/SGOT  
U/L 
High 
≥ 2x ULN 
AlkPhos  
U/L 
High 
≥ 2x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
T. Bilirubin + ALT 
µmol/L 
IU/L 
High 
Bilirubin≥1.5xULN AND ALT≥2xULN 
 


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12.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
<110 
>220 
Absolute QRS Interval 
msec 
<75 
>110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
12.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>160 
Diastolic Blood Pressure 
mmHg 
<45 
>100 
Heart Rate 
bpm 
<40 
>110 


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12.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Population pharmacokinetic analyses will be performed under a separate CPMS RAP and 
will be reported separately. 


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12.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
A detailed population PK/PD data analysis plan will be prepared in a separate RAP. 


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12.11. 
Appendix 11: Abbreviations & Trade Marks 
12.11.1. 
 Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
Ae 
Amount excreted in urine 
AIC 
Akaike's Information Criteria 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
A&R 
Analysis and Reporting  
AUC 
Area under the concentration-time curve 
AUC(0-τ)/ 
AUC(0-inf) 
AUC extrapolated from time zero to infinity 
AUC(0-τ) 
AUC over the dosing interval tau 
AUC(0-12) 
AUC from time zero to 12 hours after 
AUC(0-24) 
AUC from time zero to 24 hours after dosing 
AUC(0-t) 
AUC from time zero to the last quantifiable concentration after dosing 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
Cmax 
Maximum observed concentration 
Ctau 
Trough concentration 
Clast 
last observable concentration 
CL/F 
Apparent Clearance 
C22:24,u 
Urine concentration between 22-24 hours post dose  
C24h 
Concentration at 24 hours  
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 


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Abbreviation 
Description 
IP 
Investigational Product 
MAD 
Multiple ascending dose 
MRT 
Mean residence time 
PCI 
Potential Clinical Importance  
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SAD 
Single ascending dose 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
Tmax 
Time Taken to Maximum Observed Plasma Drug Concentration 
Tlag 
Lag time before observation of drug concentrations 
t1/2  
Terminal phase half-life 
tau 
Dosing interval 
tlast 
time of last quantifiable concentration 
Vd/F 
Apparent volume of distribution  
 
12.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
Phoenix (Pharsight Corporation)  
WinNonlin 
 
 


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12.12. 
Appendix 12: List of Data Displays 
12.12.1. 
 Data Display Numbering 
 The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.14 
 
Safety 
2.1 to 2.36 
2.1 to 2.8 
Pharmacokinetic 
3.1 to 3.29 
3.1 to 3.17 
Biomarker  
4.1  
4.1 to 4.2 
Section 
Listings 
ICH Listings 
1 to 56 
Non ICH Listings 
57 to 73 
Covid-19 Listings 
74 to 75 
Conditional Listings 
76 to78 
 
12.12.2. 
Mock Example Shell Referencing 
 Non IDSL specifications will be referenced as indicated and if required example mock-
up displays provided in Appendix 13: Example Mock Shells for Data Displays. 
 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Biomarker 
BIO_Fn 
BIO_Tn 
BIO_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
12.12.3. 
Deliverables  
Delivery [Priority] [1] 
Description 
SAC 
Final Statistical Analysis Complete 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


 
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12.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Safety 
ES1xo 
Summary of Subject Status and Subject Disposition for the Study 
Conclusion Record – Part 1 
ICH E3, FDAAA, 
EudraCT 
SAC  
1.2. 
Safety 
ES1 
Summary of Subject Status and Subject Disposition for the Study 
Conclusion Record – Part 2 
ICH E3, FDAAA, 
EudraCT 
SAC 
1.3. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation of Study 
Treatment – Part 2 
 
SAC 
1.4. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Epoch – 
Part 1 
 
SAC 
1.5. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure  
 
SAC 
Protocol Deviation 
1.6. 
Safety 
DV1 
Summary of Important Protocol Deviations – Part 1   
ICH E3, Add ’Total’ column 
as it is cross over design 
SAC 
1.7. 
Safety 
DV1 
Summary of Important Protocol Deviations – Part 2 
ICH E3 
SAC 
Population Analysed 
1.8. 
Enrolled 
SP1  
Summary of Study Populations – Part 1 
 
SAC 
1.9. 
Enrolled 
SP1 
Summary of Study Populations – Part 2 
 
SAC 
Demographic and Baseline Characteristics 
1.10. 
Safety 
DM1xo 
Summary of Demographic Characteristics – Part 1 
ICH E3, FDAAA, EudraCT 
SAC 
1.11. 
Safety 
DM1 
Summary of Demographic Characteristics – Part 2 
ICH E3, FDAAA, EudraCT 
SAC 
1.12. 
Safety 
DM6xo 
Summary of Race and Racial Combinations Details – Part 1 
 
SAC 
1.13. 
Safety 
DM6 
Summary of Race and Racial Combinations Details – Part 2 
 
SAC 


 
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12.12.5. 
Safety Tables  
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.1.  
Safety 
AE1xo 
Summary of All Adverse Events by System Organ Class and 
Preferred Term – Part 1 
ICH E3 
SAC 
2.2.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term – Part 2 
ICH E3 
SAC 
2.3.  
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade / Intensity by 
System Organ Class and Preferred Term – Part 1 
 
SAC 
2.4.  
Safety 
AE5A 
Summary of All Adverse Events by Maximum Grade / Intensity by 
System Organ Class and Preferred Term – Part 2 
 
SAC 
2.5.  
Safety 
AE1xo 
Summary All Drug-Related Adverse Events by System Organ Class 
and Preferred Term – Part 1 
 
SAC 
2.6.  
Safety 
AE1 
Summary All Drug-Related Adverse Events by System Organ Class 
and Preferred Term – Part 2 
 
SAC 
2.7.  
Safety 
AE15 
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects and 
Occurrences) – Part 1 
FDAAA, EudraCT 
 
SAC 
2.8.  
Safety 
AE15 
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects and 
Occurrences) – Part 2 
FDAAA, EudraCT 
 
SAC 
2.9.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) – Part 1 
FDAAA, EudraCT 
  
SAC 
2.10. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) – Part 2 
FDAAA, EudraCT 
 
SAC 


 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Chemistry  
2.11. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline – Part 1 
ICH E3  
SAC 
2.12. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline – Part 2 
ICH E3  
SAC 
2.13. 
Safety 
 LB17A 
Summary of Worst-Case Chemistry Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 1 
ICH E3 
SAC 
2.14. 
Safety 
 LB17 
Summary of Worst-Case Chemistry Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 2 
ICH E3 
SAC 
Laboratory: Hematology 
2.15. 
Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 1 
ICH E3  
SAC 
2.16. 
Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 2 
ICH E3 
SAC 
2.17. 
Safety 
 LB17A 
Summary of Worst-Case Hematology Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 1 
ICH E3 
SAC 
2.18. 
Safety 
 LB17 
Summary of Worst-Case Hematology Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 2 
ICH E3 
SAC 
Laboratory: Urinalysis 
2.19. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline – Part 1 
ICH E3 
SAC 
2.20. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline – Part 2 
ICH E3 
SAC 
2.21. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results (Discrete or Character 
Values) Post-Baseline Relative to Baseline – Part 1 
 
SAC 
2.22. 
Safety 
UR1 
Summary of Worst-Case Urinalysis Results (Discrete or Character 
Values) Post-Baseline Relative to Baseline – Part 2 
 
SAC 
ECG 
2.23. 
 Safety 
EG1 
Summary of ECG Findings – Part 1 
IDSL  
SAC 
2.24. 
Safety 
EG1 
Summary of ECG Findings – Part 2 
IDSL 
SAC 


 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.25. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values – Part 1 
IDSL  
SAC 
2.26. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values – Part 2 
 
SAC 
2.27. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 1 
IDSL 
 
2.28. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 2 
IDSL 
SAC 
Vital Signs 
2.29. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 1 
ICH E3   
SAC 
2.30. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 2 
 
SAC 
2.31. 
Safety 
 VS7A 
Summary of Worst-Case Vital Signs Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 1 
 
SAC 
2.32. 
Safety 
 VS7 
Summary of Worst-Case Vital Signs Results by PCI Criteria Post-
Baseline Relative to Baseline – Part 2 
 
SAC 
 
 
 


 
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12.12.6. 
Safety Figures 
 Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory 
2.1.  
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT- Part 1 
IDSL 
  
 SAC  
2.2.  
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT- Part 2 
IDSL 
  
 SAC  
2.3.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin – 
Part 1 
IDSL 
  
SAC  
2.4.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin – 
Part 2 
IDSL 
  
SAC  
 
12.12.7. 
Pharmacokinetic Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK concentration 
3.1.  
PK 
PK01 
Summary of Plasma GSK3882347 Pharmacokinetic 
Concentration -Time Data by treatment – Part 1  
 
SAC 
3.2.  
PK 
PK01 
Summary of Plasma GSK3882347 Pharmacokinetic 
Concentration -Time Data by treatment – Part 2 
 
SAC 


 
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No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Plasma PK Parameter 
3.3.  
PK 
PK03 
Summary of Derived Plasma GSK3882347 
Pharmacokinetic Parameters by treatment – Part 1 
AUC(0-12), AUC(0-24), 
AUC(0-t), AUC(0-inf), 
Cmax, C12h, C24h, CL/F, 
Vd/F, tmax, tlag, t1/2, MRT 
SAC 
3.4.  
PK 
PK03 
Summary of Derived Plasma GSK3882347 
Pharmacokinetic Parameters by treatment – Part 2 
AUC(0-12), AUC(0-tau), 
Cmax, C12h, Ctau, tmax 
SAC 
3.5.  
PK 
PK05 
Summary of Derived Plasma GSK3882347 
Pharmacokinetic Parameters (log-transformed data) by 
treatment – Part 1 
AUC(0-12), AUC(0-24), 
AUC(0-t), AUC(0-inf), 
Cmax, C12h, C24h, CL/F, 
Vd/F 
SAC 
3.6.  
PK 
PK05 
Summary of Derived Plasma GSK3882347 
Pharmacokinetic Parameters (log-transformed data) by 
treatment – Part 2 
AUC(0-12), AUC(0-tau), 
Cmax, C12h, Ctau 
SAC 
3.7.  
PK 
PK_T1 
Statistical Analysis of Log transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part 1 
AUC(0-t), AUC(0-inf), 
Cmax  
Day 1 
SAC 
3.8.  
PK 
PK_T1 
Statistical Analysis of Log-transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part 2 
AUC(0-τ), Cmax, Ctrough 
Day 1 and Day 7 
SAC 
3.9.  
PK 
PK_T2 
Statistical Analysis of Log-transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Accumulation Ratio  
Ro (AUC(0-tau)), RCmax, 
RCtrough  
SAC 
3.10. 
PK 
PK_T3 
Statistical Analysis of Log-transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Time Invariance  
AUC (0-tau) on Day 7 to 
AUC (0-inf) on Day 1            
SAC 


 
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No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.11. 
PK 
PK_T4 
Statistical Analysis of Log-transformed Plasma 
GSK3882347 Parameters Assessing Steady-State  
Ctau 
SAC 
3.12. 
PK 
PK_T5 
Statistical Analysis of Log-transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Food Effect – Part 1 
AUC(0-24), AUC(0-t), 
AUC(0-inf), C24h, Cmax 
SAC 
3.13. 
PK 
PK_T6 
Non-Parametric Analysis of Pharmacokinetic 
Parameter Assessing Food Effect – Part 1 
tmax and tlag 
SAC 
Urine PK  
3.14. 
PK 
PK02 
Summary of Urine GSK3882347 Pharmacokinetic 
Concentration -Time Data by treatment – Part 1  
 
SAC 
3.15. 
PK 
PK02 
Summary of Urine GSK3882347 Pharmacokinetic 
Concentration -Time Data by treatment – Part 2 
 
SAC 
3.16. 
PK 
PK02 
Summary of Pharmacokinetic Urine Excretion Rate-
Time Data – Part 1 
 
SAC 
3.17. 
PK 
PK02 
Summary of Pharmacokinetic Urine Excretion Rate-
Time Data – Part 2 
 
SAC 
Urine PK Parameters 
3.18. 
PK 
PK03 
Summary of Derived Urine GSK3882347 
Pharmacokinetic Parameters by treatment – Part 1 
C22-24,u, CLr, Ae, fe 
SAC 
3.19. 
PK 
PK03 
Summary of Derived Urine GSK3882347 
Pharmacokinetic Parameters by treatment – Part 2 
C22-24,u, CLr, Ae, fe 
SAC 
3.20. 
PK 
PK05 
Summary of Derived Urine GSK3882347 
Pharmacokinetic Parameters (log-transformed data) by 
treatment – Part 1 
C22-24,u, CLr 
SAC 
3.21. 
PK 
PK05 
Summary of Derived Urine GSK3882347 
Pharmacokinetic Parameters (log-transformed data) by 
treatment – Part 2 
C22-24,u, CLr 
 
SAC 


 
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No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.22. 
PK 
PK_T1 
Statistical Analysis of Log-transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part 1 
Ae  
Day 1 
SAC 
3.23. 
PK 
PK_T1 
Statistical Analysis of Log-transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (Power Model) – Part 2 
Ae  
Day 1 and Day 7 
SAC 
3.24. 
PK 
PK_T2 
Statistical Analysis of Log-transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Accumulation Ratio – Part 2 
Ro (C22-24,u) 
SAC 
3.25. 
PK 
PK_T3 
Statistical Analysis of Log-transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Time Invariance – Part 2 
C22-24,u on Day 7 to C22-24,u 
on Day 1 
SAC 
Conditional Tables (If Dose proportionality power model does not converge) 
3.26. 
PK 
PK_T7 
Statistical Analysis of Log transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (ANOVA) – Part 1 
AUC(0-t), AUC(0-inf), 
Cmax  
Day 1 
SAC 
3.27. 
PK 
PK_T7 
Statistical Analysis of Log transformed Plasma 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (ANOVA) – Part 2 
AUC(0-τ), Cmax, Ctrough 
Day 1 and Day 7 
Analysis by Day 
SAC 
3.28. 
PK 
PK_T7 
Statistical Analysis of Log transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (ANOVA) – Part 1 
Ae  
Day 1 
SAC 
3.29. 
PK 
PK_T7 
Statistical Analysis of Log transformed Urine 
GSK3882347 Pharmacokinetic Parameters Assessing 
Dose Proportionality (ANOVA) – Part 2 
Ae 
Day 1 and Day 7 
SAC 
 


 
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12.12.8. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Plasma PK Plots  
3.1.  
PK 
PK16b 
Individual Subject Plasma GSK3882347 
Concentration-time Plot (Linear and Semi-log) by 
Subject-Part 1 
 
SAC 
3.2.  
PK 
PK16a 
Individual Subject Plasma GSK3882347 
Concentration-time Plot (Linear and Semi-log) by 
Subject-Part 2 
Day 1 and Day 7 
superimposed   
SAC 
3.3.  
PK 
PK24 
Individual Subject Plasma GSK3882347 
Concentration-time Plot (Linear and Semi-log) by 
Treatment – Part 1 
 
SAC 
3.4.  
PK 
PK24 
Individual Subject Plasma GSK3882347 
Concentration-time Plot (Linear and Semi-log) by 
Treatment – Part 2 
 
SAC 
3.5.  
PK 
PK17 
Mean Plasma GSK3882347 Concentration-Time Plots 
(Linear and Semi-log) – Part 1 
 
SAC 
3.6.  
PK 
PK17 
Mean Plasma GSK3882347 Concentration-Time Plots 
(Linear and Semi-log) – Part 2 
 
SAC 
3.7.  
PK 
PK18 
Median Plasma GSK3882347 Concentration-Time 
Plots (Linear and Semi-log) – Part 1 
 
SAC 
3.8.  
PK 
PK18 
Median Plasma GSK3882347 Concentration-Time 
Plots (Linear and Semi-log) – Part 2 
 
SAC 
3.9.  
PK 
PK26 
Individual Plasma GSK3882347 Pre-dose 
Concentration versus Day (Linear and Semi-log) – 
Part2 
 
SAC 


 
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Urine PK plots  
3.10. 
 
PK 
PK21 
Individual Subject Urine GSK3882347 Concentration-
time Plot (Linear and Semi-log) by Subject-Part 1 
 
SAC 
3.11. 
 
PK 
PK21 
Individual Subject Urine GSK3882347 Concentration-
time Plot (Linear and Semi-log) by Subject-Part 2 
Day 1 and Day 7 
superimposed   
SAC 
3.12. 
 
PK 
PK21 
Individual Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 1 
 
SAC 
3.13. 
 
PK 
PK21 
Individual Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 2 
 
SAC 
3.14. 
 
PK 
PK22 
Mean Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 1 
 
SAC 
3.15. 
 
PK 
PK22 
Mean Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 2 
 
SAC 
3.16. 
 
PK 
PK23 
Median Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 1 
 
SAC 
3.17. 
 
PK 
PK23 
Median Urine Excretion Rate-Time Plots (Linear and 
Semi-log) – Part 2 
 
SAC 
 
 


 
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12.12.9. 
Biomarker Tables 
Pharmacodynamic (and or Biomarker): Tables 
No. 
Population 
GSK 
Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Biomarker 
4.1.  
Biomarker 
BIO_T1 
Summary of Ratio to Baseline in Plasma 4β-hydroxycholesterol 
and 4β-hydroxycholesterol to cholesterol ratio – Part 2 
 
SAC 
 
12.12.10. Biomarker Figures 
Pharmacodynamic (and or Biomarker): Figures 
No. 
Population 
GSK 
Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
[Insert Endpoint Category] 
4.1.  
Biomarker 
BIO_F1 
Individual Plot of Plasma 4β-Hydroxycholesterol to Cholesterol 
Ratio Over Time by Dose – Part 2 
Please note that the mock shell given 
is an example shell, not study specific. 
Change the parameter accordingly 
 
SAC 


 
CONFIDENTIAL 
 
 
 
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12.12.11. ICH Listings 
 ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable [Priority] 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure – Part 1 
and Part 2 
Journal Guidelines 
Note: Include Part as 3rd 
column 
SAC 
2.  
Safety 
ES2  
Listing of Reasons for Study Withdrawal – Part 
1  
ICH E3 
SAC 
3.  
Safety 
ES2 
Listing of Reasons for Study Withdrawal – Part 
2 
ICH E3 
SAC 
4.  
Safety 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation – Part 2 
ICH E3 
SAC 
5.  
Safety 
BL1xo 
Listing of Subjects for whom the Treatment 
Blind was Broken – Part 1 
ICH E3 
SAC 
6.  
Safety 
BL1 
Listing of Subjects for whom the Treatment 
Blind was Broken – Part 2 
ICH E3 
SAC 
7.  
Safety 
TA1xo 
Listing of Planned and Actual Treatments -Part 
1 
  
SAC 
8.  
Safety 
TA1 
Listing of Planned and Actual Treatments - Part 
2 
  
SAC 
9.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened  
 
SAC 
Protocol Deviations 
10.  
Safety 
DV2xo 
Listing of Important Protocol Deviations – Part 1    
SAC 
11.  
Safety 
DV2 
Listing of Important Protocol Deviations – Part 2 
  
SAC 


 
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 ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable [Priority] 
12.  
Randomized 
IE3xo 
Listing of Participants with Inclusion/Exclusion 
Criteria Deviations – Part 1 
ICH E3 
SAC 
13.  
Randomized 
IE3  
Listing of Participants with Inclusion/Exclusion 
Criteria Deviations – Part 2 
ICH E3 
SAC 
Populations Analysed 
14.  
Safety 
SP3xo 
Listing of Participants Excluded from Any 
Population – Part 1 
 
SAC 
15.  
Safety 
SP3 
Listing of Participants Excluded from Any 
Population – Part 2 
 
SAC 
Demographic and Baseline Characteristics 
16.  
Safety 
DM2xo 
Listing of Demographic Characteristics – Part 1 
 
SAC 
17.  
Safety 
DM2  
Listing of Demographic Characteristics – Part 2 
 
 
SAC 
18.  
Safety 
DM9xo 
Listing of Race – Part 1 
 
SAC 
19.  
Safety 
DM9  
Listing of Race – Part 2 
 
 
SAC 
Prior and Concomitant Medications 
20.  
Safety 
MH2xo 
Listing of Current (and/or Past) Medical 
Conditions – Part 1 
Include Past/current as 
page by variable  
SAC 
21.  
Safety 
MH2xo 
Listing of Current (and/or Past) Medical 
Conditions – Part 1 
Include Past/current as 
page by variable 
SAC 
22.  
Safety 
CM10xo 
Listing of Concomitant Medications – Part 1 
  
SAC 
23.  
Safety 
CM10  
Listing of Concomitant Medications – Part 2 
  
SAC 


 
CONFIDENTIAL 
 
 
 
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 ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable [Priority] 
Exposure and Treatment Compliance 
24.  
Safety 
EX3xo 
Listing of Exposure Data – Part 1 
 
SAC 
25.  
Safety 
EX3  
Listing of Exposure Data – Part 2 
 
SAC 
Adverse Events 
26.  
Safety 
AE8CPxo 
Listing of All Adverse Events – Part 1 
 
SAC 
27.  
Safety 
AE8CP  
Listing of All Adverse Events – Part 2 
 
SAC 
28.  
Safety 
AE7 
Listing of Subject Numbers for Individual 
Adverse Events Part 1 
ICH E3 
SAC 
29.  
Safety 
AE7 
Listing of Subject Numbers for Individual 
Adverse Events Part 2 
ICH E3 
SAC 
Serious and Other Significant Adverse Events 
30.  
Safety 
AE8CPxo  
 
Listing of Serious Adverse Events – Part 1 
  
SAC 
31.  
Safety 
AE8CP  
 
Listing of Serious Adverse Events – Part 2 
  
SAC 
32.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event – Part 1 
ICH E3 
SAC 
33.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event – Part 2 
ICH E3 
SAC 
34.  
Safety 
AE8CPxo 
Listing of Adverse Events Leading to 
Withdrawal from Study / Permanent 
Discontinuation of Study Treatment – Part 1 
 
SAC 


 
CONFIDENTIAL 
 
 
 
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 ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable [Priority] 
35.  
Safety 
AE8CP 
Listing of Adverse Events Leading to 
Withdrawal from Study / Permanent 
Discontinuation of Study Treatment – Part 2 
 
SAC 
All Laboratory 
36.  
Safety 
LB5xo 
Listing of All Clinical Chemistry Values for 
Subjects with Any Value Outside of Potential 
Clinical Importance – Part 1 
 
SAC 
37.  
Safety 
LB5  
Listing of All Clinical Chemistry Values for 
Subjects with Any Value Outside of Potential 
Clinical Importance – Part 2 
 
SAC 
38.  
Safety 
LB5xo  
Listing of All Haematology Values for Subjects 
with Any Value Outside of Potential Clinical 
Importance – Part 1 
 
SAC 
39.  
Safety 
LB5  
Listing of All Haematology Values for Subjects 
with Any Value Outside of Potential Clinical 
Importance – Part 2 
 
SAC 
40.  
Safety 
UR2xo 
Listing of Urinalysis Data for Subjects with Any 
Value of Potential Clinical Importance – Part 1 
 
SAC 
41.  
Safety 
UR2 
Listing of Urinalysis Data for Subjects with Any 
Value of Potential Clinical Importance – Part 2 
 
SAC 
ECG 
42.  
Safety 
EG5xo 
Listing of All ECG Findings for Subjects with an 
Abnormal Finding - Part 1 
 
SAC 
43.  
Safety 
EG5 
Listing of All ECG Findings for Subjects with an 
Abnormal Finding - Part 2 
 
SAC 


 
CONFIDENTIAL 
 
 
 
212148 
 
84 
 
 ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable [Priority] 
44.  
Safety 
EG3xo 
Listing of All ECG Values for Subjects with Any 
Value of Potential Clinical Importance – Part 1 
  
SAC 
45.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Any 
Value of Potential Clinical Importance – Part 2 
 
SAC 
Vital Signs 
46.  
Safety 
VS4xo 
Listing of All Vital Signs for Subjects with Any 
Value of Potential Clinical Importance - Part 1  
 
SAC 
47.  
Safety 
VS4 
Listing of All Vital Signs for Subjects with Any 
Value of Potential Clinical Importance - Part 2  
 
SAC 
Pharmacogenetics 
Meal 
48.  
Safety 
SAFE_L1 
Listing of Meal Consumption – Part 1 
May need to add columns 
according to the results in 
dataset 
SAC 


 
CONFIDENTIAL 
 
 
 
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12.12.12. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
49.  
Safety 
SAFE_L3 
Listing for Bristol Stool Form Scale – Part 1 
 
SAC 
50.  
Safety 
SAFE_L3 
Listing for Bristol Stool Form Scale – Part 2 
 
SAC 
51.  
Safety 
SAFE_L2 
Listing of fluid intake and output – Part 1 
 
SAC 
52.  
Safety 
SAFE_L2 
Listing of Fluid intake and output – Part 2 
 
 
SAC 
Pharmacokinetic 
53.  
PK 
PK07xo 
Listing of Plasma GSK3882347 
Pharmacokinetic Concentration-Time Data – 
Part 1 
 
SAC 
54.  
PK 
PK07 
Listing of Plasma GSK3882347 
Pharmacokinetic Concentration-Time Data – 
Part 2 
 
SAC 
55.  
PK 
PK13xo 
Listing of Derived Plasma GSK3882347 
Pharmacokinetic Parameters – Part 1 
 
SAC 
56.  
PK 
PK13 
Listing of Derived Plasma GSK3882347 
Pharmacokinetic Parameters – Part 2 
 
SAC 
57.  
PK 
PK09xo 
Listing of Urine Sample Collections – Part 1  
 
SAC 
58.  
PK 
PK09 
Listing of Urine Sample Collections – Part 2 
 
SAC 
59.  
PK 
PK13xo 
Listing of Derived Urine GSK3882347 
Pharmacokinetic Parameters – Part 1 
 
SAC 


 
CONFIDENTIAL 
 
 
 
212148 
 
86 
 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
49.  
Safety 
SAFE_L3 
Listing for Bristol Stool Form Scale – Part 1 
 
SAC 
50.  
Safety 
SAFE_L3 
Listing for Bristol Stool Form Scale – Part 2 
 
SAC 
51.  
Safety 
SAFE_L2 
Listing of fluid intake and output – Part 1 
 
SAC 
52.  
Safety 
SAFE_L2 
Listing of Fluid intake and output – Part 2 
 
 
SAC 
60.  
PK 
PK13 
Listing of Derived Urine GSK3882347 
Pharmacokinetic Parameters – Part 2 
 
SAC 
Biomarker 
61.  
Biomarker 
BIO_L1 
Listing of Plasma 4β-hydroxycholesterol and 
Cholesterol concentrations and Plasma 4β-
hydroxycholesterol to Cholesterol Ratio – Part 
2 
 
SAC 
12.12.13. Covid-19 Listings  
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
62.  
Safety 
PAN7 
Listing of All Subjects with Visits and Assessments Impacted 
by the Pandemic for Subjects with COVID-19 Adverse Events 
Part 1 and Part 2 
Add Period also in the Visit column 
SAC 
 


 
CONFIDENTIAL 
 
 
 
212148 
 
87 
 
12.12.14. Conditional Listings  
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Liver Events 
63.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting – Part 1 
and 2 
Add ‘Part’ as a column  
 
SAC 
64.  
Safety 
LIVER15 
Liver Stopping Event Profile – Part 1 and 2 
Add ‘Part’ as a column  
SAC 
65.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline – Part 1 and 2 
Add ‘Part’ as a column  
SAC 


 
CONFIDENTIAL 
 
 
 
212148 
 
88 
 
12.13. 
Appendix 13: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request.