Conditions: HIV Infections
Keywords: GSK3640254 Human immunodeficiency virus (HIV) infections Drug interaction Pharmacokinetics Probe substrate
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: yes

Brief summary:
This is an open-label, single sequence study that is being conducted to investigate the potential drug-drug interaction (DDI) when GSK3640254 is co-administered with a cocktail of cytochrome P450 (CYP) enzymes and transporter probe substrates in healthy participants. This study will aid in understanding these interactions and resulting changes in exposure (if any) when drugs that are metabolized via these pathways are given in combination with GSK3640254. The study will consist of a Screening period and 3 sequential treatment regimens. Participants will be administered a single dose of probe substrate drugs (caffeine 200 milligram (mg), metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg and pravastatin 40 mg) on Day 1. Participants will then receive GSK3640254 200 mg once daily on Days 11 to 20 followed by co-administration of probe substrate drugs with GSK3640254 on Day 21.

Detailed description:

Arms:
arm 1: All participants will receive a single dose of treatment A: Probe substrates (caffeine 200 milligram \[mg\], metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) on Day 1; followed by treatment B- GSK3640254 200 mg on Days 11 to 20; further followed by treatment C: Probe substrates (Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) co-administered with GSK3640254 200 mg on Day 21.

Interventions: intervention 1: GSK3640254 200 mg intervention 2: Caffeine 200 mg intervention 3: Metoprolol 100 mg intervention 4: Montelukast 10 mg intervention 5: Flurbiprofen 100 mg intervention 6: Omeprazole 40 mg intervention 7: Midazolam 5 mg (2.5 mL) intervention 8: Digoxin 0.25 mg intervention 9: Pravastatin 40 mg
Intervention descriptions: intervention 1: GSK3640254 will be available as oral tablets at unit dose strength of 100 mg. intervention 2: Caffeine will be available as oral tablets at unit dose strength of 200 mg. intervention 3: Metoprolol will be available as oral tablets at unit dose strength of 100 mg. intervention 4: Montelukast will be available as oral tablets at unit dose strength of 10 mg. intervention 5: Flurbiprofen will be available as oral tablets at unit dose strength of 100 mg. intervention 6: Omeprazole will be available as oral capsules at unit dose strength of 40 mg. intervention 7: Midazolam will be available as syrup for oral administration at unit dose strength of 2 milligram per milliliter (mg/mL). intervention 8: Digoxin will be available as oral tablet at unit dose strength of 0.25 mg. intervention 9: Pravastatin will be available as oral tablet at unit dose strength of 40 mg.

Protocol document:
Prot_000.pdf: 
TMF-12140653 
CONFIDENTIAL 
 
ViiV Healthcare group of companies 
 
213052 
 
1 
 
TITLE PAGE 
Protocol Title: Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe 
Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, 
Digoxin, and Pravastatin) in Healthy Subjects 
Protocol Number: 213052 Amendment-2 
Compound Number 
or Name: 
GSK3640254 
Study Phase: Phase 1  
Short Title: Evaluation of the One-way Pharmacokinetic Interaction Between 
GSK3640254 and Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, 
Midazolam, Digoxin, and Pravastatin in Healthy Adults 
Sponsor Name and Legal Registered Address:  
ViiV Healthcare UK Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK  
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity. In these instances, the appropriate company to be identified as 
Sponsor must be agreed with the global ViiV Healthcare clinical team and signed off 
by the Vice President, Global Research and Medical Strategy. 
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study. 
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual 
Regulatory Agency Identifying Number(s): IND: 139,838 
Approval Date: 12-APR-2021 
 
Copyright 2021 ViiV Healthcare group of companies. All rights reserved. Unauthorized 
copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title: Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe 
Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, 
Digoxin, and Pravastatin) in Healthy Subjects 
Protocol Number: 213052 Amendment-2 
Compound Number: GSK3640254 
 
 
 
 
 
Max Lataillade, DO, MPH 
VP, Clinical Development 
ViiV Healthcare 
 
Date 
 
The signed page is a separate document. 
 
Medical Monitor Name and Contact Information can be found in SRM. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 2 
12-Apr-2021 
TMF-12140653 
Amendment 1 
02-Jun-2020 
2019N422949_01 
Original Protocol 
25-Feb-2020 
2019N422949_00 
 
Amendment 2: XX-APR-2021 
Overall Rationale for the Amendment: The primary driver for the protocol amendment 
was to remove the analysis of Pravastatin Lactone.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Objectives & 
Endpoints 
Removed Pravastatin Lactone 
from secondary endpoint 
Not performing analysis 
3 Objectives & 
Endpoints 
Removed Pravastatin Lactone 
from secondary endpoint 
Not performing analysis 
8.5 
Pharmacokinetics 
Removed Pravastatin Lactone 
from described analysis plan 
Not performing analysis 
9.4.1 
Pharmacokinetics 
Analysis 
Removed Pravastatin Lactone 
from described analysis plan 
Not performing analysis 
 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1. 
Synopsis ....................................................................................................... 7 
1.2. 
Schema ........................................................................................................ 9 
1.3. 
Schedule of Activities (SoA) .......................................................................... 9 
2. 
INTRODUCTION .................................................................................................... 14 
2.1. 
Study Rationale .......................................................................................... 14 
2.2. 
Background ................................................................................................ 14 
2.2.1. 
Summary of GSK3640254 Clinical Pharmacokinetics .................. 14 
2.2.2. 
Summary of GSK3640254 Metabolism ........................................ 15 
2.2.3. 
Summary of GSK3640254 Safety ................................................ 15 
2.2.4. 
Probe Substrate Drugs ................................................................ 16 
2.3. 
Benefit/Risk Assessment ............................................................................ 19 
2.3.1. 
Risk Assessment ......................................................................... 21 
2.3.2. 
Benefit Assessment ..................................................................... 24 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 24 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 24 
4. 
STUDY DESIGN .................................................................................................... 25 
4.1. 
Overall Design ............................................................................................ 25 
4.2. 
Scientific Rationale for Study Design .......................................................... 26 
4.3. 
Justification for Dose .................................................................................. 27 
4.4. 
End of Study Definition ............................................................................... 27 
5. 
STUDY POPULATION ........................................................................................... 27 
5.1. 
Inclusion Criteria ......................................................................................... 27 
5.2. 
Exclusion Criteria ........................................................................................ 29 
5.3. 
Lifestyle Considerations .............................................................................. 32 
5.3.1. 
Meals and Dietary Restrictions .................................................... 32 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 33 
5.3.3. 
Activity ......................................................................................... 33 
5.4. 
Screen Failures........................................................................................... 33 
6. 
STUDY INTERVENTION ........................................................................................ 33 
6.1. 
Study Interventions Administered ............................................................... 34 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 35 
6.4. 
Study Intervention Compliance ................................................................... 35 
6.5. 
Concomitant Therapy.................................................................................. 35 
6.6. 
Dose Modification ....................................................................................... 36 
6.7. 
Intervention after the End of the Study ........................................................ 36 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 36 
7.1. 
Discontinuation of Study Intervention .......................................................... 36 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 36 


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7.1.2. 
QTc Stopping Criteria .................................................................. 36 
7.1.3. 
Columbia-Suicide Severity Rating Scale ...................................... 37 
7.1.4. 
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria ................................................................ 37 
7.1.5. 
COVID-19 .................................................................................... 37 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 38 
7.3. 
Lost to Follow-up ........................................................................................ 38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 39 
8.1. 
Efficacy Assessments ................................................................................. 39 
8.2. 
Safety Assessments ................................................................................... 39 
8.2.1. 
Physical Examinations ................................................................. 39 
8.2.2. 
Vital Signs .................................................................................... 40 
8.2.3. 
Electrocardiograms ...................................................................... 40 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................... 40 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring ........................... 41 
8.2.6. 
Gastrointestinal Toxicity Evaluation and Monitoring Plan ............. 41 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 43 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 43 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 44 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 44 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 44 
8.3.5. 
Pregnancy ................................................................................... 44 
8.3.6. 
Adverse Events of Special Interest .............................................. 45 
8.4. 
Treatment of Overdose ............................................................................... 45 
8.5. 
Pharmacokinetics ....................................................................................... 45 
8.6. 
Pharmacodynamics .................................................................................... 46 
8.7. 
Genetics ..................................................................................................... 46 
8.8. 
Biomarkers ................................................................................................. 46 
8.9. 
Medical Resource Utilization and Health Economics .................................. 46 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 46 
9.1. 
Statistical Hypotheses................................................................................. 46 
9.2. 
Sample Size Determination ........................................................................ 46 
9.2.1. 
Sample Size Assumptions ........................................................... 46 
9.2.2. 
Sample Size Sensitivity ................................................................ 47 
9.3. 
Populations for Analyses ............................................................................ 48 
9.4. 
Statistical Analyses ..................................................................................... 48 
9.4.1. 
Pharmacokinetic Analyses ........................................................... 48 
9.4.2. 
Safety Analyses ........................................................................... 49 
9.4.3. 
Other Analyses ............................................................................ 49 
9.5. 
Interim Analyses ......................................................................................... 49 
9.6. 
Data Monitoring Committee ........................................................................ 49 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 50 
10.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 50 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 53 
10.3. 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 55 
10.3.1. 
Definitions: ................................................................................... 55 


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10.3.2. 
Contraception Guidance: ............................................................. 56 
10.3.3. 
Collection of Pregnancy Information: ........................................... 56 
10.4. 
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 58 
10.4.1. 
Regulatory and Ethical Considerations ........................................ 58 
10.4.2. 
Financial Disclosure ..................................................................... 58 
10.4.3. 
Informed Consent Process .......................................................... 58 
10.4.4. 
Data Protection ............................................................................ 59 
10.4.5. 
Committees Structure .................................................................. 60 
10.4.6. 
Dissemination of Clinical Study Data ........................................... 60 
10.4.7. 
Data Quality Assurance ............................................................... 60 
10.4.8. 
Source Documents ...................................................................... 61 
10.4.9. 
Study and Site Start and Closure ................................................. 61 
10.4.10. Publication Policy ......................................................................... 62 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 63 
10.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 65 
10.6.1. 
Definition of AE ............................................................................ 65 
10.6.2. 
Definition of SAE .......................................................................... 66 
10.6.3. 
Recording and Follow-up of AE and SAE..................................... 67 
10.6.4. 
Reporting of SAE to VH/GSK ....................................................... 69 
10.7. 
Appendix 7: COVID-19 Pandemic and Clinical Trial Continuity ................... 70 
10.7.1. 
Changes to Study Visits and Study Procedures ........................... 70 
10.7.2. 
COVID-19 Experimental Agents .................................................. 70 
10.7.3. 
COVID-19 Specific Data Capture ................................................. 71 
10.8. 
Appendix 8: Division Of AIDS (DAIDS) Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 2.1 July 
2017 ........................................................................................................... 73 
10.9. 
Appendix 9: Protocol Amendment History ................................................... 74 
11. REFERENCES ....................................................................................................... 76 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe 
Substrates (Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, 
Digoxin, and Pravastatin) in Healthy Subjects 
Short Title: Evaluation of the One-way Pharmacokinetic Interaction Between 
GSK3640254 and Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, 
Midazolam, Digoxin, and Pravastatin in Healthy Adults 
Rationale: The current study is being conducted to investigate the potential drug-drug 
interactions when GSK3640254 is co-administered with a cocktail of cytochrome P450 
and transporter probe substrates in healthy participants. This study will aid in 
understanding these interactions and resulting changes in exposure (if any) when drugs 
that are metabolized via these pathways are given in combination with GSK3640254. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To assess the effect of GSK3640254 on the PK of 
caffeine, metoprolol, montelukast, flurbiprofen, 
omeprazole, midazolam, digoxin, and pravastatin under 
fed conditions in healthy participants  
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for caffeine, 
metoprolol, montelukast, flurbiprofen, omeprazole, 
midazolam, digoxin, and pravastatin 
Secondary 
• 
To assess the safety and tolerability of GSK3640254 
alone and in combination with caffeine, metoprolol, 
montelukast, flurbiprofen, omeprazole, midazolam, 
digoxin, and pravastatin in healthy participants 
• 
To characterize the steady-state PK of GSK3640254 
in the presence of caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and 
pravastatin in healthy participants 
• 
To characterize the single-dose PK of the 
metabolites for the probe substrate drugs 
(α-hydroxymetoprolol, 36-hydroxymontelukast, 
5-hydroxyomeprazole, and 1-hydroxymidazolam) 
• 
Safety and tolerability parameters for adverse 
events/serious adverse events, observed and 
change from baseline clinical laboratory 
assessments, electrocardiograms, and vital sign 
measurements 
• 
AUC(0-t), AUC(0-), Cmax, C, Tmax, and t1/2 for 
GSK3640254 
 
 
 
• 
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for 
metabolites, and metabolite-to-parent ratios for 
Cmax and AUC(0-)  
AUC(0-) = area under the plasma concentration-time curve from time zero to the end of the dosing interval at steady 
state; AUC(0-) = area under the plasma concentration-time curve from time zero extrapolated to infinity; 
AUC(0-t) = area under the plasma concentration-time curve from time zero to time t; C = plasma concentration at the 
end of the dosing interval; Cmax = maximum observed concentration; PK = pharmacokinetics; Tmax = time of 
maximum observed concentration; t1/2 = apparent terminal phase half-life. 
 


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Overall Design: This is an open-label, single-sequence, one-way drug interaction study 
to investigate the effect of GSK3640254 200 mg on the pharmacokinetics (PK) of a 
metabolic probe cocktail containing the substrate drugs caffeine 200 mg, 
metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, 
midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg. 
The study will consist of a screening period and 3 sequential treatment regimens. 
Participants will be screened within 28 days before the first dose of study intervention. 
There will be a washout of 10 days between dosing of Regimen 1 and initiation of 
Regimen 2. There is no planned washout between Regimen 2 and Regimen 3. The 
participants will fast overnight for at least 8 hours prior to dosing and will receive a 
moderate fat meal 30 minutes prior to dosing. Participants will eat this meal in 
25 minutes or less. Dose administration will occur within 5 minutes of completion of 
meal consumption. 
Pharmacokinetic blood samples for analysis of caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin (and metabolites) will be 
obtained pre-dose and up to 120 hours after Regimen 1 and Regimen 3 dosing. 
Pharmacokinetic blood samples for analysis of GSK3640254 will be obtained pre-dose 
on Days 17 to 20 during Regimen 2, and pre-dose and up to 120 hours after Regimen 3 
dosing. 
Safety and tolerability will be assessed by monitoring and recording of adverse events 
(AEs), clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram 
(ECG) results, and physical examination findings. 
Study assessments will be performed as indicated in the Schedule of Activities. 
Participants will be confined to the clinic from check-in (Day –1) until discharge on Day 
26. 
Disclosure Statement: This is a single-group, single-arm study that has no masking.  
Number of Participants: Approximately 20 participants will be treated to ensure that 
18 evaluable participants complete the study. 
Intervention Groups and Duration: 
• Treatment A: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg on Day 1 (Regimen 1) 
• Treatment B: GSK3640254 200 mg once daily on Days 11 to 20 (Regimen 2) 
• Treatment C: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg co-administered with GSK3640254 200 mg on Day 21 
(Regimen 3) 
The duration of the study, including Screening, is approximately 54 days. 


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Data Monitoring or Other Committee: No. 
1.2. 
Schema 
A summary of the overall study design is presented in Figure 1. 
Figure 1 
Study Design Schematic 
 
1. 
Probe substrate drugs: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, 
omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg 
1.3. 
Schedule of Activities (SoA) 
• 
Screening procedures may be completed over more than one visit, but must all 
be completed within 28 days prior to the first dose of study intervention. 
• 
The following demographic parameters will be captured: year of birth, sex, race, 
and ethnicity. 
• 
Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria. 


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Screening Visit 
Procedure 
Screening (up to 28 days 
before Day 1) 
Outpatient visit 
X 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Full physical examination including height and weight1 
X 
Laboratory assessments (hematology, chemistry, urinalysis)  
X 
12-lead electrocardiogram 
X 
Vital sign measurements 
X 
Medication/drug/alcohol history 
X 
Past and current medical conditions 
X 
Columbia-Suicide Severity Rating Scale 
X 
Serum pregnancy test 
X 
Follicle-stimulating hormone (as needed, to confirm postmenopausal status) 
X 
Drug, alcohol, and cotinine screen 
X 
HIV, Hepatitis B and C screening 
X 
HIV = human immunodeficiency virus. 
1. 
A full physical examination will include, at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 
 


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Time and Events Table 
Procedure 
 
Regimen 1 
Treatment A (Day 1)  
Washout (Days 2-10) 
Regimen 2 
Treatment B 
Regimen 3 
Treatment C 
Notes 
 
Check-in 
Day –1 
Day 
1 
Day 
2-5 
Day 
6 
Days 
7-9 
Day 
10 
Days 
11-19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Brief physical 
examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Includes, at a minimum, assessments of 
the skin, lungs, cardiovascular system, 
and abdomen (liver and spleen). 
Vital sign 
measurements 
X 
X 
D2 
 
 
X 
D11, 
D14, 
and 
D17 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse measured in 
triplicate at pre-dose on Days 1, 11, and 
21.  
Respiratory rate measured pre-dose and 
post-dose every 15 minutes for the first 
2 hours and every 30 minutes for the 
subsequent 2  hours on Days 1 and 21 
(may be monitored longer if indicated by 
clinical condition). 
Temperature check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse oximetry 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Continuous pulse oximetry measured 
pre-dose and through 4 hours after 
dosing on Days 1 and 21 (may be 
monitored longer if indicated by clinical 
condition).  
Twelve-lead ECG 
X 
X 
D2, 
D3, 
and D5 
 
 
X 
D11 
X 
X 
X 
X 
 
X 
 
ECGs on Days 1, 11, and 21, will be 
taken pre-dose, and at 2 and 4 hours 
post-dose. 
Pre-dose ECGs on Days 1, 11, and 21 
will be taken in triplicate. 


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Procedure 
 
Regimen 1 
Treatment A (Day 1)  
Washout (Days 2-10) 
Regimen 2 
Treatment B 
Regimen 3 
Treatment C 
Notes 
 
Check-in 
Day –1 
Day 
1 
Day 
2-5 
Day 
6 
Days 
7-9 
Day 
10 
Days 
11-19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Drug, alcohol, and 
cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 2 for tests. 
Laboratory 
assessments 
(hematology, 
chemistry, urinalysis) 
X 
 
D2 and 
D5 
 
 
X 
D15 
X 
 
X 
 
 
X 
 
See Appendix 2 for tests. 
Pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Columbia-Suicide 
Severity Rating Scale  
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Study intervention: 
probe substrate drugs 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
See Section 6.1 for study intervention 
details. 
Study intervention: 
GSK3640254 200 mg 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
See Section 6.1 for study intervention 
details. 
Probe substrate drug 
PK sampling 
 
Pre-dose and 0.25, 0.5, 
1, 1.5, 2, 3, 4, 6, 8, 12, 
16, 24, 48, 72, 96, and 
120 hours post-dose. 
 
 
 
 
Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12, 16, 24, 48, 72, 96, and 120 hours 
post-dose 
 
GSK3640254 PK 
sampling 
 
 
 
 
 
 
Pre-dose on Days 17, 18, 19, 20 and 21. 
Post Day 21 dose at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 
24, 48, 72, 96, and 120 hours. 
 
AE review 
 
=========================================================================→  
SAE review 
==================================================================================→  
Concomitant 
medication review 
==================================================================================→  
Abbreviations: AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 


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• 
Participants will fast overnight for at least 8 hours prior to dosing and will receive the moderate fat meal 30 minutes prior to 
dosing. Participants will eat this meal in 25 minutes or less. Dose administration will occur within 5 minutes of completion of 
meal consumption. Refer to Section 5.3.1 for meal timings. 
• 
Evaluations scheduled for Day 25 will also be performed for participants who discontinue prior to completing Day 26, including 
PK samples for GSK3640254 and probe substrate drugs. 
• 
The Institutional Review Board/Independent Ethics Committee 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. The changes will 
be approved by the health authority and the ethics committee before implementation. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This is an open-label, single-sequence, one-way drug interaction study to investigate the 
effect of GSK3640254 200 mg on the pharmacokinetics (PK) of a metabolic probe 
cocktail of substrate drugs containing caffeine 200 mg, metoprolol 100 mg, 
montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, 
digoxin 0.25 mg, and pravastatin 40 mg. This study will aid in understanding these 
interactions and resulting changes in exposure (if any) when given in combination with 
GSK3640254.  
2.2. 
Background 
GSK3640254 is a human immunodeficiency virus (HIV) maturation inhibitor (MI) which 
is improved over prior developmental MIs in the following ways: (1) it exhibits 
significantly improved pan-genotypic coverage and potency against polymorphic 
variants; (2) in vitro data suggest that GSK3640254 exhibits a higher barrier to 
emergence of resistant viruses (except for A364V); (3) GSK3640254 has improved 
potency in vitro toward all HIV-1 subtypes; and (4) it has a projected lower once daily 
(QD) human dose. Summaries of the pre-clinical and clinical studies are included in the 
Clinical Investigator's Brochure (CIB) [GSK Document Number 2018N379610_01]. 
2.2.1. 
Summary of GSK3640254 Clinical Pharmacokinetics 
Pharmacokinetic data for clinical studies performed to date are summarized as follows: 
• Following multiple-dose administration over 50 to 320 mg dose range for 14 days 
with a moderate fat meal in the single ascending dose (SAD)/multiple ascending 
dose (MAD) first time in human (FTIH) Study 207187: 
o Median time of maximum observed concentration (Tmax) ranged between 3.8 
to 4.3 hours. 
o The mean half-life ranged from approximately 22 to 29 hours. 
o There was a slightly less than dose-proportional increase in maximum 
observed concentration (Cmax) and area under the plasma concentration-time 
curve (AUC) from time zero to the end of the dosing interval at steady state 
(AUC[0-τ]) from 50 to 320 mg QD. 
o The exposure on Day 14 was, on average, 1.9- to 2.3-fold higher for Cmax 
and 2.2- to 2.6-fold higher for AUC(0-τ) compared to those on Day 1. 
o PK variability (between-subject variability) ranged from 8% to 50%. 
• There was no clinically meaningful drug interaction between GSK3640254 and 
either tenofovir alafenamide/emtricitabine (Study 208134) or dolutegravir 
(Study 209712). 


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• Using a population PK model, a comparison of Phase 1 SAD/MAD 
(Study 207187) and Phase 2a proof of concept (Study 208132) showed the PK in 
HIV-1 infected subjects was similar to that in healthy volunteers. 
Additional information regarding clinical PK data can be found in the CIB [GSK 
Document Number 2018N379610_01]. 
2.2.2. 
Summary of GSK3640254 Metabolism 
With recombinant cytochrome P450 (CYP) enzymes, GSK3640254 was mainly 
metabolized by CYP3A4/3A5, CYP2C9, CYP1A2 and CYP2C8. GSK3640254 was 
stable in recombinant uridine diphosphate glucuronosyltransferase (UGT) enzymes. In rat 
and dog plasma, GSK3640254 was either the only or the predominant drug-related 
component with minor oxidative metabolites (e.g., hydroxylation and N-dealkylation). 
Preliminary analysis of bile samples of bile duct cannulated rats dosed with unlabeled 
GSK3640254 suggested that GSK3640254 was eliminated mainly by direct 
glucuronidation followed by biliary excretion in rats. In human plasma, GSK3640254 
was the predominant drug-related component with low levels of oxidative metabolites as 
shown by preliminary human metabolism study following repeat oral doses of 
320 mg/day. Additional information regarding GSK3640254 metabolism can be found in 
the CIB [GSK Document Number 2018N379610_01 
2.2.3. 
Summary of GSK3640254 Safety 
A summary of safety data from the clinical studies performed to date is summarized 
below: 
• No deaths or treatment-related serious adverse events (SAEs) have been reported 
during clinical studies with GSK3640254.  
• The majority of adverse events (AEs) were mild (Grade 1).  
• Treatment-related AEs leading to study discontinuation included maculopapular 
rash (Study 207187 [SAD/MAD]) and urticaria (Study 208134 [drug-drug 
interaction (DDI) with tenofovir alafenamide/emtricitabine]). 
• Clinically notable AEs of elevated transaminases occurred in Studies 207187 
(SAD/MAD, n = 1 healthy volunteer) and 208135 (DDI with oral contraceptive 
Portia [ethinyl estradiol/levonorgestrel], n = 8 healthy volunteers). Subsequent 
analysis in Study 208135 showed no PK/pharmacodynamic relationship with 
either GSK3640254 or Portia (ethinyl estradiol/levonorgestrel) and elevated 
transaminases. 
• Treatment-related AEs reported in more than 1 study included headache 
(Studies 207187, 208131, and 208132) and nausea (Studies 207187 and 208132). 
• With the exception of elevated transaminases as noted above, across studies there 
were generally no clinically significant changes in vital sign measurements, 
electrocardiogram (ECG) results, or safety laboratory parameters. 


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The full safety profile for GSK3640254 can be found in the CIB [GSK Document 
Number 2018N379610_01]. 
2.2.3.1. 
Cardiac Safety  
A cardiodynamic evaluation of healthy participants in the MAD portion of Study 207187 
[GSK Document Number 2020N430256_00] (placebo or GSK3640254 dose range 50 to 
320 mg daily for 14 days) was performed. Serial ECGs were extracted from continuous 
Holter monitors at time-matched baseline on Day –1 and for approximately 24 hours 
post-dose on Days 1 and 14. There were no abnormal clinically significant arrhythmias or 
QT prolongations (values >500 ms or increases >60 ms from baseline) observed for any 
participant in the SAD or MAD cohorts. In the concentration-corrected QT interval 
(QTc) analysis, a final model with a treatment effect-specific intercept reasonably 
represented the data. The slope of the concentration-QTc relationship was 0.004 ms per 
ng/mL (90% CI: 0.0023 to 0.0048) with a small treatment effect-specific intercept of 
-0.9 ms (90% CI: -4.47 to 2.69). The QT effect (∆ΔQTcF) of GSK3640254 could be 
predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms (90% CI: 2.79 to 10.61) for 
the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) doses, respectively, on Day 14. 
Based on this concentration-QTc analysis, a QTc using the Fridericia formula (QTcF) 
effect above 10 ms could be excluded in GSK3640254 plasma concentrations of up to 
approximately 2000 ng/mL (corresponding to doses approximately ≤ 200 mg QD; note, 
the dose used in the current study will be 200 mg QD).  
2.2.4. 
Probe Substrate Drugs 
GSK3640254 is primarily metabolized by CYP3A4/3A5, CYP2C9, CYP1A2, and 
CYP2C8. Co-administration of CYP inhibitors could, therefore, affect the metabolism 
and/or elimination of GSK3640254. The probe substrate cocktail for CYP1A2, CYP2D6, 
CYP2C8, CYP2C9, CYP2C19, CYP3A4, P-glycoprotein (P-gp), and organic 
anion-transporting polypeptide (OATP)1B1 has been tested and no evidence of mutual 
PK interaction between the cocktail drugs was found [Tye, 2016; Garimella, 2018]. 
Therefore, it is unlikely that the probe cocktail will impact the PK of GSK3640254. 
2.2.4.1. 
Caffeine 
Caffeine was chosen as a substrate for CYP1A2. Following oral administration, caffeine 
is rapidly and nearly completely absorbed from the gastrointestinal (GI) tract. An oral 
dose of caffeine of 1 mg/kg (equivalent to a cup of coffee) produces a Cmax of 1 to 
2 mg/L. The dose used in this study (200 mg; i.e., approximately 3 mg/kg) is equivalent 
to about 2 cups of coffee. The mean Tmax for caffeine is 1 hour (range 0.5 to 1.5 hours). 
The mean apparent terminal phase half-life (t1/2) for caffeine is 5.4 hours (range 2.3 to 
13.9 hours). The main route of elimination is via formation of 1,7-dimethylxanthine 
(paraxanthine) by demethylation which is catalysedby CYP1A2 [Newton, 1981; Tangh-
Liu, 1983]. Participants will take 2 single doses of 200 mg caffeine administered 21 days 
apart in this study. Caffeine is contraindicated in participants who have demonstrated 
hypersensitivity to any of its components. Potential AEs, although not likely to be seen 
with this dose, include GI irritation, central nervous system stimulation, and increases in 
systolic and diastolic blood pressure and heart rate [Vivarin, 2014] prescribing 
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2.2.4.2. 
Metoprolol 
Metoprolol was chosen as a substrate for CYP2D6. Metoprolol is a selective 
β1-adrenoreceptor blocking agent and is used as an antihypertensive agent either alone or 
in combination with thiazide-type diuretics. Metoprolol is highly metabolized with less 
than 5% excreted in urine as unchanged drug with the rest being metabolites. Metoprolol 
is metabolized by CYP2D6 and; therefore, poor metabolizers have several-fold higher 
concentrations than extensive metabolizers. This causes a difference in the t1/2 of 
metoprolol: approximately 7 to 9 hours in poor metabolizers and 3 to 4 hours in extensive 
metabolizers. However, the CYP2D6-dependent metabolism has little effect on safety or 
tolerability of the drug. The Tmax occurs approximately 1.5 hours after dosing. 
Metoprolol is metabolized into at least 4 metabolites: α-hydroxylation (mediated by 
CYP2D6) into α-hydroxymetoprolol; O-demethylation into O-demethylmetoprolol, and 
subsequent oxidation into metoprolol acid; and by deamination into deaminated 
metoprolol. Doses in patients are 100 to 450 mg per day. Asthmatic patients should not 
take beta blockers. Contraindications for metoprolol are generally related to cardiac 
conditions (which are excluded for this healthy participant study). Other 
contraindications include hypersensitivity to metoprolol and related derivatives or to any 
of the excipients or other beta-blockers. Potential AEs include tiredness, dizziness, 
shortness of breath, bradycardia, palpitations, wheezing and dyspnea, diarrhea, nausea, 
dry mouth, gastric pain, constipation, flatulence, and hypersensitivity reactions (pruritus 
or rash) [Metoprolol tartrate prescribing information, 2013]. In this study, participants 
will receive only 2 single doses of 100 mg metoprolol administered 21 days apart, 
decreasing the probability of the aforementioned risks. 
2.2.4.3. 
Montelukast 
Montelukast was chosen as a substrate for CYP2C8. Montelukast is a prescription 
medication used to treat patients with asthma and allergic rhinitis. Montelukast is rapidly 
absorbed following oral administration and has an absolute oral bioavailability of 64%. 
Peak plasma concentrations occur approximately 3 to 4 hours after dosing. The t1/2 is 
2.7 to 5.5 hours. Montelukast is extensively metabolized to one major oxidative 
metabolite (M6) (36-hydroxymontelukast) via CYP2C8 (and CYP2C9, although minor) 
and several minor metabolites that are mainly excreted into the bile. Montelukast is 
contraindicated in patients who are hypersensitive to it or any of its components. 
Potential AEs include upper respiratory infection, fever, headache, abdominal pain, and 
diarrhea [Singulair prescribing information, 2019]. Dosing in patients is usually 10 mg 
daily; in this study, participants will take 2 single doses of 10 mg montelukast 
administered 21 days apart, decreasing the probability of the aforementioned risks. 
2.2.4.4. 
Flurbiprofen 
Flurbiprofen was chosen as a substrate for CYP2C9. Flurbiprofen is a chiral, nonsteroidal 
anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and 
antipyretic activities, likely through prostaglandin synthetase inhibition. Flurbiprofen is 
metabolized via CYP2C9 to several hydroxylated metabolites with the major metabolite 
being 4-hydroxy-flurbiprofen which is not known to have any anti-inflammatory activity. 
Approximately 70% of the administered dose is excreted in the urine with only 3% of the 
dose excreted as unchanged drug. The Tmax occurs at approximately 1.9 hours. The t1/2 


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of both enantiomers are similar, being approximately 4.7 and 5.7 hours for the R- and 
S-enantiomers, respectively. The primary concern with NSAIDs is GI bleeding or 
irritation. Contraindications include a history of asthma (excluded for this healthy 
participant study), urticaria, or allergic-type reactions after taking aspirin or other 
NSAIDs, or hypersensitivity to any component of the product [Flurbiprofen prescribing 
information, 2009]. The highest recommended starting dose in patients is 100 mg given 
several times a day; participants in this study will receive only 2 single doses of 100 mg 
flurbiprofen administered 21 days apart, decreasing the probability of the aforementioned 
risks. 
2.2.4.5. 
Omeprazole 
Omeprazole was chosen as a substrate for CYP2C19. Omeprazole is a proton pump (H+, 
K+-ATPase) inhibitor used as a blocker of gastric acid secretion in gastric parietal cells. 
Omeprazole is extensively metabolized to the primary metabolites 5-hydroxyomeprazole 
(mediated by CYP2C19) and omeprazole sulfone. The Tmax is approximately 0.5 to 
3.5 hours after oral administration. The mean t1/2 is 0.5 to 1 hour. Hypersensitivity to 
substituted benzimidazoles or to any component of the formulation is a contraindication. 
Overdosage is associated with central nervous system symptoms (headache) and GI 
symptoms (abdominal pain, nausea, diarrhea, vomiting, and flatulence) [Omeprazole 
prescribing information, 2015]. While patients receive 20 to 60 mg per day, participants 
in this study will receive only 2 single doses of 40 mg omeprazole administered 21 days 
apart, decreasing the probability of the aforementioned risks. 
2.2.4.6. 
Midazolam 
Midazolam was chosen as a substrate for CYP3A4. Midazolam is an ultra-short acting 
benzodiazepine used clinically for brief sedation. After oral administration, midazolam is 
almost completely absorbed from the GI tract. The mean t1/2 of midazolam and 
1-hydroxymidazolam, its major metabolite (mediated by CYP3A4), are about 3 hours in 
humans. The Cmax is reached at about 1 hour after oral administration. Midazolam is 
contraindicated in patients with a known hypersensitivity to the drug or allergies to 
cherries or formulation excipients. Potential AEs may include transient drowsiness, 
nausea and emesis, and respiratory depression [Allonen, 1981; Midazolam hydrochloride 
syrup prescribing information, 2012]. Participants in this study will receive 2 single doses 
of 5 mg midazolam administered 21 days apart, decreasing the probability of the 
aforementioned risks. 
2.2.4.7. 
Digoxin 
Digoxin was chosen as a substrate for P-gp. Digoxin is indicated for the treatment of mild 
to moderate heart failure and for rate control in chronic atrial fibrillation. Following oral 
administration, Cmax of digoxin occurs between 1 and 3 hours. Oral absorption of 
digoxin tablets is between 60% and 80%. In healthy participants with normal renal 
function, t1/2 is 1.5 to 2 days; therefore, steady-state concentrations are not achieved until 
approximately 10 days. When given after a meal, the rate of absorption is slowed, but the 
total amount of digoxin absorbed is usually unchanged. Digitalis glycosides are 
contraindicated in patients with ventricular fibrillation or in patients with a known 
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usually constitutes a contraindication to digoxin. Because digoxin slows sinoatrial and 
atrioventricular conduction, the drug commonly prolongs the PR interval. The drug may 
cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node 
disease and may cause advanced or complete heart block in patients with pre-existing 
incomplete atrioventricular block. Common adverse reactions (1% to 10%) associated 
with digoxin include anorexia, nausea, vomiting, visual disturbance (blurred or yellow 
vision), mental disturbance (such as anxiety, depression, delirium, and hallucination). 
Although toxic symptoms may appear within the therapeutic range, they are more 
frequent and serious with concentrations above 2.5 ng/mL, which occur with loading 
doses or dosing to steady state only [Lanoxin prescribing information, 2011]. In the 
current study, 2 single doses of 0.25 mg will be administered 21 days apart; therefore, 
these types of events are not expected. 
2.2.4.8. 
Pravastatin 
Pravastatin was chosen as a substrate for OATP1B1. Pravastatin is a reversible inhibitor 
of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that 
catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in 
the biosynthetic pathway for cholesterol. In addition, pravastatin reduces 
very-low-density lipoprotein and triglycerides and increases high-density lipoprotein 
cholesterol. Peak plasma pravastatin concentrations occur 1 to 1.5 hours after oral 
administration and approximately 50% of the circulating drug is bound to plasma 
proteins. The major biotransformation pathways for pravastatin are (a) isomerization to 
6epi pravastatin and the 3α-hydroxyisomer of pravastatin (lactone form which has 1/20 to 
1/40 the HMG-CoA reductase inhibitory activity of pravastatin), and (b) enzymatic ring 
hydroxylation. Approximately 20% of the administered dose is excreted into the urine via 
metabolites. The t1/2 of pravastatin is approximately 2 hours. Standard adult dosage is 
40 to 80 mg/day. Contraindications to pravastatin include hypersensitivity to any 
component of this medication. The most commonly reported adverse reactions include 
musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and 
headache. Although rhabdomyolysis can occur rarely after chronic high exposures to 
statins, large single doses of pravastatin (e.g., overdosage) are generally well-tolerated 
[Pravachol prescribing information, 2016]. In this study, participants will receive 2 single 
doses of 40 mg pravastatin administered 21 days apart, decreasing the probability of the 
aforementioned risks. 
2.3. 
Benefit/Risk Assessment 
Based upon preclinical and clinical studies (including studies with GSK3532795), the 
major risks for GSK3640254 are GI intolerability (e.g., abdominal pain and diarrhea) and 
toxicity (e.g., single-cell parietal cell necrosis), prolongation of the QTc, and 
neuropsychiatric safety. Reproduction of preclinical GI toxicity findings would be 
expected to be minimal and reversible. One preclinical study showed 1 dog with an 
increased QTc when given a single dose of GSK3640254. As described in 
Section 2.2.3.1, a cardiodynamic analysis showed a QT effect (∆ΔQTcF) of 
GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms 
(90% CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) doses, 
respectively, on Day 14 in Study 207187. Importantly, there were no abnormal clinically 


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significant arrhythmias or QTc prolongations (values >500 ms or increases >60 ms from 
Baseline). This study contains specific cardiac exclusion criteria, has ECG monitoring (at 
Tmax once GSK3640254 attains steady-state concentration), and has QTcF-based 
stopping criteria. 
Finally, the protocol will exclude potential participants with any significant pre-existing 
psychiatric condition or positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee)-administered Columbia-Suicide Severity Rating Scale 
(C-SSRS). The C-SSRS assessment will also be administered by a clinician (or qualified 
designee) during the on-treatment portion of the study. 
Since digoxin and metoprolol are both cardiotropic/cardioactive drugs, participants will 
be monitored by serial ECGs on probe substrate drug dosing days. To monitor for the 
respiratory effects of midazolam, continuous pulse oximetry and timed respiratory rate 
will be measured on probe substrate drug dosing days. More detailed information about 
the expected risks and benefits of the probe substrate drugs may be found in the 
prescribing information as cited in Section 2.2.4. 
To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability, QTc prolongation, and neuropsychiatric safety), this study will include 
healthy adults who will receive clinical, ECG, and laboratory evaluations during their 
participation while confined to the clinic. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of GSK3640254 may be found 
in the CIB [GSK Document Number 2018N379610_01]. 
 


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2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) GSK3640254 
Cardiovascular (QT 
prolongation)  
Preclinically, GSK3640254 inhibited cardiac hERG/IKr potassium, cardiac SCN5A 
sodium and L-type calcium channel currents recorded from HEK 293 cells stably 
transfected with complementary Deoxyribonucleic acid (DNA) from the ion channels. In 
a single-dose safety pharmacology study in telemeterized dogs, increases in QT 
interval (up to 20 ms) occurred primarily in 1 dog given 17 mg/kg. The no observed 
adverse effect level in the study was 12.5 mg/kg, which produced similar systemic 
exposures (8.79 μg/mL, 6.4 × the mean Cmax associated with the 200 mg multiple 
dose (1.4 μg/mL) in the FTIH study. Later, there were no GSK3640254-related effects 
on ECG parameters in dogs given up to 25 mg/kg/day for 4 weeks. 
In the FTIH study 207187 (doses up to 700 mg in SAD and 320 mg QD for 14 days in 
MAD), no participant exhibited QTc change from Baseline >60 ms or QTc >500 ms. As 
described in Section 2.2.3.1, in the concentration-QTc analysis, a QTcF effect above 
10 ms could be excluded for GSK3640254 plasma concentrations of up to 
approximately 2000 ng/mL (corresponding to doses approximately ≤200 mg QD). 
Screening: Protocol exclusion criteria based on screening ECG 
parameters and cardiac medical history. 
On-Treatment: Participants will have ECG monitoring (at a 
clinically reasonable frequency) during the course of the study 
(see SoA, Section 1.3) with QTc stopping criteria (see 
Section 7.1.2). 
GI intolerability and 
toxicity 
Observations indicative of GI intolerability (sporadic vomiting and abnormal feces 
beginning on Day 1 and continuing throughout the dosing periods) occurred mainly in 
dogs at 1 mg/kg/day (Note: in the FTIH study 207187, AUC = 46.4 to 73.3 μg*h/mL; 
2.6 to 4.2 × the mean AUC associated with the 200 mg multiple dose [17.5 μg*h/mL]). 
Additionally, toxicity findings of single-cell necrosis of parietal cells and/or chief cells 
were present in preclinical species. These findings were reversible. Gastrointestinal 
intolerability (predominantly abdominal pain and diarrhea) was seen with a structurally 
related compound GSK3532795 which was evaluated through Phase 2b dosing. 
No clinical trends in the system organ class of GI AEs have been seen across Phase 1 
to 2a GSK3640254 clinical trials. 
Screening: Protocol exclusion criterion based on pre-existing GI 
pathology or baseline GI signs/symptoms. 
On-Treatment: Participants will undergo continuous evaluation 
for AEs during their participation in the study; there will be 
individual clinical stopping criteria based upon intensity of 
treatment-emergent AEs. A GI toxicity evaluation and monitoring 
plan will be available to guide investigators should GI AEs 
emerge (see Section 8.2.6). 
Neurologic/psychiatric 
safety 
Two psychiatric SAEs in previous maturation inhibitor GSK3532795 clinical program 
(acute psychosis, homicidal/suicidal ideation) were seen at supratherapeutic doses in 
healthy participants in the thorough QT (TQT) study. 
From a neurologic and psychiatric AE summary and PK/pharmacodynamic analysis for 
GSK3532795 across all studies, Grade 1 headache and Grade 1 sleep abnormalities 
Screening: Protocol exclusion criterion based on any pre-
existing psychiatric condition (including results of psychological 
assessment) for participants. Participants will have a clinician (or 
qualified designee) administered C-SSRS and will be included 
given no positive (abnormal) response. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
were the predominant AEs, with a trend for increasing neurologic and psychiatric AEs 
with increasing dose (based on TQT and Phase 2b studies). No exposure-response 
relationship was seen for select neurologic and psychiatric AEs (based on TQT and 
Phase 2b studies). Central nervous system penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low brain distribution/penetration. 
No clinical trends in the system organ class of neurologic or psychiatric AEs have been 
observed across the Phase 1 to 2a clinical trials. 
On-Treatment: Participants will undergo physical examinations 
and laboratory testing. In addition, participants will undergo 
continuous evaluation for AEs during their participation in the 
study; there are individual clinical stopping criteria and monitoring 
based upon incidence and intensity of treatment-emergent 
psychiatric AEs (Section 7.1.4 and Section 8.2.5).  
Participants will be housed throughout study conduct to ensure 
rapid diagnosis and management of any potential event. 
The C-SSRS will be administered during and after the treatment 
phase of the study. In the event of new onset suicidal ideation, 
the participant will discontinue from the trial and the investigator 
will arrange for urgent specialist psychiatric evaluation and 
management. Guidance for the investigator on the management 
of emergent psychiatric symptoms will be available. 
Rash 
Across clinical trials, AEs leading to discontinuation have included urticaria and 
maculopapular rash. 
• 
Participants will undergo continuous evaluation for adverse 
events during their participation in the trial supplemented by 
the use of physical exams. 
• 
Protocol includes individual participant stopping criteria, 
including:  
• 
Any Grade 3 or higher rash or Grade 2 rash with 
evidence of systemic involvement 
• 
Any allergic or hypersensitivity reactions  
(see Section 7.1 for complete list of stopping criteria) 
Digoxin and Metoprolol 
Cardiovascular 
(bradycardia, 
prolonged PR interval) 
Digoxin: slows sinoatrial and atrioventricular conduction and commonly prolongs the 
PR interval.  
Metoprolol: may cause bradycardia and palpitations. 
Screening: Protocol exclusion criteria based on screening ECG 
parameters and cardiac medical history. 
On-Treatment: Participants will be monitored by serial ECGs on 
probe substrate drug dosing days (see SoA, Section 1.3). 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Midazolam 
Respiratory 
depression and 
transient drowsiness 
Midazolam may cause respiratory depression and transient drowsiness. 
Screening: Eligible participants will be overtly healthy as 
determined by a medical professional based on medical 
evaluation. 
On Treatment: Participants will be housed throughout study 
conduct to ensure rapid diagnosis and management of any 
potential event. To monitor for the respiratory effects of 
midazolam, continuous pulse oximetry and timed respiratory rate 
will be measured on probe substrate drug dosing days (See SoA, 
Section 1.3). 
 


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2.3.2. 
Benefit Assessment 
This is a study in healthy participants; no medical benefit will be derived by participants’ 
participation. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the clinical data gathered from Phase 1 and 2a studies, and the 
planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 and coadministered single doses of the probe 
substrate drugs (in Regimens 1 and 3) are low, evaluable, and manageable. 
The probe substrate drugs being administered in this study are used commonly in clinical 
practice and have a well-characterized and acceptable safety profile. As digoxin and 
metoprolol are both cardiotropic/cardioactive drugs, participants will be monitored via 
serial ECGs on probe substrate drug dosing days. To monitor for the respiratory effects of 
midazolam, continuous pulse oximetry and timed respiratory rate will be measured on 
probe substrate drug dosing days. Given that only healthy participants will be enrolled, 
that relatively low (relative to the usual therapeutic dose range), single doses are being 
administered, and that participants will be confined to a clinical facility after dosing with 
the probe substrate drugs, the safety risk of participation in this study is expected to be 
low. To minimize risk further, the protocol contains exclusions relevant to the study 
intervention and prohibits the concurrent intake of potentially interacting drugs or foods 
that might increase the concentrations of study intervention. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
To assess the effect of GSK3640254 on the PK of 
caffeine, metoprolol, montelukast, flurbiprofen, 
omeprazole, midazolam, digoxin, and pravastatin under 
fed conditions in healthy participants  
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for caffeine, 
metoprolol, montelukast, flurbiprofen, omeprazole, 
midazolam, digoxin, and pravastatin 
Secondary 
• 
To assess the safety and tolerability of GSK3640254 
alone and in combination with caffeine, metoprolol, 
montelukast, flurbiprofen, omeprazole, midazolam, 
digoxin, and pravastatin in healthy participants 
• 
To characterize the steady-state PK of GSK3640254 
in the presence of caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and 
pravastatin in healthy participants 
• 
To characterize the single-dose PK of the 
metabolites for the probe substrate drugs 
(α-hydroxymetoprolol, 36-hydroxymontelukast, 
5-hydroxyomeprazole, and 1-hydroxymidazolam) 
• 
Safety and tolerability parameters for adverse 
events/serious adverse events, observed and 
change from baseline clinical laboratory 
assessments, electrocardiograms, and vital sign 
measurements 
• 
AUC(0-t), AUC(0-), Cmax, C, Tmax, and t1/2 for 
GSK3640254 
 
 
• 
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for 
metabolites, and metabolite to parent ratios for 
Cmax and AUC(0-)  


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AUC(0-) = area under the plasma concentration-time curve from time zero to the end of the dosing interval at steady 
state; AUC(0-) = area under the plasma concentration-time curve from time zero extrapolated to infinity; 
AUC(0-t) = area under the plasma concentration-time curve from time zero to time t; C = plasma concentration at the 
end of the dosing interval; Cmax = maximum observed concentration; PK = pharmacokinetics; Tmax = time of 
maximum observed concentration; t1/2 = apparent terminal phase half-life. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, single-sequence, one-way drug interaction study to investigate the 
effect of GSK3640254 200 mg on the PK of a metabolic probe cocktail containing the 
substrate drugs caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg. 
The study will consist of a screening period and 3 sequential treatment regimens. 
Participants will be screened within 28 days before the first dose of study intervention. 
Participants will receive the following treatments: 
• Treatment A: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg on Day 1 (Regimen 1) 
• Treatment B: GSK3640254 200 mg once daily on Days 11 to 20 (Regimen 2) 
• Treatment C: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg co-administered with GSK3640254 200 mg on Day 21 
(Regimen 3) 
There will be a washout of 10 days between dosing of Regimen 1 and initiation of 
Regimen 2. There is no planned washout between Regimen 2 and Regimen 3. The 
participants will fast overnight for at least 8 hours prior to dosing and will receive a 
moderate fat meal 30 minutes prior to dosing. Participants will eat this meal in 
25 minutes or less. Dose administration will occur within 5 minutes of completion of 
meal consumption. 
Pharmacokinetic blood samples for analysis of caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin (and metabolites) will be 
obtained pre-dose and up to 120 hours after Regimen 1 and Regimen 3 dosing. 
Pharmacokinetic blood samples for analysis of GSK3640254 will be obtained pre-dose 
on Days 17 to 20 during Regimen 2, and pre-dose and up to 120 hours after Regimen 3 
dosing. 
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings. 


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Study assessments will be performed as indicated in the Schedule of Activities 
(Section 1.3). Participants will be confined to the clinic from check-in (Day –1) until 
discharge on Day 26. 
4.2. 
Scientific Rationale for Study Design 
This study is being conducted to investigate the potential DDIs when GSK3640254 is 
co-administered with a cocktail of CYP and transporter probe substrates in healthy 
participants. This study will aid in understanding these interactions and resulting changes 
in exposure (if any) when drugs that are metabolized via these pathways are given in 
combination with GSK3640254.  
The inhibitory potential (direct and metabolism-dependent inhibition) of GSK3640254 
towards 7 major human hepatic CYP enzymes was evaluated in human liver microsomes 
(CIB) [GSK Document Number 2018N379610_01]. GSK3640254 demonstrated minimal 
direct inhibition of all 7 CYP isoforms tested (half-maximal inhibitory concentration 
[IC50] values >13.3 µM). At the maximum projected clinical dose of 200 mg, there is a 
low risk for clinically meaningful CYP-mediated DDIs with substrates of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. 
GSK3640254 did not demonstrate human pregnane X receptor or vitamin D receptor 
mediated transactivation of CYP3A. Therefore, it is unlikely that GSK3640254 would 
induce CYP3A, or other pregnane X receptor and vitamin D receptor regulated 
enzymes/transporters in humans. In addition, GSK3640254 was tested in a panel of CYP 
induction assays using inducible cryopreserved human primary hepatocytes and showed 
no induction (50% inhibitory effect >5 µM) of CYP3A4, CYP2B6, and CYP1A2. 
GSK3640254 is an inhibitor of OATP1B3 and multi-drug resistance protein (MRP)2 
in vitro and has a potential of generating DDIs with substrates of these transporters at the 
projected human systemic exposures. The IC50 values of GSK3640254 against 
OATP1B3 and MRP2 were 0.55 and 2.2 µM, respectively. In addition, GSK3640254 was 
an inhibitor of UGT1A1 in vitro (IC50 = 3.9 µM) and clinical DDIs via this mechanism 
could be possible although literature reports have not revealed clinical DDIs with greater 
than 2-fold change in exposure, with a few exceptions, due to UGT1A1 inhibition 
[Lin, 2002; Williams, 2004]. A clinically meaningful DDI risk due to UGT1A1 inhibition 
by GSK3640254 is likely minimal. This is supported by the fact that following repeat 
oral administration of 50 mg dolutegravir (primarily metabolized by UGT1A1 with 
smaller contribution by CYP3A4), mean steady-state plasma exposure values for Cmax 
and AUC(0-τ) were similar when dolutegravir was administered alone or in combination 
with 200 mg GSK3640254. 
This study is designed in accordance with the US Food and Drug Administration 
Guidance for Industry, Clinical Drug Interaction Studies - Study Design, Data Analysis, 
and Clinical Implications [DHHS, 2017] to assess the PK, safety, and tolerability of 
GSK3640254 and cocktail of CYP and transporter probe substrate drugs when 
administered alone and in combination. The probe substrate drugs used in this study are 
caffeine 200 mg (CYP1A2), metoprolol 100 mg (CYP2D6), montelukast 10 mg 


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(CYP2C8), flurbiprofen 100 mg (CYP2C9), omeprazole 40 mg (CYP2C19), 
midazolam 5 mg (CYP3A4), digoxin 0.25 mg (P-gp), and pravastatin 40 mg (OATP1B1). 
4.3. 
Justification for Dose 
A dose of 200 mg GSK3640254 was selected for this study as it is the maximum 
projected clinical dose. The t1/2 of GSK3640254 was approximately 22 hours in the 
MAD portion of Study 207187 (GSK Document Number 2020N430256_00) at the 
200-mg dose, and predicted time to steady state is approximately 5 days. Dosing of 
GSK3640254 QD from Days 11 to 20 during Regimen 2 will be sufficient to bring 
plasma concentrations to steady state. There is no subsequent need for a washout of 
GSK3640254 since the primary remaining evaluation is for the co-administered probe 
substrate drugs and GSK3640254 at steady state. 
Doses of the probe substrate drugs (caffeine 200 mg, metoprolol 100 mg, 
montelukast 10 mg, flurbiprofen 100 mg, omeprazole 40 mg, midazolam 5 mg, 
digoxin 0.25 mg, and pravastatin 40 mg) are standard for this type of study. Further 
information on the probe substrate drugs is provided in Section 2.2.4. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including final date on which data were or are expected to be 
collected. 
The end of the study is defined as the date of the last visit of the last participant in the 
study or the last scheduled procedure shown in the SoA (Section 1.3) for the last 
participant in the study. 
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 of 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 the investigator or medically 
qualified designee based on a medical evaluation including medical history, physical 
examination (including cardiopulmonary examination), laboratory tests, and cardiac 
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Weight 
3. Body weight ≥50.0 kg (110 lbs) for men and ≥45.0 kg (99 lbs) for women and body 
mass index within the range 18.5 to 31.0 kg/m2 (inclusive). 
Sex 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
4. Male or female 
a.  Male participants 
1. Male participants should not engage in intercourse while confined in the 
clinic. There is no need for an extended period of double barrier use or 
prolonged abstinence after study discharge. 
b. Female participants: 
1. A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least 1 of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) as defined in 
Appendix 3. 
OR 
• Is a WOCBP and using a nonhormonal contraceptive method that is 
highly effective, with a failure rate of <1%, as described in 
Appendix 3, for 28 days before intervention, during the intervention 
period, and for at least 28 days after the last dose of study intervention. 
The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 
2. A WOCBP must have a negative highly sensitive serum pregnancy test 
(Appendix 2) at Screening and check-in (Day –1). 
3. Additional requirements for pregnancy testing during and after study 
intervention are outlined in Appendix 2. 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
5. Capable of giving signed informed consent as described in Appendix 4 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones). 
2. A pre-existing condition interfering with normal GI anatomy or motility 
(e.g., gastro-esophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or 
renal function that could interfere with the absorption, metabolism, and/or excretion 
of the study intervention or render the participant unable to take oral study 
intervention. 
3. Prior cholecystectomy surgery (prior appendectomy is acceptable). 
4. Any history of significant underlying psychiatric disorder, including, but not limited 
to, schizophrenia, bipolar disorder with or without psychotic symptoms, other 
psychotic disorders, or schizotypal (personality) disorder. 
5. Any history of major depressive disorder with or without suicidal features, or anxiety 
disorders that required medical intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient 
treatment. Participants with other conditions such as adjustment disorder or 
dysthymia that have required shorter term medical therapy (<6 months) without 
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the ViiV Healthcare 
(VH)/GSK Medical Monitor. 
6. Any pre-existing physical or other psychiatric condition (including alcohol or drug 
abuse), which, in the opinion of the investigator (with or without psychiatric 
evaluation), could interfere with the participant’s ability to comply with the dosing 
schedule and protocol evaluations or which might compromise the safety of the 
participant. 
7. Medical history of cardiac arrhythmias, prior myocardial infarction in the past 
3 months, or cardiac disease or a family or personal history of long QT syndrome. 
8. History of asthma, bronchospasm, or sleep apnea. 
9. History of chronic musculoskeletal pain (myalgias). 
10. History of rhabdomyolysis. 
11. History of a bleeding disorder. 
12. History of Raynaud’s disease. 


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13. History indicative of an increased risk of a cardiac arrhythmia or cardiac disease, 
including the following: 
a. History of cardiac arrhythmias or palpitations associated with presyncope or 
syncope, or history of unexplained syncope. 
b. History of clinically relevant cardiac disease including symptomatic or 
asymptomatic arrhythmias (including but not limited to ventricular fibrillation, 
ventricular tachycardia, any degree of atrioventricular block, Brugada syndrome, 
Wolff-Parkinson-White syndrome, and sinus bradycardia, defined as heart rate 
less than 50 beats per minute [bpm] based on vital signs or ECG), presyncope or 
syncopal episodes, or additional risk factors for torsades de pointes (e.g., heart 
failure). 
c. History of clinically relevant structural cardiac disease including hypertrophic 
obstructive cardiomyopathy. 
d. History of hypokalemia. 
e. History of heart disease (e.g., coronary heart disease). 
Laboratory Assessments 
14. Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study intervention. 
15. Positive hepatitis C antibody test result at Screening or within 3 months prior to 
starting study intervention AND positive on reflex to hepatitis C RNA. 
16. Positive HIV-1 and -2 antigen/antibody immunoassay at Screening. 
17. Alanine aminotransferase (ALT) ≥1.5 × upper limit of normal (ULN). A single 
repeat of ALT is allowed within a single screening period to determine eligibility. 
18. Bilirubin ≥1.5 × ULN (isolated bilirubin ≥1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). A single repeat of any laboratory 
abnormality is allowed within a single screening period to determine eligibility. 
19. Any acute laboratory abnormality at Screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound. 
20. Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of lipid 
abnormalities (e.g., total cholesterol, triglycerides), and ALT (described above), will 
exclude a participant from the study unless the investigator can provide a compelling 
explanation for the laboratory result(s) and has the assent of the sponsor. A single 
repeat of any laboratory abnormality is allowed within a single screening period to 
determine eligibility. 
21. A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine 
(indicating active current smoking) at Screening or before the first dose of study 
intervention. 


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Prior/Concomitant Therapy 
22. Unable to refrain from the use of prescription or nonprescription 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) prior to the first dose of study intervention and for the duration of the study. 
(Note: acetaminophen/paracetamol at doses of 2 g/day and topical hydrocortisone 
cream 1% are permitted for use any time during the study.) 
23. Treatment with any vaccine within 30 days prior to receiving study intervention. 
24. Unwillingness to abstain from excessive consumption of any food or drink 
containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or 
pomelos or their fruit juices within 7 days prior to the first dose of study 
intervention(s) until the end of the study. 
Prior/Concurrent Clinical Study Experience 
25. Participation in another concurrent clinical study or prior clinical study (with the 
exception of imaging trials) prior to the first dosing day in the current study: 30 days, 
5 half-lives, or twice the duration of the biological effect of the study intervention 
(whichever is longer). 
26. Prior exposure to GSK3640254 in another clinical study. 
27. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days. 
Diagnostic Assessments 
28. Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS. 
29. Systolic blood pressure <100 mm Hg. Up to 2 repeats are allowed for confirmation. 
30. Any significant arrhythmia or ECG finding (e.g., prior myocardial infarction in the 
past 3 months, symptomatic bradycardia, non-sustained or sustained atrial 
arrhythmias, non-sustained or sustained ventricular tachycardia, any degree of 
atrioventricular block, or conduction abnormality) which, in the opinion of the 
investigator or VH/GSK Medical Monitor, will interfere with the safety for the 
individual participant. 
31. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination): 
 
Males and Females 
Heart rate1 
<50 or >100 bpm 
PR interval  
>200 ms 
QTc2  
>450 ms 
1 
A heart rate from 100 to 110 bpm can be rechecked by ECG or vital signs within 30 minutes to verify eligibility. 
2 
The QTc is the QT interval corrected for heart rate using Fridericia’s formula (QTcF). It is either machine read or 
manually over-read. The specific formula used to determine eligibility and discontinuation for an individual 
participant will be Fridericia’s formula. 


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Other Exclusions 
32. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a 
half-pint (~240 mL) of beer, 1 glass (125 mL) of wine, or 1 (25 mL) measure of 
spirits. 
33. Unable to refrain from tobacco or nicotine-containing products within 3 months prior 
to Screening. 
34. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates their participation. 
35. History of aspirin allergy. 
36. A participant with known or suspected active COVID-19 infection OR contact with 
an individual with known COVID-19, within 14 days of study enrollment (WHO 
definitions Section 10.7.3.2.1)  
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• 
Abstain from consumption of red wine, grapefruit and grapefruit juice, Seville 
oranges, blood oranges, or pomelos or their fruit juices within 7 days prior to the 
first dose of study intervention(s) until the end of the study. 
• 
Unless otherwise indicated, all doses of GSK3640254 and probe substrate drugs 
in this study will be administered in the fed state. The participants will fast 
overnight for at least 8 hours prior to dosing and will receive a moderate fat 
meal 30 minutes prior to dosing. Participants will eat this meal in 25 minutes or 
less. Dose administration will occur within 5 minutes of completion of meal 
consumption. Participants will not receive any further food until 4 hours 
post-dose on serial PK sampling days (Day 1 and Day 21). The moderate fat 
meal will contain about 600 calories with approximately 30% of the calories 
coming from fat. 
• 
No water is allowed from 1 hour prior to dosing until 1 hour after dosing with 
GSK3640254 and/or probe substrate drugs except for the glass of water needed 
to administer the study intervention (e.g., 240 mL). Water is allowed ad libitum 
at all other times. If necessary, additional water may be administered to allow 
dosing of all medications, but the additional volume of water must be kept to a 
minimum. The amount of additional water should be documented in the source 
documents. 
• 
A standard lunch will be provided 4 hours after dosing. A standard dinner will 
be served approximately 10 hours after dosing. The food content of meals must 
be identical on serial PK sampling days. 


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5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
Participants will abstain from ingesting caffeine- or xanthine-containing 
products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours before the 
start of dosing until after collection of the final PK sample. 
• 
Participants will abstain from alcohol for 48 hours before the start of dosing 
until after collection of the final PK sample.  
• 
Use of tobacco- and nicotine-containing products will not be allowed from 
3 months prior to Screening until after the final visit. 
• 
Participants must have a negative drug test at Screening and check-in (Day –1) 
and must abstain from recreational drug use from Screening until after the final 
visit. 
5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (e.g., watching television, reading). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations, and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.  
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
 


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6.1. 
Study Interventions Administered 
Intervention Name 
GSK3640254 
Probe Substrate Drugs 
Caffeine 
Metoprolol 
Montelukast Flurbiprofen Omeprazole 
Midazolam 
Digoxin 
Pravastatin 
Type  
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet 
Capsule 
Syrup 
Tablet 
Tablet 
Unit Dose 
Strengths  
100 mg 
200 mg 
100 mg 
10 mg 
100 mg 
40 mg 
2 mg/mL 
0.25 mg 
40 mg 
Dosage Levels 
200 mg 
200 mg 
100 mg 
10 mg 
100 mg 
40 mg 
5 mg (2.5 mL) 
0.25 mg 
40 mg 
Route of 
Administration 
oral 
IMP and NIMP 
IMP 
Sourcing 
Sourced by Sponsor 
Sourced by Investigator 
Packaging and 
Labeling 
Provided in bulk by 
the Sponsor. The 
investigator will 
package in 
high-density 
polyethylene bottles. 
Each bottle will be 
labeled as required 
per country 
requirement. 
In accordance with product label 
IMP = investigational medicinal product; NIMP = non-investigational medicinal product. 
 


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6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and that any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM).  
5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or VH/GSK study 
contact. 
6. A Material Safety Data Sheet/equivalent document describing occupational hazards 
and recommended handling precautions will either be provided to the investigator, 
where this is required by local laws, or is available upon request from VH/GSK. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. All participants will receive the same treatments in the same 
sequence. 
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 
Acetaminophen/paracetamol at doses of 2 g/day and topical hydrocortisone cream 1% 
are permitted for use any time during the study and their use should be documented in the 
case report form (CRF). Other medications are not permitted without prior discussion 
with the VH/GSK Medical Monitor. 


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6.6. 
Dose Modification 
Not applicable. 
6.7. 
Intervention after the End of the Study 
Participants will not receive any additional treatment from VH/GSK or with 
GSK3640254 or the probe substrate drugs after the completion of the study because only 
healthy volunteers are eligible for study participation. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention. If study intervention is definitively 
discontinued, the participant will remain in the study to be evaluated for safety. See the 
SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention.  
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the Food and Drug 
Administration premarketing clinical liver safety guidance: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf). 
Discontinuation of study intervention for abnormal liver tests is required when the 
participant has an ALT ≥3 × ULN or if the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Note, if ALT ≥3 × ULN AND bilirubin 2 × ULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, the event will be reported as an SAE. 
Details of liver safety follow-up procedures are described in Appendix 5. 
7.1.2. 
QTc Stopping Criteria 
The same 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. 
• 
The Baseline QTcF for each regimen will be based on averaged QTcF values of 
triplicate ECGs obtained over a brief (e.g., 5-10 minute) recording period 
obtained pre-dose on the first day of each respective regimen (i.e., Days 1, 11, 
and 21) 


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• 
An enrolled participant that develops an on-treatment QTcF >500 ms or an 
increase from Baseline QTcF >60 ms should have 2 repeat unscheduled ECGs 
within 10 minutes. Using these triplicate ECGs, if the average QTcF >500 ms or 
an increase from Baseline QTcF >60 ms, the participant will be withdrawn from 
the study. Finally, this participant should have repeated unscheduled ECGs until 
their QTcF measurement returns to their original averaged QTcF value at 
Baseline for the respective regimen. 
Refer to the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.3. 
Columbia-Suicide Severity Rating Scale 
Emergence of any positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered C-SSRS during the treatment phase of the 
study will be cause for immediate clinical assessment of suicidality (by the investigator 
or a consulting psychiatrist). Emergence of new onset suicidal ideation or a Grade 3 or 
higher psychiatric AE will result in immediate discontinuation and urgent specialist 
psychiatric evaluation and management. 
Refer to the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.4. 
Individual Participant Laboratory Abnormality and Adverse Event 
Stopping Criteria 
Investigators should make every effort to have a discussion with the medical monitor 
before the next dose to help assess if the study intervention should be stopped.  
• 
Any clinically significant AE or abnormalities in vital sign measurements, 
laboratory results or ECGs deemed to require discontinuation of study 
intervention; however, participants will continue to be clinically evaluated as 
necessary to ensure their safety 
• 
Any Division of AIDS (DAIDS) Grade 3 or higher rash or Grade 2 rash with 
evidence of systemic involvement  
• 
Any allergic or hypersensitivity reactions to study intervention 
• 
Any DAIDS Grade 3 or higher psychiatric AE 
• 
New onset suicidal ideation 
• 
Any DAIDS Grade 3 or higher AE related to study intervention 
• 
Any DAIDS Grade 4 AE 
• 
DAIDS Grade 3 or higher laboratory abnormalities  
7.1.5. 
COVID-19 
A participant must permanently discontinue study intervention and be discontinued from 
the study if they have COVID infection as clinically determined by the investigator 


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(suspect, probable, or confirmed using the most recent version of the WHO case 
definition) or by laboratory testing. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his or her own request 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. This is expected to be 
uncommon. 
• 
A participant who is withdrawn from the study for any reason related to safety 
(listed in Section 7.1.4 or otherwise) will be continued to be followed to assess 
the outcome of the safety event that triggered discontinuation of study 
intervention. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. 
• 
The participant will be permanently discontinued both from the study 
intervention and from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
If a participant withdraws from the study, he or she may request destruction of 
any samples taken and not tested, and the investigator must document this in the 
site study records. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he or she will be considered 
to have withdrawn from the study.  


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Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 4. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
• 
Protocol waivers or exemptions are not allowed.  
• 
Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in 
the SoA. 
• 
The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
• 
A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, GI, and neurological systems. Height and weight 
will also be measured and recorded at Screening. 
• 
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 
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8.2.2. 
Vital Signs 
• 
Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. In addition, pulse oximetry will be assessed on Day 1 and Day 21 as 
per the SoA (Section 1.3). 
• 
Blood pressure and pulse measurements will be assessed in the 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 will be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones). 
• 
At each time point at which triplicate measurements are required, 3 consecutive 
blood pressure and pulse readings will be recorded at intervals of at least 
1 minute. Each measurement will be recorded in the CRF. 
• 
When vital signs are scheduled at the same time as blood collections for 
laboratory tests, vital signs are to be taken first. Pharmacokinetic blood 
collection should occur as close to the nominal time as possible. 
8.2.3. 
Electrocardiograms 
• 
Twelve-lead ECGs will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. Refer 
to Section 7.1.2 for QTcF withdrawal criteria and additional QTcF readings that 
may be necessary. 
• 
Twelve-lead ECGs will be performed with the participant in a supine position 
after a rest of at least 10 minutes. 
• 
At each time point at which triplicate ECGs are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed over a brief 
(e.g., 5 to 10 minutes) recording period. Each measurement will be recorded in 
the CRF. 
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the 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 by 
the investigator during participation in the study or within 7 days after the last 
dose of study intervention should be repeated until the values return to normal or 


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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.  
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring 
GSK3640254 is not a central nervous system active drug nor is it being developed for a 
neurologic or psychiatric condition. However, given the risk of suicidal ideation 
identified with a previous MI compound, GSK3532795, all participants will undergo 
screening using the C-SSRS administered by a clinician (or qualified designee); any 
positive (abnormal) response confirmed by the investigator, will exclude them from 
participating. A repeat assessment will be done during the treatment phase of the study. 
In case of positive (abnormal) response confirmed by the investigator, the participant will 
undergo immediate clinical assessment of suicidality (by the investigator or a consulting 
psychiatrist). Emergence of new onset suicidal ideation or a Grade 3 or higher psychiatric 
AE will result in immediate discontinuation and urgent specialist psychiatric evaluation 
and management. 
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation. Screening visit questions will be in 
relation to lifetime experiences and current experiences (within the past 2 months) and all 
subsequent questioning in relation to the last assessment. 
Emergent non-suicidal psychiatric AE evaluation and management: 
• 
Any DAIDS Grade 1 or 2 psychiatric AE: A Grade 1 or 2 psychiatric AE may 
result in additional unscheduled visits (in-clinic or at home) as clinically 
indicated. This may include a more in-depth assessment of the AE through 
interview, additional unscheduled clinical laboratory tests, and/or imaging. 
Psychiatric consultation may be required at the discretion of the investigator. 
Any pharmacotherapy should be discussed with the medical monitor. 
• 
Any DAIDS Grade 3 or 4 psychiatric AE: As described in Section 7.1.4, a 
Grade 3 or 4 psychiatric AE will result in discontinuation from the study and 
emergency psychiatric evaluation (including potential hospitalization and 
pharmacotherapy as indicated). 
8.2.6. 
Gastrointestinal Toxicity Evaluation and Monitoring Plan 
Preclinical toxicology studies in rats and dogs have suggested a potential for GI-related 
toxicity with GSK3640254. This section provides general guidance to the investigator on 
the evaluation and management of primarily upper GI symptoms (Table 1). The 
investigator may contact the VH/GSK Medical Monitor to discuss evaluation and 


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management (including discontinuation of a participant) of any GI symptoms throughout 
the study. 
For any DAIDS Grade 4 or related Grade 3 AE, the investigator will discontinue the 
participant from the study and perform an evaluation/management plan incorporating the 
elements in Table 1. 
Table 1 
Gastrointestinal Toxicity Evaluation and Management 
HISTORY 
For symptoms of all grades, a thorough history forms the foundation of proper 
evaluation and management. The following are potential manifestations of some 
GI clinical syndromes that may occur (possibly in combination) during the clinical 
study.  
Nausea and Vomiting 
The investigator should attempt to identify the etiology of these symptoms (and whether 
it is intraperitoneal, extraperitoneal, medication related, infection related, or due to a 
metabolic disorder [Hasler, 2012]. Medications can cause nausea and vomiting acutely.  
Dyspepsia 
The investigator should identify the presence of red flags (odynophagia, unexplained 
weight loss, recurrent vomiting, GI bleeding, jaundice, palpable mass or adenopathy, or 
family history of GI malignancy). Symptoms of dyspepsia could include early satiety, 
bloating, or belching. Additionally, atypical symptoms of dyspepsia could include: 
pharyngitis, asthma, bronchitis, hoarseness, chest pain, or abdominal pain.  
Other Clinical Syndromes 
Additional diagnostic criteria for other GI disorders potentially encountered in the clinical 
study are available elsewhere [Rome Foundation, 2019]. 
PHYSICAL 
EXAMINATION 
Physical examination should complement elements obtained from the history 
[Hasler, 2012]. Acutely, the investigator may assess for signs of intravascular 
volume depletion (e.g., orthostasis) and/or aspiration of vomitus as appropriate. 
Abdominal tenderness and guarding may indicate inflammation. The presence of 
fecal blood can indicate mucosal damage (e.g., from an ulcer). Complete 
evaluation of dyspepsia should include an oral examination (poor dentition or 
pharyngeal erythema) and lungs for wheezing.  
DIAGNOSTIC 
EVALUATION AND 
MANAGEMENT 
A major goal in the diagnostic evaluation of a participant with upper GI symptoms 
is to quickly arrive at a final diagnosis without exposing the participant to 
unnecessary (invasive) testing; investigators should exercise good clinical 
judgment in this regard [Soll, 2009]. A major goal of therapy is directed at 
correcting the underlying identifiable medical or surgical abnormalities. 
Consultation (e.g., gastroenterologist) is recommended as clinically indicated. 
Grade 1 symptoms 
Participants may be treated symptomatically. If participants develop dyspepsia alone, 
generally only limited and direct diagnostic testing should be performed. If the participant 
has dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, and eating directly 
before bedtime.  
Grade 2 symptoms 
Diagnostic testing may include but is not limited to the following (as clinically indicated): 
• 
Serum chemistries and assessment of hemoglobin if not recently performed  
• 
Testing for Helicobacter pylori  
• 
Polymerase chain reaction for viruses (e.g., cytomegalovirus) 
For participants who are infected with H. pylori, discontinuation from the study is 
necessary. Management should be targeted at addressing the underlying pathology. 
Grade 3 symptoms 
Diagnostic testing may include but is not limited to the following (as clinically indicated): 
• 
The testing outlined above in Grade 2 
• 
A barium swallow  
• 
Computed tomography scan to identify GI inflammation  
• 
Upper endoscopy with biopsy as indicated (e.g., mucosal injury or the presence of 
red flags) 
Management should be targeted at addressing the underlying pathology. 
Grade 4 symptoms 
Diagnostic testing may include but is not limited to the following (as clinically indicated): 
• 
The testing outlined above in Grade 2 and Grade 3 


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• 
An acute abdominal series 
Initial management can include correction of hemodynamic and electrolyte abnormalities 
as clinically indicated. After stabilization, management should be targeted at addressing 
the underlying pathology. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 6. As described in 
Appendix 6, intensity of AEs (and laboratory abnormalities) will be graded using the 
most recent version of the DAIDS grading table (Appendix 7) at the time of the last 
participant last visit. While the study population will consist of HIV-1 seronegative 
healthy participants, the DAIDS criteria is being used in later phase clinical studies (e.g., 
Phase 2); additionally, the DAIDS criteria have a more conservative grading scale 
relative to other scales (e.g., Common Terminology Criteria for Adverse Events 
[CTCAE] v 4.0). Thus, participant safety evaluation and monitoring will be more 
conservative. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7). 
See Section 10.7.3.2 for the assessment and capture of AEs and SAEs related to COVID-
19. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the ICF until the end of the study 
at the time points specified in the SoA (Section 1.3). 
• 
All AEs will be collected from the start of intervention until the end of the study 
at the time points specified in the SoA (Section 1.3). 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be considered medical history, not an AE, and 
will be recorded in the source documents. 
• 
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 6. 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 or she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor. 


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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 6. 
• 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. 
Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest 
(as defined in Section 8.3.6), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 6. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRBs)/ Independent Ethics Committees (IECs), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the CIB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female participants and, if indicated, female 
partners of male participants will be collected after the start of study intervention 
and through the end of pregnancy (termination or delivery). 
• 
If a pregnancy is reported, the investigator should inform VH/GSK within 
24 hours of learning of the pregnancy. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 


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• 
A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
8.3.6. 
Adverse Events of Special Interest 
Adverse events of special interest include all AEs classified in the cardiovascular (per the 
the Medical Dictionary for Regulatory Activities) system organ class, seizure, and 
syncope. Additional AEs of special interest within other system organ classes (e.g., GI, 
neurologic, or psychiatric) may be defined in the reporting and analysis plan. 
8.4. 
Treatment of Overdose 
For this study, any dose of GSK3640254 or any of the probe substrate drugs greater than 
the planned dose within a 24-hour time period (±2 hours) will be considered an overdose. 
VH/GSK does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 or any of the probe substrate drugs can no longer be detected 
systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis immediately and through 7 days after the 
date of the last dose of study intervention if requested by the medical monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the 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 
• 
Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3640254 as specified in the SoA (Section 1.3). 
• 
Separate whole blood samples of approximately 13 mL will be collected for 
measurement of plasma concentrations of the probe substrate drugs (caffeine, 
metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, digoxin, and 
pravastatin and metabolites α-hydroxymetoprolol, 36-hydroxymontelukast, 
5-hydroxyomeprazole, and 1-hydroxymidazolam) as specified in the SoA 
(Section 1.3). In addition, Coproporphyrin-1 (CP-1) will be investigated as an 
exploratory aim as a biomarker of OATP inhibition, alongside pravastatin.  


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• 
A maximum of 10 samples (approximately 20 mL) 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. 
• 
Samples will be used to evaluate the PK of GSK3640254 and the probe 
substrate drugs. Samples collected for analyses of plasma concentrations may 
also be used to evaluate safety aspects related to concerns arising during or after 
the study. 
• 
Once the plasma has been analyzed for GSK3640254 and the probe substrate 
drugs, any remaining plasma may be analyzed for other compound-related 
metabolites and the results provided in a separate report. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this 
study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
There is no formal hypothesis that will be statistically tested in this study. 
Administration of GSK3640254 under fed conditions may change the exposure to 
caffeine, metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, digoxin and 
pravastatin. 
9.2. 
Sample Size Determination 
9.2.1. 
Sample Size Assumptions 
As there is no formal research hypothesis being statistical tested in this study, the sample 
size is not selected based on statistical considerations but was determined using 
feasibility. Approximately 20 participants will be enrolled to ensure that 18 evaluable 
participants complete the study. If participants prematurely discontinue the study, 


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additional participants may be enrolled after consultation with the sponsor to ensure that 
the required number of evaluable participants complete the study. 
9.2.2. 
Sample Size Sensitivity 
The statistical analysis will be performed to compare Treatment C versus Treatment A. 
For a sensitivity analysis, with a sample size of 18 evaluable participants and across a 
range for intrasubject coefficient of variability (CVw) of 10%, 20%, 30%, and 40% and a 
range for as point estimates (PEs) of 0.9, 1.0, and 1.1 were explored. It is estimated that 
the precision (i.e., half-width of the 90% confidence interval (CI) on the log and ratio 
scale), and CI on the original scale for each PE will be: 
CVw (%) 
Half-Width 
(log scale) 
Half-Width 
(original scale) 
Point Estimate 
90% CI 
10 
0.058 
0.059 
0.9 
(0.849, 0.954) 
1.0 
(0.944, 1.06) 
1.1 
(1.038, 1.166) 
20 
0.115 
0.122 
0.9 
(0.802, 1.01) 
1.0 
(0.891, 1.122) 
1.1 
(0.981, 1.234) 
30 
0.170 
0.185 
0.9 
(0.759, 1.067) 
1.0 
(0.844, 1.185) 
1.1 
(0.928, 1.304) 
40 
0.223 
0.250 
0.9 
(0.72, 1.125) 
1.0 
(0.8, 1.25) 
1.1 
(0.88, 1.375) 
 


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9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
All participants who sign the ICF. 
Safety 
All participants who receive at least 1 dose of study medication. This 
population will be used for all demographic and safety summaries. 
Pharmacokinetic Concentration 
The PK Concentration Population will include all participants who undergo 
plasma PK sampling and have evaluable PK assay results. This population 
will be used for the PK concentration listings, summary tables, and plotting 
of concentration/time data. 
Pharmacokinetic Parameter 
The PK Parameter Population will include all participants who undergo 
plasma PK sampling and have evaluable PK parameters estimated. This 
population will be used for PK parameter listings, summary tables, and 
statistical analysis tables. 
 
9.4. 
Statistical Analyses 
9.4.1. 
Pharmacokinetic Analyses 
Plasma GSK3640254 and probe substrate drugs (caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin; and metabolites 
α-hydroxymetoprolol, 36-hydroxymontelukast, 5-hydroxyomeprazole, and 
1-hydroxymidazolam) concentration-time data will be analyzed by PPD, under the 
oversight of Clinical Pharmacology Modeling & Simulation department within GSK, 
using noncompartmental methods with Phoenix WinNonlin Version 8.0 or higher. 
Statistical analysis will be performed by PPD, under the oversight of Clinical Statistics, 
GSK. Calculations will be based on the actual sampling times recorded during the study. 
Endpoint 
Statistical Analysis Methods 
Primary 
• 
The primary endpoints of this study are PK-related. The analysis for the primary PK endpoints 
will be performed for the PK Parameter Population. Plasma concentrations of probe substrates 
will be subjected to PK analyses using noncompartmental methods. 
• 
Based on the individual concentration-time data the following primary plasma PK parameters 
will be estimated: 
• AUC(0-t), AUC(0-), and Cmax 
• 
Analysis will be performed to compare the PK exposure of probe drugs with and without 
GSK3640254. Analyses will be performed on the natural logarithms of AUC(0-t), AUC(0-), 
and Cmax using linear mixed-effect models with treatment as a fixed effect and measurements 
within participant as repeated measures. Effects will be estimated, and 90% CIs will be 
constructed for the following treatment comparison: 
• Treatment C versus Treatment A  
Point estimates and 90% CIs for treatment differences on the log scale derived from the model 
will be exponentiated to obtain estimates for geometric mean ratios and CIs on the original 
scale. 


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Endpoint 
Statistical Analysis Methods 
• 
Summary statistics (arithmetic mean, geometric mean, median, standard deviation, minimum, 
maximum, and coefficient of variation) for plasma probe substrate primary plasma PK 
parameter (AUC[0-t], AUC[0-], Cmax, Tmax, and t1/2) values will be summarized by 
treatment. 
Secondary 
• 
Plasma concentrations of the metabolites for the probe substrates (α-hydroxymetoprolol, 
36-hydroxymontelukast, 5-hydroxyomeprazole, and 1-hydroxymidazolam) will be subjected to 
PK analyses as described above for the parent analytes. Based on the individual concentration-
time data the following plasma PK parameters will be estimated: 
• Treatment A and C: AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 and metabolite-to-parent 
ratios for Cmax and AUC(0-) 
• 
Plasma concentrations of GSK3640254 will be subjected to PK analyses using 
noncompartmental methods. Based on the individual concentration-actual time data the 
following plasma PK parameters will be estimated: 
• Treatment C: AUC(0-t), AUC(0-), Cmax, C, Tmax, and t1/2 
• Summary statistics (arithmetic mean, geometric mean, median, standard deviation, 
minimum, maximum, and coefficient of variation) for plasma GSK3640254 PK parameter 
values will be presented.  
• 
Additionally, pre-dose (trough) PK plasma concentrations of GSK3640254 (Treatment B) will be 
summarized and used to assess achievement of steady state. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. No formal statistical analysis 
of the safety data will be conducted. 
The details of the statistical analyses of safety data will be provided in the reporting and 
analysis plan. 
9.4.3. 
Other Analyses 
Special statistical and data analysis considerations may be warranted in the event that the 
COVID-19 or related epidemics or natural disasters may affect the study and data 
integrity. To the extent possible, these will be described in the main study SAP; 
alternatively, a separate SAP focussing on modified data handling rules and analyses may 
be prepared, taking into account applicable regulatory guidance and industry best 
practices for handling such situations [FDA, 2020; EMA March 2020; EMA April 2020]. 
9.5. 
Interim Analyses 
No interim analysis is planned. 
9.6. 
Data Monitoring Committee 
Not applicable. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Abbreviations and Trademarks 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC(0-) 
Area under the plasma concentration-time curve from 
time zero extrapolated to infinity 
AUC(0-) 
Area under the plasma concentration-time curve from 
time zero to the end of the dosing interval at steady state 
AUC(0-t) 
Area under the plasma concentration-time curve from 
time zero to time t 
bpm 
Beats per minute 
CI 
Confidence interval 
CIB 
Clinical Investigator's Brochure  
Cmax 
Maximum observed concentration  
CONSORT 
Consolidated Standards of Reporting Trials  
CP-1 
Coproporphyrin-1 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
C 
Plasma concentration at the end of the dosing interval 
CVw 
Intrasubject coefficient of variation 
CYP 
Cytochrome P450 
DAIDS 
Division of AIDS 
DDI 
Drug-drug interaction 
ECG 
Electrocardiogram  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A 
HRT 
Hormonal replacement therapy 
IC50 
Half-maximal inhibitory concentration 
ICF 
Informed consent form  
ICH 
International Council for Harmonisation 


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IDSL 
Integrated Data Standards Library 
IEC 
Independent Ethics Committee  
IgM 
Immunoglobulin M 
INR 
International normalized ratio 
IRB 
Institutional Review Board  
MAD 
Multiple-ascending dose 
MI 
Maturation inhibitor 
MRP 
Multi-drug resistance protein 
NCA 
National Competent Authority 
NSAID 
Nonsteroidal anti-inflammatory drug 
OATP 
Organic anion-transporting polypeptide 
P-gp 
P-glycoprotein 
PE 
Point estimate 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval using the Fridericia formula 
QTL 
Quality tolerance limits 
SAD 
Single-ascending dose 
SAE 
Serious adverse event  
SoA 
Schedule of activities 
SRM 
Study Reference Manual  
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2 
Apparent terminal phase half-life 
Tmax 
Time of maximum observed concentration  
TQT 
Thorough QT 
UGT 
Uridine diphosphate glucuronosyltransferase 
ULN 
Upper limit of normal  
VH 
ViiV Healthcare 
WOCBP 
Woman of childbearing potential  


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• 
Trademark Information 
Trademarks of ViiV Healthcare 
 
Trademarks not owned by the ViiV 
Healthcare 
NONE 
 
DAIDS 
 
 
Phoenix WinNonlin 
 
 
Portia 
 
 
Pravachol 
 
 
Singulair 
 
 
Vivarin 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by the local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the time points indicated in the SoA (Section 1.3). 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
Red Blood Cell Indices: 
White blood cell count with 
differential: 
 
Red Blood Cell Count 
Mean corpuscular volume 
Neutrophils 
 
Hemoglobin 
Mean corpuscular hemoglobin  
Lymphocytes 
 
Hematocrit 
 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
 
 
 
Absolute neutrophil count 
Clinical Chemistry1 
Blood urea nitrogen 
Carbon dioxide 
Total protein 
 
Creatinine 
Aspartate aminotransferase 
Albumin 
 
Glucose (fasting) 
Alanine aminotransferase 
Globulin 
 
Potassium 
Gamma-glutamyl transferase 
Anion gap 
 
Sodium 
Total and direct bilirubin 
Alkaline phosphatase 
 
Calcium 
Lactate dehydrogenase 
Uric acid 
 
Chloride 
Total cholesterol 
Creatine phosphokinase 
 
Phosphorus 
Triglycerides 
Serum lipase 
 
 
 
Serum amylase 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, nitrite, and leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood, leukocyte esterase, or protein is abnormal) 


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Laboratory 
Assessments 
Parameters 
Other Screening 
Tests 
• 
Serology: HIV-1 and -2 antigen/antibody immunoassay, hepatitis B surface 
antigen, hepatitis C antibody 
• 
Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines) 
• 
Pregnancy 2 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Appendix 5. All events of ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis). 
2. 
Local serum testing will be standard for the protocol. 


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10.3. 
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.3.1. 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
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 
• 
Documented bilateral tubal ligation 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Müllerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (>40 IU/L or mIU/mL) is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 


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10.3.2. 
Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly. 
• Nonhormonal intrauterine device 
• 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. The documentation on male sterility can come from the site 
personnel’s: review of participant’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner. If not, an additional highly 
effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days. 
• For the 28 days after study exit, women may resume oral hormonal contraceptives but double 
barrier methods (a combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide) must be used in addition. 
Highly Effective Methodsb That Are User Dependent: Failure rate of <1% per year when used 
consistently and correctly. 
• 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. 
Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. 
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. 
 
10.3.3. 
Collection of Pregnancy Information: 
Female participants who become pregnant 
• The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study.  
• The initial information will be recorded on the appropriate form and submitted to 
VH/GSK within 24 hours of learning of a participant’s pregnancy.  


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• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on participant and neonate, which 
will be forwarded to VH/GSK. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
• Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
VH/GSK as described in Appendix 6. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
intervention or be withdrawn from the study. 


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10.4. 
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations 
10.4.1. 
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 International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, CIB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require IRB/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 IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations 
10.4.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient and accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.4.3. 
Informed Consent Process 
• 
The investigator or his or her representative will explain the nature of the study 
to the participant or his or her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 Code of Federal Regulations 
Part 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK3640254 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have GSK3640254 approved for 
medical use or approved for payment coverage.  
The ICF may contain a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorized designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate tick box will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
10.4.4. 
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 or 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 who will be required to give 
consent for their data to be used as described in the informed consent.  
• 
The participant must be informed that his or her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 


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10.4.5. 
Committees Structure 
Not applicable. 
10.4.6. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
VH/GSK site or other mutually-agreeable location. 
• 
VH/GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with VH/GSK Policy. 
• 
VH/GSK intend 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. 
10.4.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF.  
• 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These pre-
defined parameters will be monitored during and at the end of the study and all 
deviations from the QTLs and remedial actions taken will be summarized in the 
clinical study report. 
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the monitoring plan. 


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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/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.  
10.4.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the electronic CRF that are transcribed 
from source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in the SRM. 
10.4.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant screened and will be the study start 
date. 
VH/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 VH/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. 


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IRB/IEC, 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 
participants and should assure appropriate participant therapy and/or follow-up. 
10.4.10. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT ≥3 × ULN 
If ALT ≥3 × ULN AND bilirubin1,2 2 × ULN (>35% direct bilirubin) or 
international normalized ratio (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 VH/GSK within 
24 hours 
• Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow-up assessments 
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within Baseline 
(see MONITORING below) 
MONITORING: 
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5 
• Repeat liver chemistries (include ALT, 
aspartate aminotransferase, alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow-up assessments within 
24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within Baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, 
aspartate aminotransferase, alkaline 
• Viral hepatitis serology3 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminase values show downward trend 
• Obtain blood sample for PK analysis, 
obtained within 48 hours of last dose4  
• Serum creatine phosphokinase and lactate 
dehydrogenase 
• Fractionate bilirubin, if total bilirubin 
≥2 × ULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over-the-counter medications 
• Record alcohol use on the liver event 
alcohol intake CRF 
 
 
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 


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Liver Chemistry Stopping Criteria  
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 
microsomal antibodies, and quantitative 
total immunoglobulin G or gamma 
globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]. NOTE: 
not required in China. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete liver imaging and/or liver 
biopsy CRF. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3 × ULN and bilirubin  2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, which 
may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants. 
3. 
Includes: hepatitis A immunoglobulin (IgM) antibody, hepatitis B surface antigen, and hepatitis B core antibody; 
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. 
Pharmacokinetic 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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10.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.6.1. 
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 sign 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 DDI. 
• 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. 
• Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
10.6.2. 
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: 
Results in death 
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 AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE. 
Results in persistent or significant 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 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 


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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. 
 
10.6.3. 
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 VH/GSK in lieu of completion of the VH/GSK AE/SAE CRF 
page. 
• There may be instances when copies of medical records for certain cases are 
requested by VH/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 VH/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 using the DAIDS grading table Version 2.1, July 2017 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) and assign it to 
1 of the following categories:  
• Mild: no or minimal interference with usual social and functional activities.  
• Moderate: greater than minimal interference with usual social and functional 
activities. 
• Severe: inability to perform usual social and functional 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. 
• Life Threatening: inability to perform basic self-care functions. 
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 CIB and/or Product Information, for marketed 
products, in his or her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he or she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to VH/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 VH/GSK. 
• The investigator may change his or 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 VH/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 VH/GSK with a copy of any postmortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information. 
 


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10.6.4. 
Reporting of SAE to VH/GSK 
SAE Reporting to VH/GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to VH/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 electronic CRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to study intervention/study participation (causality) 
within 72 hours of SAE entry into the electronic CRF. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to VH/GSK via Paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the SRM. 
 
 
 


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10.7. 
Appendix 7: COVID-19 Pandemic and Clinical Trial 
Continuity 
The COVID-19 pandemic may impact the conduct of clinical studies. Significant 
logistical challenges may arise from quarantines, variable restrictions on site resource and 
operations, site closures, travel limitations and the inability of an individual participant to 
attend clinic visit, 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 dispensation of the investigational product to the participant or adhering to 
protocol-mandated visits and laboratory/diagnostic testing.   
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in study 
treatment for participants enrolled in this clinical study. 
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database. 
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety, welfare and rights, and to ensure data integrity and 
the integrity of the clinical trial, as a result of COVID-19 only. These measures may be 
implemented in accordance with any requirements and expectations set out by local 
Independent Review Boards/Independent Ethics Committees and National Competent 
Authorities (NCAs), as necessary. 
This appendix does not apply for participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19.  
10.7.1. 
Changes to Study Visits and Study Procedures 
• There may be cases where the current principal investigator (PI) of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the sponsor. 
• There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the 
NCA/IRB/IEC regulations. 
10.7.2. 
COVID-19 Experimental Agents 
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study medical monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate. 


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The protocol does not allow for concurrent enrolment in other interventional studies, 
though, there may be exceptions in this pandemic. If a participant is being considered for 
enrolment into clinical studies for COVID-19 treatment or vaccinations, please reach out 
to the Medical Monitor who will discuss with the study team (to include Safety Review 
Team and input from the PK Scientist/Clinical Pharmacologist) who will consider 
relevant drug interactions and to ensure that continued study participation remains 
appropriate. 
10.7.3. 
COVID-19 Specific Data Capture 
10.7.3.1. 
Capturing COVID-19 Specific Protocol Deviations 
Please refer to the SRM for specific details on capturing protocol deviations as a result of 
COVID-19. 
10.7.3.2. 
Capturing COVID-19 Specific AEs and SAEs 
ViiV Healthcare are monitoring the evolving situation with respect to COVID-19 
carefully and the impact this may have on ongoing or planned clinical trials.  It is 
important for the study team to describe COVID-19 related AEs/SAEs and their impact 
on study data and outcomes. Standardization of case definitions will facilitate future data 
analysis.  
Please use the following guidance:  
1. 
AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual study 
procedures and timelines.  
2. 
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to evolve; 
the most recent definitions should be consulted for each case (WHO). When 
reporting both serious and non- serious adverse events (related to COVID-19 
infection), investigators should use the following Verbatim terms:  
a) Suspected COVID-19 infection; or  
b) Probable COVID-19 infection; or  
c) Confirmed COVID-19 infection  
 
3. 
Sites should contact the study Medical Monitor for questions related to definitions 
and reporting, and decisions around impact to study drug continuation in the 
setting of clinically defined mild COVID-19 infection.  
 
4. 
A new COVID-19 infection Case Report Form will be included in the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important that the correct information is collected from each participant reporting 
a COVID-19 AE or SAE.  Therefore, please use the CRF templates to help you 
collect this information for all COVID-19 related AEs/SAEs. 


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10.7.3.2.1. WHO Case Definition (March 20, 2020 Version):  
Suspected case:  
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset;  
OR  
B. A patient with any acute respiratory illness AND having been in contact (see 
definition of “contact” below) with a confirmed or probable COVID-19 case (see 
definition of contact) in the last 14 days prior to symptom onset;  
OR  
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation.  
 
Probable case:  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory).  
OR  
B. A suspect case for whom testing could not be performed for any reason.  
 
Confirmed case:  
A person with laboratory confirmation of COVID-19 infection, irrespective of clinical 
signs and symptoms.  
COVID-19 Contact: 
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case:  
1. Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes;  
2. Direct physical contact with a probable or confirmed case;  
3. Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; OR  
4. Other situations as indicated by local risk assessments.  
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation. 


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10.8. 
Appendix 8: Division Of AIDS (DAIDS) Table For Grading 
The Severity Of Adult And Pediatric Adverse Events 
Version 2.1 July 2017 
The DAIDS grading table can be found at the following link: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf  


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10.9. 
Appendix 9: 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 the Amendment: The primary driver for the protocol amendment 
was to add the new rash risk. Following recent events involving COVID-19, additional 
changes around COVID-19 guidance was added to this amendment.   
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SoA) 
Addition of daily temperature 
check. 
Daily temperature check as added as a 
measure to monitor COVID-19 
infection. 
2.3.1 Risk 
Assessment 
Addition of rash as potential risk 
of clinical significance. 
In previous ‘254 clinical studies 
episodes of rash have been reported 
and some cases have led to study 
discontinuation. As a result, rash has 
been included as a risk for participants 
who are dosed with ‘254. 
5.1 Inclusion Criteria 
Age change 
Max entry age of study participants was 
changed from 55 to 50 years of age.  
5.2 Exclusion Criteria Liver chemistry updated 
 
WHO COVID-19 update  
Liver chemistry updated as per the 
VSLC liver safety guidance April 2020. 
Addition of WHO COVID-19 exclusion 
guidance. 
7.1.5 Discontinuation 
of Study Intervention 
Addition of COVID-19 as 
discontinuation criteria. 
Addition of permanently discontinuing 
from study due to  COVID-19 infection. 
8.3 Adverse Events 
and Serious Adverse 
Events 
Reference to Appendix for AE’s 
and SAE’s related to COVID-19 
Reference to Appendix for adverse 
events and serious adverse events 
related to COVID-19. 
8.5 
Pharmacokinetics 
 
Addition of CP-1 Assay & total 
blood volume collected. 
Addition of Coproporphyrin-1 as a 
biomarker of OATP inhibition for 
exploratory aim.  
 
9.4.3 Other Analyses Addition of special statistical and 
data analysis considerations. 
Special statistical and data analysis 
considerations may be warranted in the 
event that the COVID-19 or related 
epidemics or natural disasters may 


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Section # and 
Name 
Description of Change 
Brief Rationale 
affect the study and data integrity. 
10.4.7 Data Quality 
Assurance 
Quality tolerance limits (QTLs) 
Addition of QTLs to be pre-defined and 
summarized in the clinical study report. 
10.7 COVID-19 
Pandemic and 
Clinical Trial 
Continuity 
Addition of appendix to 
document requirements to 
mitigate for any actions related 
to COVID-19 
This appendix outlines the measures 
which are approved for implementation 
within this clinical trial, to protect patient 
safety, welfare and rights, and to 
ensure data integrity and the integrity of 
the clinical trial, as a result of COVID-
19 only. 
 


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11. 
REFERENCES 
Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 
1981;30(5):653-61. 
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Draft Guidance: Clinical Drug Interaction Studies - Study Design, Data Analysis, 
and Clinical Implications. October 2017 [32 screens]. Available from: 
https://www.fda.gov/files/drugs/published/Clinical-Drug-Interaction-Studies-
%E2%80%94-Study-Design--Data-Analysis--and-Clinical-Implications-Guidance-for-
Industry.pdf. 
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry, Investigators, and Institutional Review Boards. FDA 
Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 
Public Health Emergency. April 2020. Available from: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-
medical-products-during-covid-19-public-health-emergency. 
European Medicines Agency (EMA). Science Medicines Health, Committee for Human 
Medicinal Products. Points to Consider on Implications of Coronavirus (COVID-19) on 
methodological Aspects of Ongoing Clinical Trials. March 2020. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-
implications-coronavirus-disease-covid-19-methodological-aspects-ongoing-
clinical_en.pdf. 
European Medicines Agency (EMA). Science Medicines Health, Heads of Medicines 
Agencies. Guidance on the Management of Clinical Trials During the COVID-19 
(Coronavirus) Pandemic. April 2020. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 
Flurbiprofen prescribing information (Mylan Pharmaceuticals Inc.), June 2009. 
Garimella T, Tao X, Sims K, Chang YT, Rana J, Myers E, et al. Effects of a fixed-dose 
co-formulation of daclatasvir, asunaprevir, and beclabuvir on the pharmacokinetics of a 
cocktail of cytochrome p450 and drug transporter substrates in healthy subjects. 
Drugs R D. 2018;18(1):55-65. 
GlaxoSmithKline Document Number 2018N379610_01. GSK3640254 Investigator’s 
Brochure, Version 02. Effective Date: 24 Oct 2019. 
GlaxoSmithKline Document Number 2020N430256_00. A Double-Blind (Sponsor 
Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation 
Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3640254 in 
Healthy Participants, 09 Sept 2018. 


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Hasler WL. Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrison’s 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779-84. 
Lanoxin® (digoxin) prescribing information (GlaxoSmithKline), November 2011. 
Lin JH and Wong BK. Complexities of glucuronidation affecting in vitro in vivo 
extrapolation. Curr Drug Metab. 2002;3(6):623-46.  
Metoprolol tartrate prescribing information (Mylan Pharmaceuticals Inc.), March 2013.  
Midazolam hydrochloride syrup prescribing information (Roxane Laboratories, Inc), 
September 2012. 
Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID. Plasma and 
salivary pharmacokinetics of caffeine in man. Eur J Clin Pharmacol. 1981;21(1):45-52. 
Omeprazole delayed-release capsules prescribing information (Mylan Pharmaceuticals 
Inc), February 2015. 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164(7):1035-43.  
Pravachol® (pravastatin sodium) prescribing information (Bristol-Myers Squibb Co), 
July 2016. 
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal 
Disorders. Available from: 
http://www.theromefoundation.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
18 Nov 2019.  
Singulair® (montelukast sodium) prescribing information (Merck and Co, Inc), 
February 2019. 
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of 
Gastroenterology. 5th edition. 2009. Blackwell Publishing. 
Tangh-Liu DD, Williams RL, Riegelman S. Disposition of caffeine and its metabolites in 
man. J Pharmacol Exp Ther 1983;224(1):180-5.  
Tye CK, Wang Z, Dockens RC, Vakkalagadda B, Wang C, Zhang Y et al. Pre-absorption 
physicochemical compatibility assessment of 8-drug metabolic cocktail. Int J Pharm. 
2016;514(2):364–73. 
Vivarin® (caffeine) prescribing information (Meda Consumer Healthcare Inc), May 2014. 


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Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC et al. Drug-drug 
interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation 
for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 
2004;32(11):1201-8. 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
213052 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for the Effects of 
GSK3640254 on the Single-Dose Pharmacokinetics of 
Probe Substrates (Caffeine, Metoprolol, Montelukast, 
Flurbiprofen, Omeprazole, Midazolam, Digoxin, and 
Pravastatin) in Healthy Subjects 
Compound Number  : GSK3640254 
Effective Date  
: 19-JUL-2021 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 213052. 
• 
This RAP is intended to describe the full analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited. 
 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 4 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 4 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 4 
2.3. 
Study Design ................................................................................................ 6 
2.4. 
Statistical Hypotheses................................................................................... 6 
3. 
PLANNED ANALYSES ............................................................................................ 8 
3.1. 
Final Analyses .............................................................................................. 8 
4. 
ANALYSIS POPULATIONS ..................................................................................... 9 
4.1. 
Protocol Deviations ....................................................................................... 9 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 11 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 11 
5.2. 
Baseline Definitions .................................................................................... 11 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 12 
6. 
STUDY POPULATION ANALYSES ....................................................................... 13 
6.1. 
Overview of Planned Study Population Analyses ........................................ 13 
7. 
PHARMACOKINETIC ANALYSES ......................................................................... 14 
7.1. 
Primary Pharmacokinetic Analyses ............................................................. 14 
7.1.1. 
Endpoint / Variables ..................................................................... 14 
7.1.1.1. 
Drug Concentration Measures .................................... 14 
7.1.1.2. 
Derived Pharmacokinetic Parameters......................... 14 
7.1.2. 
Summary Measure ...................................................................... 14 
7.1.3. 
Population of Interest ................................................................... 15 
7.1.4. 
Statistical Analyses / Methods ..................................................... 15 
7.1.4.1. 
Statistical Methodology Specification .......................... 15 
7.2. 
Secondary Pharmacokinetic Analyses ........................................................ 16 
7.2.1. 
Endpoint / Variables ..................................................................... 16 
7.2.1.1. 
Drug Concentration Measures .................................... 16 
7.2.2. 
Summary Measure ...................................................................... 17 
7.2.3. 
Population of Interest ................................................................... 17 
7.2.4. 
Statistical Analyses / Methods ..................................................... 17 
9. 
SAFETY ANALYSES ............................................................................................. 21 
9.1. 
Adverse Events Analyses ........................................................................... 21 
9.2. 
Clinical Laboratory Analyses ....................................................................... 21 
9.3. 
Adverse Events of Special Interest ............................................................. 21 
9.4. 
Other Safety Analyses ................................................................................ 22 
10. REFERENCES ....................................................................................................... 24 


 
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11. APPENDICES ........................................................................................................ 25 
11.1. 
Appendix 1: Schedule of Activities .............................................................. 25 
11.1.1. 
Protocol Defined Schedule of Events ........................................... 25 
11.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 28 
11.3. 
Appendix 3: Data Display Standards & Handling Conventions .................... 30 
11.3.1. 
Reporting Process ....................................................................... 30 
11.3.2. 
Reporting Standards .................................................................... 30 
11.3.3. 
Reporting Standards for Pharmacokinetics .................................. 33 
11.4. 
Appendix 4: Derived and Transformed Data ............................................... 34 
11.4.1. 
General ........................................................................................ 34 
11.4.2. 
Study Population .......................................................................... 35 
11.4.3. 
Safety .......................................................................................... 35 
11.5. 
Appendix 5: Reporting Standards for Missing Data ..................................... 37 
11.5.1. 
Premature Withdrawals ................................................................ 37 
11.5.2. 
Handling of Missing Data ............................................................. 37 
11.5.2.1. Handling of Missing and Partial Dates ........................ 38 
11.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events .......................................... 39 
11.6.1. 
Laboratory Values ........................................................................ 39 
11.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 42 
11.7.1. 
ECG ............................................................................................. 42 
11.7.2. 
Vital Signs .................................................................................... 42 
11.8. 
Appendix 8: Abbreviations & Trade Marks .................................................. 43 
11.8.1. 
Abbreviations ............................................................................... 43 
11.8.2. 
Trademarks ................................................................................. 43 
11.9. 
Appendix 9: List of Data Displays ............................................................... 44 
11.9.1. 
Data Display Numbering .............................................................. 44 
11.9.2. 
Mock Example Shell Referencing ................................................ 44 
11.9.3. 
Deliverables ................................................................................. 44 
11.9.4. 
Study Population Tables .............................................................. 45 
11.9.5. 
Safety Tables ............................................................................... 46 
11.9.6. 
Safety Figures ............................................................................. 49 
11.9.7. 
Pharmacokinetic Tables ............................................................... 50 
11.9.11. ICH Listings ................................................................................. 61 
11.9.12. Non-ICH Listings .......................................................................... 63 
 


 
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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: 213052 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
This is an open-label, single-sequence, one-way drug interaction study to investigate the 
effect of GSK3640254 200 mg on the pharmacokinetics (PK) of a metabolic probe 
cocktail containing the substrate drugs caffeine 200 mg, metoprolol 100 mg, montelukast 
10 mg, flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg. 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The Pharmacodynamic Concentration analysis population and Pharmacodynamic 
Parameter analysis population were added for the purpose of presenting biomarker 
coproporphyrin-1 (CP-1) data. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To assess the effect of GSK3640254 
on the PK of caffeine, metoprolol, 
montelukast, flurbiprofen, omeprazole, 
midazolam, digoxin, and pravastatin 
under fed conditions in healthy 
participants 
• 
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for caffeine, 
metoprolol, montelukast, flurbiprofen, omeprazole, 
midazolam, digoxin, and pravastatin 
Secondary Objectives 
Secondary Endpoints 
• 
To assess the safety and tolerability of 
GSK3640254 alone and in 
combination with caffeine, metoprolol, 
montelukast, flurbiprofen, omeprazole, 
midazolam, digoxin, and pravastatin in 
healthy participants 
• 
Safety and tolerability parameters for adverse events 
(AEs) /serious adverse events (SAEs), observed and 
change from baseline clinical laboratory assessments, 
electrocardiograms (ECG), and vital sign measurements 
• 
To characterize the steady-state PK of 
GSK3640254 in the presence of 
caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, 
digoxin, and pravastatin in healthy 
participants 
• 
AUC(0-t), AUC(0-), Cmax, C, Tmax, and t1/2 for 
GSK3640254 
• 
To characterize the single-dose PK of 
the metabolites for the probe 
substrate drugs (α-hydroxymetoprolol, 
36-hydroxymontelukast, 
5-hydroxyomeprazole, 
1-hydroxymidazolam and pravastatin 
lactone) 
• 
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for 
metabolites, and metabolite to parent ratios for Cmax and 
AUC(0-) 


 
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AUC(0-) = area under the plasma concentration-time curve from time zero to the end of the dosing interval 
at steady state; AUC(0-) = area under the plasma concentration-time curve from time zero extrapolated to 
infinity; AUC(0-t) = area under the plasma concentration-time curve from time zero to time t; C = plasma 
concentration at the end of the dosing interval; Cmax = maximum observed concentration; PK = 
pharmacokinetics; Tmax = time of maximum observed concentration; t1/2 = apparent terminal phase half-
life. 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Figure 2-1 Study Design Schematic 
Probe substrate drugs: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 100 mg, 
omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg 
Design 
Features 
• 
A phase 1, open-label, single-sequence, one-way drug-drug interaction study. 
• 
The study will consist of a screening period and 3 sequential treatment 
regimens. 
o Screening Period: within 28 days before the first dose of study 
intervention 
o Treatment A: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 
mg, flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 
0.25 mg, and pravastatin 40 mg on Day 1 (Regimen 1) 
o Treatment B: GSK3650254 200 mg once daily on Days 11 to 20 
(Regimen 2) 
o Treatment C: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 
mg, flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 
0.25 mg, and pravastatin 40 mg co-administered with GSK3650254 
200 mg on Day 21 (Regimen 3) 
• 
Approximately 20 participants will be enrolled to ensure that 18 evaluable 
participants complete the study. 
Dosing 
• 
Treatment A: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg on Day 1  
• 
Treatment B: GSK3650254 200 mg once daily on Days 11 to 20 
• 
Treatment C: Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg co-administered with GSK3650254 200 mg on Day 21  
Time & 
Events 
• 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
• 
This is an open-label study. All eligible participants will receive the same treatment. 
Interim 
Analysis 
• 
No interim analysis is planned for this study 
2.4. 
Statistical Hypotheses 
There is no formal hypothesis that will be statistically tested in this study. 


 
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Administration of GSK3640254 under fed conditions may change the exposure to 
caffeine, metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, digoxin and 
pravastatin. 


 
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3. 
PLANNED ANALYSES 
3.1. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) have been declared by Data Management. 
 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who signed the informed consent form 
• 
Study Population 
Safety 
• 
All participants who received at least 1 dose of study 
medication. 
• 
This population will be used for all demographic, 
disposition (exclude screen failure), and safety listings, 
summaries, and figure 
• 
Study Population 
• 
Safety 
Pharmacokinetic 
Concentration 
• 
The PK Concentration Population will include all 
participants who undergo plasma PK sampling and 
have evaluable PK assay results. This population will 
be used for the PK concentration listings, summary 
tables, and plotting of concentration/time data. 
• 
PK Concentration 
Pharmacokinetic 
Parameter 
• 
The PK Parameter Population will include all 
participants who undergo plasma PK sampling and 
have evaluable PK parameters estimated. This 
population will be used for PK parameter listings, 
summary tables, and statistical analysis tables. 
• 
PK Parameter 
• 
PK statistical 
analysis 
Pharmacodynamic 
Concentration 
• 
The PD Concentration Population will include all 
participants who undergo plasma PD sampling and 
have evaluable PD assay results. This population will 
be used for the PD concentration listings, summary 
tables, and plotting of concentration/time data. 
• 
PD Concentration 
Pharmacodynamic 
Parameter 
• 
The PD Parameter Population will include all 
participants who undergo plasma PD sampling and 
have evaluable PD parameters estimated. This 
population will be used for PD parameter listings, 
summary tables, and statistical analysis tables. 
• 
PD Parameter 
• 
PD statistical 
analysis 
Refer to Appendix 9: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Study Deviation Tool and Rules. The “significant” protocol 
deviation in the Study Deviation Tool and Rules is equivalent to “important” protocol 
deviations. 
o Data will be reviewed prior to freezing the database to ensure all significant 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 


 
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A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the electronic 
case record form (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 
Data Displays for Reporting  
Description 
Code 
Order in TLF  
Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, 
digoxin 0.25 mg, and pravastatin 40 mg on Day 1 
Treatment A 
1 
GSK3650254 200 mg once daily on Days 11 to 20 
Treatment B 
2 
Caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, 
digoxin 0.25 mg, and pravastatin 40 mg co-administered with 
GSK3650254 200 mg on Day 21 
Treatment C 
3 
 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions), baseline for treatment A is 
defined as the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits, before the dose of Treatment A on Day 1; baseline for treatment B is 
defined as the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits, before the first dose on Day 11; baseline for treatment C is defined as 
the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits, before the dose of Treatment C on Day 21. If time is not collected, 
Day 1 or Day 11 or Day 21 assessments are assumed to be taken prior to the dose and 
used as baseline.  
Parameter 
 
Study Assessments Considered as 
Baseline 
Baseline Used in Data Display 
 
Check
-in 
(Day -
1) 
Day 1 
(Pre-
Dose) 
Day 
10 
Day 
11 
(Pre-
Dose) 
Day 
20 
Day 
21 
(Pre-
Dose) 
Treatment 
A 
Treatment 
B 
Treatment 
C 
Vital Sign 
X 
X 
X 
X 
X 
X 
Day 1 
(Pre-
Dose)[1] 
Day 11 
(Pre-
Dose)[1] 
Day 21 
(Pre-
Dose) )[1] 
12-Lead 
ECG 
X 
X 
X 
X 
X 
X 
Day 1 
(Pre-
Dose)[1] 
Day 11 
(Pre-
Dose)[1] 
Day 21 
(Pre-
Dose) )[1] 
Hematology 
X 
 
X 
 
X 
 
Check-in 
Day -1  
Day 10 
Day 20 
Clinical 
Chemistry 
X 
 
X 
 
X 
 
Check-in 
Day -1  
Day 10 
Day 20 


 
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Parameter 
 
Study Assessments Considered as 
Baseline 
Baseline Used in Data Display 
 
Check
-in 
(Day -
1) 
Day 1 
(Pre-
Dose) 
Day 
10 
Day 
11 
(Pre-
Dose) 
Day 
20 
Day 
21 
(Pre-
Dose) 
Treatment 
A 
Treatment 
B 
Treatment 
C 
Urinalysis 
X 
 
X 
 
X 
 
Check-in 
Day -1  
Day 10 
Day 20 
Biomarker 
CP-1 plasma 
concentratio
n 
 
X 
 
 
 
X 
Day 1 
(Pre-
Dose) 
 
Day 21 
(Pre-
Dose) 
[1] The average (for blood pressure and pulse) or the worst case (for interpretation) of the predose triplicate 
assessments will be used as the baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
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 
10.1 
Appendix 1: Schedule of Activities  
10.2 
Appendix 2: Study Phases and Treatment Emergent Adverse Events 
10.3 
Appendix 3: Data Display Standards & Handling Conventions 
10.4 
Appendix 4: Derived and Transformed Data 
10.5 
Appendix 5: Reporting Standards for Missing Data 
10.6 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
10.7 
Appendix 7: 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” or “Screened” population, 
unless otherwise specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations (including inclusion/exclusion criteria deviations), demographic and baseline 
characteristics, prior and concomitant medications, and exposure will be based on GSK 
Core Data Standards. Details of the planned displays are presented in Appendix 9: List of 
Data Displays. 


 
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7. 
PHARMACOKINETIC ANALYSES 
7.1. 
Primary Pharmacokinetic Analyses 
7.1.1. 
Endpoint / Variables 
7.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3  
Reporting Standards for Pharmacokinetics). Plasma concentrations of the probe substrate 
drugs (caffeine, metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, digoxin, 
and pravastatin) will be measured and reported. 
7.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or SAS (9.4 or higher), as applicable. All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacokinetic 
parameters listed will be determined from the plasma concentration-time data, as data 
permit. 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
AUC(0-t) 
Area under the plasma concentration-time curve from time zero to time t, to be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid. 
AUC(0-) 
Area under the plasma concentration-time curve from time zero extrapolated to infinity, to 
be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
Tmax 
Time of maximum observed concentration 
t1/2 
Apparent terminal phase half-life 
NOTES: 
• 
Additional parameters may be included as required. 
 
 
7.1.2. 
Summary Measure 
AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2 for caffeine, metoprolol, montelukast, 
flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin following a single dose of 
probe drugs (caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 
50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) on 
Day 1 in Treatment A (Regimen 1) and a single dose of probe drugs (caffeine 200 mg, 
metoprolol 100 mg, montelukast 10 mg, flurbiprofen 50 mg, omeprazole 40 mg, 
midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) coadministered with 
GSK3640254 200 mg on Day 21 in Treatment C (Regimen 3) following GSK3640254 
200 mg QD administration during days 11 through 20 of Treatment B (Regimen 2) in 
healthy subjects. 


 
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7.1.3. 
Population of Interest  
The primary PK analyses will be based on the PK concentration population for plasma 
PK concentrations and the PK parameter population for plasma PK parameters and 
statistical analysis. 
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Primary plasma PK parameters (AUC(0-t), AUC(0-), Cmax, Tmax, and t1/2) will be 
estimated for caffeine, metoprolol, montelukast, flurbiprofen, omeprazole, midazolam, 
digoxin, and pravastatin (Treatments A and C). Summary statistics (mean (arithmetic and 
geometric), 95% confidence interval (arithmetic and geometric), median, standard 
deviation (SD) for observed and ln-transformed data, minimum, maximum, and 
geometric coefficient of variation) for plasma PK parameter values will be summarized 
by treatment. 
7.1.4.1. 
Statistical Methodology Specification 
The following PK statistical analyses will only be performed if sufficient data are 
available (i.e., if participants have well defined plasma profiles). 
Endpoint / Variables 
• 
Plasma primary PK endpoints include AUC(0-t), AUC(0-), and Cmax for caffeine, metoprolol, 
montelukast, flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin (Treatments A and C), 
as data permit 
Model Specification 
• 
Analyses will be performed on the natural logarithms of AUC(0-t), AUC(0-), and Cmax using a 
linear mixed-effect models with treatment as a fixed effect and measurements within participant as 
repeated measures. 
• 
Effects will be estimated, and 90% confidence intervals (CIs) will be constructed for the following 
treatment comparison: 
Treatment C versus Treatment A  
• 
Point estimates and 90% CIs for treatment differences on the log scale derived from the model will 
be exponentiated to obtain estimates for geometric mean ratios and CIs on the original scale. 
Model Checking & Diagnostics 
• 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
• 
Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with 
geometric mean ratios for: 
Treatment C versus Treatment A  


 
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• 
The geometric mean ratios and associated 90% CIs will also be presented in a forest plot. 
7.2. 
Secondary Pharmacokinetic Analyses 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Drug Concentration Measures  
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3 
Reporting Standards for Pharmacokinetic). Plasma concentrations of GSK3640254 and 
the metabolites for the probe substrate drugs (α-hydroxymetoprolol, 
36-hydroxymontelukast, 5-hydroxyomeprazole, 1-hydroxymidazolam, and pravastatin 
lactone) will be measured and reported. 
7.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher). All calculations of non-compartmental parameters will be 
based on actual sampling times.  
Plasma PK parameters listed below will be determined from the total plasma 
concentration-time data, as data permit. 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data.  
Cτ 
Plasma concentration at the end of the dosing interval (GSK3640254 only) 
AUC(0-t) 
Area under the plasma concentration-time curve from time zero to time t, to be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid  
AUC(0-) 
Area under the plasma concentration-time curve from time zero extrapolated to infinity, to 
be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid (probe substrate metabolites only) 
AUC(0-τ) 
Area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
(GSK3640254 only) 
Tmax 
Time of maximum observed concentration 
t1/2 
Apparent terminal phase half-life 
Cmax m/p1 
Metabolite-to-parent ratio based on Cmax with correction for molecular weight. (probe 
substrate metabolites only) 
AUC m/p1 
Metabolite-to-parent ratio based on AUC(0-) with correction for molecular weight. If data 
for AUC(0-) is insufficient then AUC(0-t) may be used. (probe substrate metabolites only) 
NOTES: 
• 
Additional parameters may be included as required. 
1Molecular weights by analyte: metoprolol: 267.36, α-hydroxymetoprolol: 283.36, montelukast: 586.18, 
36-hydroxymontelukast: 602.18, omeprazole: 345.4, 5-hydroxyomeprazole: 361.42, midazolam: 325.78, 
1-hydroxymidazolam: 341.77, pravastatin: 424.53, and pravastatin lactone: 406.51. 
 
 


 
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7.2.2. 
Summary Measure 
AUC(0-t), AUC(0-), Cmax, Tmax, t1/2, Cmax m/p, and AUC m/p for the probe 
substrate metabolites α-hydroxymetoprolol, 36-hydroxymontelukast, 
5-hydroxyomeprazole, 1-hydroxymidazolam, and pravastatin lactone following a single 
dose of probe drugs (caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, 
flurbiprofen 50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and 
pravastatin 40 mg) on Day 1 in Treatment A (Regimen 1) and a single dose of probe 
drugs (caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 50 mg, 
omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) 
coadministered with GSK3640254 200 mg on Day 21 in Treatment C (Regimen 3) 
following GSK3640254 200 mg QD administration during days 11 through 20 of 
Treatment B (Regimen 2) in healthy subjects. GSK3640254 AUC(0-t), AUC(0-), Cmax, 
C, Tmax, and t1/2 at steady state following a dose of GSK3640254 200 mg on Day 21 
in Treatment C (Regimen 3). 
7.2.3. 
Population of Interest  
The secondary PK analyses will be based on the PK concentration population for plasma 
PK concentrations, and the PK parameter population for plasma and statistical analysis, 
unless otherwise specified. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.2.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate), and 
listed. 
Secondary plasma PK parameters (AUC(0-t), AUC(0-), Cmax, Tmax, t1/2, Cmax m/p, 
and AUC m/p) will be estimated for the probe substrate metabolites 
α-hydroxymetoprolol, 36-hydroxymontelukast, 5-hydroxyomeprazole, 
1-hydroxymidazolam, and pravastatin lactone (Treatments A and C) and secondary 
plasma PK parameters (AUC(0-t), AUC(0-), Cmax, C, Tmax, and t1/2) will be 
estimated for GSK3640254 (Treatment C). Summary statistics (mean (arithmetic and 
geometric), 95% confidence interval (arithmetic and geometric), median, standard 
deviation (SD) for observed and ln-transformed data, minimum, maximum, and 
geometric coefficient of variation) for secondary plasma PK parameters of GSK3640254 
and probe substrate metabolites will be summarized by treatment. 
Predose (trough) PK plasma concentrations for GSK3640254 (Days 17, 18, 19, and 20 
[Treatment B]; and Day 21 [Treatment C]) will be summarized using the PK 
Concentration Population and used to assess achievement of steady state.  


 
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7.2.4.1. 
Statistical Methodology Specification 
The following PK statistical analyses will only be performed if sufficient data are 
available (i.e., if participants have well defined plasma profiles). 
Endpoint / Variables 
• 
Plasma primary PK endpoints include AUC(0-t), AUC(0-), and Cmax for α-hydroxymetoprolol, 
36-hydroxymontelukast, 5-hydroxyomeprazole, 1-hydroxymidazolam, and pravastatin lactone 
(Treatments A and C), as data permit 
• 
For steady state analysis, predose (trough) plasma PK concentrations of GSK3640254. 
Model Specification 
• 
Analyses will be performed on the natural logarithms of AUC(0-t), AUC(0-), and Cmax using a 
linear mixed-effect models with treatment as a fixed effect and measurements within participant as 
repeated measures.  
• 
Effects will be estimated, and 90% confidence intervals (CIs) will be constructed for the following 
treatment comparison: 
Treatment C versus Treatment A  
• 
Point estimates and 90% CIs for treatment differences on the log scale derived from the model will 
be exponentiated to obtain estimates for geometric mean ratios and CIs on the original scale. 
• 
If data permit, log-transformed predose (trough) plasma PK concentrations of GSK3640254 will be 
analysed to determine whether steady state was achieved using the Helmert transformation 
approach. A mixed effect model (ANOVA) will be fitted with day as a fixed effect term and participant 
as a random effect term. The comparison will begin with Day 17 vs. the average of Day 18 through 
Day 21. If the p-value for Day 17 vs. the average of Day 18 through Day 21 is ≤0.05 (i.e. steady 
state not achieved at Day 17), then the comparison will continue with Day 18 vs. Day 19 through Day 
21. 
Model Checking & Diagnostics 
• 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
• 
Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with 
geometric mean ratios for: 
Treatment C versus Treatment A  
• 
For steady state analysis, the ratio of Geometric LS means and its 90% CI will be presented for the 
comparison(s). 


 
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8. 
PHARMACODYNAMIC/BIOMARKER ANALYSES 
8.1. 
Exploratory Pharmacodynamic/Biomarker Analyses 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Drug Concentration Measures 
Plasma concentrations of the biomarker CP-1 will be measured, and observed and 
baseline-adjusted CP-1 concentrations will be reported. For Treatment A, the Day 1 
predose assessment will serve as baseline. For Treatment C, the day 21 predose 
assessment will serve as baseline. 
8.1.1.2. 
Derived Pharmacodynamic Parameters 
Pharmacodynamic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher) or SAS (9.4 or higher), as applicable. All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacodynamic 
parameters listed will be determined from the baseline-adjusted plasma concentration-
time data, as data permit. 
Parameter 
Parameter Description 
Emax 
Maximum PD effect, determined directly from the PD concentration-time data. 
AUEC(0-24) 
Area under the plasma effect-time curve from time zero to time 24 hours postdose, to be 
calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
AUC(0-120) 
Area under the plasma effect-time curve from time zero extrapolated to 120 hours postdose, 
to be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
TEmax 
Time of maximum PD effect 
NOTES: 
• 
Additional parameters may be included as required. 
 
 
8.1.2. 
Summary Measure 
AUEC(0-24), AUEC(0-), Emax, and TEmax for CP-1 following a single dose of 
probe drugs (caffeine 200 mg, metoprolol 100 mg, montelukast 10 mg, flurbiprofen 
50 mg, omeprazole 40 mg, midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) on 
Day 1 in Treatment A (Regimen 1) and a single dose of probe drugs (caffeine 200 mg, 
metoprolol 100 mg, montelukast 10 mg, flurbiprofen 50 mg, omeprazole 40 mg, 
midazolam 5 mg, digoxin 0.25 mg, and pravastatin 40 mg) coadministered with 
GSK3640254 200 mg on Day 21 in Treatment C (Regimen 3) following GSK3640254 
200 mg QD administration during days 11 through 20 of Treatment B (Regimen 2) in 
healthy subjects. 


 
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8.1.3. 
Population of Interest  
The exploratory PD analyses will be based on the PD concentration population for 
plasma PD concentrations and the PD parameter population for plasma PD parameters 
and statistical analysis. 
8.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Exploratory plasma PD parameters (AUEC(0-24), AUEC(0-), Emax, and TEmax) 
will be estimated for CP-1 (Treatments A and C). Summary statistics (mean (arithmetic 
and geometric), 95% confidence interval (arithmetic and geometric), median, standard 
deviation (SD) for observed and ln-transformed data, minimum, maximum, and 
geometric coefficient of variation) for plasma PD parameter values will be summarized 
by treatment. 
8.1.4.1. 
Statistical Methodology Specification 
The following PD statistical analyses will only be performed if sufficient data are 
available (i.e., if participants have well defined plasma profiles). 
Endpoint / Variables 
• 
Plasma exploratory PD endpoints include AUEC(0-24), AUEC(0-120), and Emax for CP-1 
(Treatments A and C), as data permit 
Model Specification 
• 
Analyses will be performed on the natural logarithms of AUEC(0-24), AUEC(0-120), and Emax using 
a linear mixed-effect models with treatment as a fixed effect and measurements within participant as 
repeated measures. 
• 
Effects will be estimated, and 90% confidence intervals (CIs) will be constructed for the following 
treatment comparison: 
Treatment C versus Treatment A  
• 
Point estimates and 90% CIs for treatment differences on the log scale derived from the model will 
be exponentiated to obtain estimates for geometric mean ratios and CIs on the original scale. 
Model Checking & Diagnostics 
• 
Model assumptions will be applied, but appropriate adjustments may be made based on the data. 
Model Results Presentation 
• 
Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with 
geometric mean ratios for: 
Treatment C versus Treatment A  


 
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9. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population unless otherwise specified. 
9.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of AEs, SAEs, AEs of special interest, 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9: List of Data Displays. 
For studies with greater than one treatment period (e.g., crossover study), if AE onset is 
during one period and worsens during a later period, it would be counted in both periods. 
For the later period the onset date of AE with elevated grade would be the first dose date 
of the later treatment period. 
9.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, liver function tests, and pregnancy test will be based on GSK 
Core Data Standards and will be graded using the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017). 
The details of the planned displays are in Appendix 9: List of Data Displays. 
9.3. 
Adverse Events of Special Interest 
At the end of the study, QT prolongation, gastrointestinal intolerability/toxicity, 
psychiatric events, and nervous system disorders will be summarized by treatment. 
A listing will also be provided accordingly. 
QT prolongation AE of special interest will be defined as cardiac disorders system organ 
class (SOC) plus preferred terms (PTs) using the Medical Dictionary for Regulatory 
Activities (MedDRA) Standardized MedDRA Query (SMQ) “Torsade de pointes/QT 
Prolongation” (narrow and broad terms) plus seizure. 
Gastrointestinal intolerability/toxicity AEs of special interest will be defined within three 
narrow sub-SMQs [Gastrointestinal nonspecific symptoms and therapeutic procedures 
SMQ; Gastrointestinal nonspecific dysfunction SMQ; Gastrointestinal nonspecific 
inflammation (SMQ)] plus a selection of relevant broad PTs from the Gastrointestinal 
non-specific symptoms and therapeutic procedures SMQ.  
Psychiatric AEs of special interest will be defined within the following:  
• Sub-SMQ “Suicide/self-injury” (SMQ) from parent SMQ of “Depression and 
Suicide/Self Injury”. Only narrow terms from the sub-SMQ selected. 
• Sub-SMQ “Depression (excluding suicide and self-injury)” (SMQ) from parent SMQ 
of “Depression and Suicide/Self Injury”. Only narrow terms from the sub-SMQ 
selected. 
• All preferred terms from high level group term (HLGT) “Manic and Bipolar mood 
disorders and disturbances” under SOC “Psychiatric disorders”. 


 
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• Narrow terms from SMQ “Psychosis and psychotic disorders” selected. 
• All preferred terms from HLGT “Anxiety disorders and symptoms”, under SOC 
'Psychiatric disorders'. 
• All preferred terms from HLGT “Sleep Disorders and Disturbances” and HLGT 
“Sleep disturbances (incl subtypes)”. 
Nervous system disorders AEs of special interest will be defined within the following:  
• Four HLGTs under Nervous System Disorders SOC: “Headaches”; “Mental 
impairment disorders (excluding dementia)”; “Disturbance in consciousness” and 
“Seizures and seizure disorder” 
Skin and subcutaneous tissue disorder AEs of special interest will be defined with the 
following preferred terms:  
Dermatitis, Dermatitis allergic, Dermatitis atopic, Eczema, Eczema eyelids, Eczema 
nummular, Eyelid irritation, Skin irritation, Urticarial dermatitis, Eyelid pruritis, Pruritus, 
Pruritus allergic, Rash pruritic, Rash, Rash macular, Rash maculopapular, Rash 
morbilliform, Rash papular, Rash pruritic, Urticaria, Drug eruption and Rash pustular.  
9.4. 
 Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs, vital signs, liver 
events, and Columbia Suicide Severity Rating Scale (C-SSRS) will be based on GSK 
Core Data Standards, unless otherwise specified. A figure of mean change from baseline 
in QTcF interval along with the 2-sided 95% CI using Student’s t distribution will be 
presented by treatment and visit. The details of the planned displays are presented in 
Appendix 9: List of Data Displays. 
9.5. 
COVID 19 Related Analyses 
Based on GSK’s “Impact of Covid-19 on Assessment of Safety in Clinical Trials Points 
to Consider”, it is GSK’s recommendation that study teams should capture COVID-19 
cases based on the WHO criteria using the categories of: suspected, probable, and 
confirmed cases. COVID-19 eCRF pages are used in the study for data collection and 
analysis purposes. After a discussion with the study team, the following analyses will be 
included:  
• Number of subjects with suspected, probable or confirmed for COVID-19 
infection 
• Number of subjects who had a COVID-19 diagnosis test performed and the 
number of subjects with positive, negative, or indeterminate results 
• Incidence of COVID-19 as reported as an AE and SAE  
• Incidence of treatment discontinuation due to AE of COVID-19 infection 
• Severity, duration, and outcome of COVID-19 AEs 
If percentage of COVID-19 cases is >10% (> 5 subjects with an AE of COVID-19), a 
summary of COVID-19 symptoms for subjects with COVID-19 AE will be added. 


 
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Further display details are provided in Appendix 9: List of Data Displays. 


 
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10. 
REFERENCES 
ViiV Healthcare group of companies Document Number 2019N422949_00 (25Feb2020) 
Effects of GSK3640254 on the Single-Dose Pharmacokinetics of Probe Substrates 
(Caffeine, Metoprolol, Montelukast, Flurbiprofen, Omeprazole, Midazolam, Digoxin, and 
Pravastatin) in Healthy Subjects 
 


 
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11. 
APPENDICES 
11.1. 
Appendix 1: Schedule of Activities 
11.1.1. 
Protocol Defined Schedule of Events 
Screening Visit 
Procedure 
Screening (up to 28 days 
before Day 1) 
Outpatient visit 
X 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Full physical examination including height and weight1 
X 
Laboratory assessments (hematology, chemistry, urinalysis)  
X 
12-lead electrocardiogram 
X 
Vital sign measurements 
X 
Medication/drug/alcohol history 
X 
Past and current medical conditions 
X 
Columbia-Suicide Severity Rating Scale 
X 
Serum pregnancy test 
X 
Follicle-stimulating hormone (as needed, to confirm postmenopausal 
status) 
X 
Drug, alcohol, and cotinine screen 
X 
HIV, Hepatitis B and C screening 
X 
HIV = human immunodeficiency virus. 
1 
A full physical examination will include, at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal, and neurological systems. 


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Time and Events Table 
Procedure 
 
Regimen 1 
Treatment A (Day 1)  
Washout (Days 2-10) 
Regimen 2 
Treatment B 
Regimen 3 
Treatment C 
Notes 
 
Check-in 
Day –1 
Day 
1 
Day 
2-5 
Day 
6 
Days 
7-9 
Day 
10 
Days 
11-19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Admit to clinic 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Brief physical 
examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Includes, at a minimum, assessments of 
the skin, lungs, cardiovascular system, 
and abdomen (liver and spleen). 
Vital sign 
measurements 
X 
X 
D2 
 
 
X 
D11, 
D14, 
and 
D17 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse measured in 
triplicate at pre-dose on Days 1, 11, and 
21.  
Respiratory rate measured pre-dose 
and post-dose every 15 minutes for the 
first 2 hours and every 30 minutes for 
the subsequent 2 hours on Days 1 and 
21 (may be monitored longer if indicated 
by clinical condition). 
Pulse oximetry 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Continuous pulse oximetry measured 
pre-dose and through 4 hours after 
dosing on Days 1 and 21 (may be 
monitored longer if indicated by clinical 
condition).  
Twelve-lead ECG 
X 
X 
D2, 
D3, 
and D5 
 
 
X 
D11 
X 
X 
X 
X 
 
X 
 
ECGs on Days 1, 11, and 21, will be 
taken pre-dose, and at 2 and 4 hours 
post-dose. 
Pre-dose ECGs on Days 1, 11, and 21 
will be taken in triplicate. 
Drug, alcohol, and 
cotinine screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 2 for tests. 


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Procedure 
 
Regimen 1 
Treatment A (Day 1)  
Washout (Days 2-10) 
Regimen 2 
Treatment B 
Regimen 3 
Treatment C 
Notes 
 
Check-in 
Day –1 
Day 
1 
Day 
2-5 
Day 
6 
Days 
7-9 
Day 
10 
Days 
11-19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Laboratory 
assessments 
(hematology, 
chemistry, urinalysis) 
X 
 
D2 and 
D5 
 
 
X 
D15 
X 
 
X 
 
 
X 
 
See Appendix 2 for tests. 
Pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Columbia-Suicide 
Severity Rating Scale  
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Study intervention: 
probe substrate drugs 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
See Protocol Section 6.1 for study 
intervention details. 
Study intervention: 
GSK3640254 200 mg 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
See Protocol Section 6.1 for study 
intervention details. 
Probe substrate drug 
PK sampling 
 
Pre-dose and 0.25, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12, 16, 24, 48, 72, 96, 
and 120 hours post-
dose. 
 
 
 
 
Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12, 16, 24, 48, 72, 96, and 120 hours 
post-dose 
 
GSK3640254 PK 
sampling 
 
 
 
 
 
 
Pre-dose on Days 17, 18, 19, 20 and 21. 
Post Day 21 dose at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 
12, 24, 48, 72, 96, and 120 hours. 
 
AE review 
 
=========================================================================
→ 
 
SAE review 
==================================================================================
→ 
 
Concomitant 
medication review 
==================================================================================
→ 
 
 Abbreviations: AE = adverse event; D = day; ECG = electrocardiogram; PK = pharmacokinetic; SAE = serious adverse event. 


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11.2. 
Appendix 2: Study Phases and Treatment Emergent Adverse Events 
11.2.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to study treatment start date(/time) and stop 
date(/time). 
11.2.1.1. 
Study Phases for Lab, Electrocardiograms, and Vital Signs 
Assessments and events will be classified according to the time of occurrence relative to study treatment start date(/time) and stop 
date(/time). 
Study Phase 
Definition 
Pre-Treatment  
Date and Time ≤ Study Treatment Start Date and Time 
On-Treatment 
Study Treatment Start Date and Time <Date and Time ≤ Study Treatment Stop Date 
and Time + 5 days 
Post-Treatment  
Date and Time >Study Treatment Stop Date and Time + 5 days 
 
11.2.1.2. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before Day 1 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 


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11.2.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment Emergent 
• 
If AE onset date and time is on or after treatment start date and time & on or before treatment stop date and time + 5 days.  
• 
Study Treatment Start Date and Time ≤ AE Start Date and Time ≤ Study Treatment Stop Date and Time + 5 days. 
• 
If the AE onset date is completely missing, the AE is considered as treatment emergent. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for AEs. Use the rules in this table if the adverse event onset date is 
completely missing. 
 


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11.3. 
Appendix 3: Data Display Standards & Handling Conventions 
11.3.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software (9.4) will be used. 
Reporting Area 
HARP Server 
\\us1salx00259.corpnet2.com 
HARP Compound 
\gsk3640254\mid213052\final_01 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG Version 1.1).  
• 
For creation of ADaM datasets (ADC1/ADCM/ADAE), the same version of dictionary datasets will be implemented for conversion from SI to SDTM. 
Generation of RTF Files 
• 
RTF files will be generated for all reporting efforts described in the RAP. 
11.3.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include participant level listings in the main body of the GSK Clinical Study Report. All participant level listings should be located in the modular appendices as ICH or 
non-ICH listings. 
Formats 
• 
All data will be reported according to the actual treatment the participant received unless otherwise stated. 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be rounded to integer, unless otherwise specified.  
• 
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. 


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Planned and Actual Time 
• 
Reporting for tables, figures, and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses, and calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit days on the analyses and interpretation of the results will be assessed as 
appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
• 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be included in listings but omitted from figures (mean figures only for PK 
concentrations), summaries, and statistical analyses (excluding statistical analyses of PK parameters). 
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables except for determining the worst-case values. 
• 
Unscheduled visits will not be included in figures. 
• 
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. 
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 participant level listings in the main body of the GSK Clinical Study Report. All participant level listings should be located in the modular 
appendices as ICH or non-ICH listings. 
Formats 
• 
All data will be reported according to the actual treatment the participant received unless otherwise stated. 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be rounded to integer, unless otherwise specified.  


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• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• 
Reporting for tables, figures, and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
• 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be included in listings but omitted from figures (mean figures only 
for PK concentrations), summaries, and statistical analyses (excluding statistical analyses of PK parameters). 
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables except for determining the worst-case values. 
• 
Unscheduled visits will not be included in figures. 
• 
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. 
 
 
 


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11.3.3. 
Reporting Standards for Pharmacokinetics 
Pharmacokinetic Concentration Data 
Descriptive Summary Statistics, 
Graphical Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
For continuous data: 
• 
Not quantifiables (NQs) at the beginning of a participant profile (i.e. before the first incidence of a measurable 
concentration) are deemed to be zero as it is assumed that in this circumstance no drug is yet measurable in the blood. 
• 
For NQs at the end of the participant profile (i.e. after the last incidence of a measurable concentration); 
• 
for individual plots and PK analyses these are dropped (set to missing) as they do not provide any useful information 
(and can erroneously indicate that absolutely no drug is present) 
• 
for summary statistics, these are set to 0 (to avoid skewing of the summary statistics) 
• 
Individual NQs which fall between two measurable concentrations are set to missing (individual values of this nature are 
assumed to be an anomaly) 
If two or more NQ values occur in succession between measurable concentrations, the profile will be deemed to have 
terminated at the last measurable concentration prior to these NQs. For the purpose of individual participant plots, these NQs 
will be set to 0, and the subsequent measurable concentrations will be retained. For the derivation of pharmacokinetic 
parameters, these NQs and any subsequent measurable concentrations will be omitted (set to missing). 
Note: Concentration values will be imputed as per GUI_51487 for descriptive summary statistics/analysis and summarized 
graphical displays only. 
Pharmacokinetic Parameter Data 
Descriptive Summary Statistics, 
Graphical Displays and Listings 
N, n, arithmetic mean, 95% CI of arithmetic mean, geometric mean, 95% CI of geometric mean, SD, SD of logged data CV (%), 
and between-subject geometric coefficient of variation (CVb (%)) will be reported. 
CVb (%) = √ (exp(SD2) - 1) * 100 
(SD = SD of Ln-Transformed data) 
Parameters Not Being Ln-
Transformed 
Tmax, Cmax m/p, AUC m/p, λz, λz lower, λz upper, and λz no. of points. 
Parameters Not Being 
Summarized 
λz, λz lower, λz upper, and λz no. of points. 
Listings 
Include the first point, last point and number of points used in the determination of λz and Rsq_adjusted for listings. 
 


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11.4. 
Appendix 4: Derived and Transformed Data 
11.4.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if listed, all data will be presented. 
• 
The worst finding/interpretation associated with multiple measurements as the finding/interpretation for that time point. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety parameters will be counted in both the High and Low 
categories of “Any visit post-baseline” row of related summary tables. This will also be applicable to relevant Potential Clinical Importance summary tables. 
Study Day 
• 
Calculated as the number of days from Dose Date on Day 1: 
• 
Assessment Date = Missing  
  → Study Day = Missing  
• 
Assessment Date <Dose Date on Day 1  
  → Study Day = Assessment Date –Dose Date on Day 1 
• 
Assessment Date >= Dose Date on Day 1  
  → Study Day = Assessment Date – Dose Date on Day 1 + 1 
Period Day 
• 
Calculated as the number of days from First Dose Date for the respective period: 
• 
Assessment Date = Missing  
  → Period Day = Missing  
• 
Assessment Date <Dose Date on Day 1  
  → Period Day = Assessment Date – Dose Date on Day 1 
• 
First Dose Date on Day 1 <= Assessment Date <First Dose Date on Day 11  
  → Period Day = Assessment Date – Dose Date on Day 1 + 1 
• 
First Dose Date on Day 11 <=Assessment Date <= First Dose Date on Day 21 
  → Period Day = Assessment Date – First Dose Date on Day 11 + 1 
• 
Assessment Date >= First Dose Date on Day 21  
  → Period Day = Assessment Date – First Dose Date on Day 21 + 1 
 


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11.4.2. 
Study Population 
Age 
• 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as follows: 
o Any participant with a missing day will have this imputed as day ‘15’. 
o Any participant with a missing day and month will have this imputed as ‘30th June’. 
• 
Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)2] 
 
11.4.3. 
Safety 
Adverse Events 
AEs of Special Interest 
• QT prolongation 
• Gastrointestinal intolerability/toxicity 
• Psychiatric events 
• Nervous system disorders 
• Skin and subcutaneous tissue disorders 
 


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12-Lead Electrocardiograms 
QTcB Interval 
• 
QTcB interval in msec will be calculated using QT interval (msec) and RR interval (msec) as 
 
𝑄𝑇𝑐𝐵= 
𝑄𝑇
√𝑅𝑅
1000
 
where RR interval in msec is calculated using QT interval (msec) and QTcF interval (msec) as 
𝑅𝑅= ( 𝑄𝑇
𝑄𝑇𝑐𝐹)3 × 1000 
 


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11.5. 
Appendix 5: Reporting Standards for Missing Data 
11.5.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e., as specified in the protocol) was defined as the participant had completed all phases of the study 
including the final date on which data were or are expected to be collected.  
• 
Withdrawn participants will not 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.  
11.5.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. Unless all data for a specific visit are missing in 
which case the data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be documented along with the reason for exclusion in the 
clinical study report. 


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11.5.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
Adverse Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be recorded for AE start and end dates; that is, the day of the 
month may be missing. In such a case, the following conventions will be applied for calculating the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start date of study treatment; in this case the study treatment 
start date will be used and hence the event is considered On-treatment as per Appendix 2: Study Phases and Treatment Emergent 
Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop date of study treatment; in this case the study treatment 
stop date will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. Consequently, time to onset and duration of such 
events will be missing. 
Concomitant 
Medications 
o 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 
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. 
o The recorded partial date will be displayed in listings. 


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11.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events 
11.6.1. 
Laboratory Values 
Laboratory abnormalities will be graded according to the DAIDS grading table Version 2.1, July 2017. Laboratory results are converted to 
use SI units; only the numeric part of the criteria will be used. If for a laboratory parameter there are multiple grades sharing the same 
criteria, the maximum grade will be used. 
Hematology 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute Lymphocyte Count, Low 
(cell/mm3; cells/L) 
>5 years of age (not HIV infected) 
600 to <650 
0.600 × 109 to <0.650 × 109 
500 to <600 
0.500 × 109 to <0.600 × 109 
350 to <500 
0.350 × 109 to <0.500 × 109 
<350 
<0.350 × 109 
Absolute Neutrophil Count, Low 
(cells/mm3; cells/L) 
>7 days of age 
800 to 1,000 
0.800 × 109 to 1.000 × 109 
600 to 799 
0.600 × 109 to 0.799 × 109 
400 to 599 
0.400 × 109 to 0.599 × 109 
<400 
<0.400 × 109 
Hemoglobin, Low (g/dL; mmol/L) 
≥13 years of age (male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to <10.0 
5.57 to <6.19 
7.0 to <9.0 
4.34 to <5.57 
<7.0 
<4.34 
Hemoglobin, Low (g/dL; mmol/L) 
≥13 years of age (female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
Platelets, Decreased (cells/mm3; 
cells/L) 
100,000 to <125,000 
100.000 × 109 to <125.000 × 
109 
50,000 to <100,000 
50.000 × 109 to <100.000 × 109 
25,000 to <50,000 
25.000 × 109 to <50.000 × 
109 
<25,000 
<25.000 × 109 
White Blood Cell, Decreased 
(cells/mm3; cells/L) 
>7 days of age 
2,000 to 2,499 
2.000 × 109 to 2.499 × 109 
1,500 to 1,999 
1.500 × 109 to 1.999 × 109 
1,000 to 1,499 
1.000 × 109 to 1.499 × 109 
<1,000 
<1.000 × 109 
 


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Clinical Chemistry 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin, Low (g/dL; g/L) 
3.0 to <LLN 
30 to <LLN 
≥2.0 to <3.0 
≥20 to <30 
<2.0 
<20 
NA 
Alkaline Phosphatase, High 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 × ULN 
Alanine Aminotransferase, High 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 ULN 
Amylase (Total), High 
1.1 to <1.5 × ULN 
1.5 to <3.0 × ULN 
3.0 to <5.0 × ULN 
≥5.0 × ULN 
Aspartate Aminotransferase, High 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 × ULN 
Bicarbonate, Low (mEq/L; mmol/L) 
16.0 to <LLN 
16.0 to <LLN 
11.0 to <16.0 
11.0 to <16.0 
8.0 to <11.0 
8.0 to <110. 
<8.0 
<8.0 
Direct Bilirubin, High 
>28 days of age 
NA 
NA 
>ULN with other signs and 
symptoms of hepatotoxicity 
>ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
Total Bilirubin, High 
>28 days of age 
1.1 to <1.6 × ULN 
1.6 to <2.6 × ULN 
2.6 to <5.0 × ULN 
≥5.0 × ULN 
Calcium, High (mg/dL; mmol/L) 
≥7 days of age 
10.6 to <11.5 
2.65 to <2.88 
11.5 to <12.5 
2.88 to <3.13 
12.5 to <13.5 
3.13 to <3.38 
≥13.5 
≥3.38 
Calcium, Low (mg/dL; mmol/L) 
≥7 days of age 
7.8 to <8.4 
1.95 to <2.10 
7.0 to <7.8 
1.75 to <1.95 
6.1 to <7.0 
1.53 to <1.75 
<6.1 
<1.53 
Creatine Kinase, High 
3 to <6 × ULN 
6 to <10 × ULN 
10 to <20 × ULN 
≥20 × ULN 
Creatinine, High 
Choose the method that selects for 
the higher grade 
1.1 to 1.3 × ULN 
>1.3 to 1.8 × ULN OR Increase to 
1.3 to <1.5 × participant’s baseline 
>1.8 to <3.5 ULN OR 
Increase to 1.5 to <2.0 × 
participant’s baseline 
≥3.5 × ULN OR Increase 
of ≥2.0 × participant’s 
baseline 
Glucose Fasting, High (mg/dL; 
mmol/L) 
110 to 125 
6.11 to <6.95 
>125 to 250 
6.95 to <13.89 
>250 to 500 
13.89 to <27.75 
≥500 
≥27.75 
Glucose, Low (mg/dL; mmol/L) 
≥1 month of age 
55 to 64 
3.05 to <3.55 
40 to <55 
2.22 to <3.05 
30 to <40 
1.67 to <2.22 
<30 
<1.67 
Lipase, High 
1.1 to <1.5 × ULN 
1.5 to <3.0 × ULN 
3.0 to <5.0 × ULN 
≥5.0 × ULN 


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Cholesterol, Fasting, High (mg/dL; 
mmol/L) 
≥18 years of age 
200 to <240 
5.18 to <6.19 
240 to <300 
6.19 to <7.77 
≥300 
≥7.77 
NA 
Triglycerides, Fasting, High (mg/dL; 
mmol/L) 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to <1.000 
>5.7 to 11.4 
>1,000 
>11.4 
Phosphate, Low (mg/dL; mmol/L) 
>14 years of age 
2.0 to <LLN 
0.65 to <LLN 
1.4 to <2.0 
0.45 to <0.65 
1.0 to <1.4 
0.32 to <0.45 
<1.0 
<0.32 
Potassium, High (mEq/L; mmol/L) 
5.6 to <6.0 
5.6 to <6.0 
6.0 to <6.5 
6.0 to <6.5 
6.5 to <7.0 
6.5 to <7.0 
≥7.0 
≥7.0 
Potassium, Low (mEq/L; mmol/L) 
3.0 to <3.4 
3.0 to <3.4 
2.5 to <3.0 
2.5 to <3.0 
2.0 to <2.5 
2.0 to <2.5 
<2.0 
<2.0 
Sodium, High (mEq/L; mmol/L) 
146 to <150 
146 to <150 
150 to <154 
150 to <154 
154 to <160 
154 to <160 
≥160 
≥160 
Sodium, Low (mEq/L; mmol/L) 
130 to <135 
130 to <135 
125 to <130 
125 to <130 
121 to <125 
121 to <125 
≤ 120 
≤ 120 
Uric Acid, High (mEq/L; mmol/L) 
7.5 to <10.0 
0.45 to <0.59 
10.0 to <12.0 
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0 
≥0.89 
NA=not applicable; LLN = lower limit of normal; ULN=upper limit of normal. 
 
Urinalysis 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Glucose/Glycosuria (random 
collection tested by dipstick) 
Trace to 1+ or ≤ 250 mg 
2+ or >250 to ≤ 500 mg 
>2+ or >500 mg 
NA 
Protein/Proteinuria (random 
collection tested by dipstick) 
1+ 
2+ 
3+ or higher 
NA 
Red Blood Cells (RBCs)/Hematuria 
(not to be reported based on dipstick 
findings or on blood believed to be of 
menstrual origin) 
6 to <10 RBCs per high 
power field 
≥10 RBCs per high power field 
Gross, with or without clots 
OR with RBC casts OR 
intervention indicated 
Life-threatening 
consequences 
NA=not applicable 
 
 


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11.7. 
Appendix 7: Values of Potential Clinical Importance 
11.7.1. 
ECG 
ECG Parameter 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
<110 
>200 
Absolute QRS Interval 
msec 
<75 
>110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
 
 
11.7.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>140 
Diastolic Blood Pressure 
mmHg 
<45 
>90 
Heart Rate 
bpm 
<40 
>100 
 


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11.8. 
Appendix 8: Abbreviations & Trade Marks 
11.8.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
analysis data model 
AE 
adverse event 
ALT 
alanine aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC(0-) 
auc from time 0 to the end of the dosing interval at steady state 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
Cmax 
maximum observed concentration 
C-SSRS 
columbia suicide severity rating scale 
C 
plasma concentration at the end of the dosing interval 
CVb  
coefficient of variation (between)  
DBF 
database freeze 
DBR 
database release 
DP 
decimal places 
ECG 
electrocardiogram 
eCRF 
electronic case record form 
GSK 
GlaxoSmithKline 
HIV 
human immunodeficiency virus 
ICH 
international conference on harmonization 
IDSL 
integrated data standards library 
LLN 
lower limit of normal 
NQ 
not quantifiable 
PK 
pharmacokinetic 
QD 
once daily 
RAP 
reporting & analysis plan 
SAC 
statistical analysis complete 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
Tmax 
time of maximum observed concentration 
ULN 
upper limit of normal 
11.8.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group of 
Companies 
 
Trademarks not owned by the GlaxoSmithKline 
Group of Companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 
 
 


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11.9. 
Appendix 9: List of Data Displays 
11.9.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.9 
 
Safety 
2.1 to 2.29 
2.1 to 2.1 
Pharmacokinetic 
3.1 to 3.37 
3.1 to 3.39 
Pharmacodynamic 
4.1 to 4.4 
4.1 to 4.4 
Section 
Listings 
ICH Listings 
1 to 34 
Non-ICH Listings 
35 to 54 
 
11.9.2. 
Mock Example Shell Referencing 
Non-IDSL specifications will be referenced as indicated and if required example 
mock-up displays provided in the Table/Listing/Figure Shells. 
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 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
11.9.3. 
Deliverables 
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 


 
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11.9.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
Enrolled 
NS1 
Summary of Number of Subjects Enrolled by Country and Site ID 
 
SAC 
1.2. 
Screened 
SP1 
Summary of Study Population 
 
SAC 
1.3. 
Safety 
ES1 
Summary of Subject Disposition for the Subject Conclusion Record 
 
SAC 
1.4. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failures 
 
SAC 
Protocol Deviation 
1.5. 
Safety 
DV1 
Summary of Important Protocol Deviations 
 
SAC 
Demographic and Baseline Characteristics 
1.6. 
Safety 
DM1 
Summary of Demographic Characteristics 
 
SAC 
1.7. 
Safety 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
1.8. 
Safety  
EX1 
Summary of Exposure to Study Treatment 
 
SAC 
 
 
 
 


 
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11.9.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
2.1. 
Safety 
AE1CP 
Summary of Adverse Events by System Organ Class and Preferred 
Term 
 
SAC 
2.2. 
Safety 
AE1CP 
Summary of Drug-Related Adverse Events by System Organ Class 
and Preferred Term 
 
SAC 
2.3. 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall Frequency 
 
SAC 
2.4. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by System 
Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
2.5. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
2.6. 
Safety 
AE5A 
Summary of Adverse Events by System Organ Class and Preferred 
Term and Maximum Intensity 
 
SAC 
2.7. 
Safety 
AE1CP 
Summary of Adverse Events of Special Interest 
 
SAC 
Laboratory: Chemistry  
2.8. 
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline 
 
SAC 
2.9. 
Safety 
LB1 
Summary of Clinical Chemistry Values 
 
SAC 
2.10. 
Safety 
LB16 
Summary of Clinical Chemistry Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline 
 
SAC 
Laboratory: Hematology 
2.11. 
Safety 
LB1 
Summary of Hematology Changes from Baseline 
 
SAC 
2.12. 
Safety 
LB1 
Summary of Hematology Values 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.13. 
Safety 
LB16 
Summary of Hematology Results by Maximum Grade Increase Post-
Baseline Relative to Baseline 
 
SAC 
Laboratory: Urinalysis 
2.14. 
Safety 
UR3 
Summary of Urinalysis Dipstick Results 
 
SAC 
2.15. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline 
 
SAC 
2.16. 
Safety 
LB1 
Summary of Urine Concentration Values 
 
SAC 
2.17. 
Safety 
LB16 
Summary of Urinalysis by Maximum Grade Increase Post-Baseline 
Relative to Baseline 
 
SAC 
ECG 
2.18. 
Safety 
SAFE_T1 
Summary of ECG Findings  
 
SAC 
2.19. 
Safety 
EG2 
Summary of ECG Changes from Baseline 
 
SAC 
2.20. 
Safety 
EG2 
Summary of ECG Values 
 
SAC 
2.21. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to Baseline 
by Category 
 
SAC 
2.22. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline Relative 
to Baseline by Category 
 
SAC 
Vital Signs 
2.23. 
Safety 
VS1 
Summary of Vital Sign Changes from Baseline 
 
SAC 
2.24. 
Safety 
VS1 
Summary of Vital Sign Values 
 
SAC 
C-SSRS 
2.25. 
Safety 
CSSRS4 
Listing of C-SSRS Suicidal Ideation and Behavior Data 
Only include participants who have 
suicidal ideation or behavior 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Liver Event 
2.26. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
 
SAC 
2.27. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
 
SAC 
COVID-19 Related AE 
2.28. 
Safety 
PAN1 
Summary of COVID-19 Assessment 
 
SAC 
2.29 
Safety 
SAFE_T2 
Summary of COVID-19 Adverse Event Summary 
 
SAC 
2.30 
Safety 
PAN11 
Summary of COVID-19 Symptoms for Subjects with Adverse Events 
Conditional Display 
SAC 


 
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11.9.6. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
ECG 
2.1.  
Safety 
EG9 
Mean (95% CI) Change from Baseline in QTcF Interval by Timepoint 
and Treatment 
 
SAC 
 


 
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11.9.7. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data 
3.1. 
PK 
Concentration 
PKCT1 
Summary of Caffeine Plasma Pharmacokinetic Concentration-Time 
Data (units) by Treatment 
 
SAC 
3.2. 
PK 
Concentration 
PKCT1 
Summary of Metoprolol and Alpha-hydroxymetoprolol Plasma 
Pharmacokinetic Concentration-Time Data (units) by Treatment 
 
SAC 
3.3. 
PK 
Concentration 
PKCT1 
Summary of Montelukast and 36-Hydroxymontelukast Plasma 
Pharmacokinetic Concentration-Time Data (units) by Treatment 
 
SAC 
3.4. 
PK 
Concentration 
PKCT1 
Summary of Flurbiprofen Plasma Pharmacokinetic Concentration-
Time Data (units) by Treatment 
 
SAC 
3.5. 
PK 
Concentration 
PKCT1 
Summary of Omeprazole and 5-Hydroxyomeprazole Plasma 
Pharmacokinetic Concentration-Time Data (units) by Treatment 
 
SAC 
3.6. 
PK 
Concentration 
PKCT1 
Summary of Midazolam and 1-Hydroxymidazolam Plasma 
Pharmacokinetic Concentration-Time Data (units) by Treatment 
 
SAC 
3.7. 
PK 
Concentration 
PKCT1 
Summary of Digoxin Plasma Pharmacokinetic Concentration-Time 
Data (units) by Treatment 
 
SAC 
3.8. 
PK 
Concentration 
PKCT1 
Summary of Pravastatin Acid and Pravastatin Lactone Plasma 
Pharmacokinetic Concentration-Time Data (units) by Treatment 
 
SAC 
3.9. 
PK 
Concentration 
PKCT1 
Summary of GSK3640254 Plasma Pharmacokinetic Concentration-
Time Data (units) 
 
SAC 
3.10. 
PK 
Concentration 
PKCT1 
Summary of Predose (Trough) GSK3640254 Plasma Concentration 
Data (ng/mL) by Treatment 
 
SAC 
PK Derived Parameters 
3.11. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Caffeine Plasma Pharmacokinetic 
Parameters (Non-Transformed) Based on Actual Time by Treatment 
Parameters with units  
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.12. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Metoprolol and Alpha-
hydroxymetoprolol Plasma Pharmacokinetic Parameters (Non-
Transformed) Based on Actual Time by Treatment 
Parameters with units  
SAC 
3.13. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Montelukast and 36-
Hydroxymontelukast Plasma Pharmacokinetic Parameters (Non-
Transformed) Based on Actual Time by Treatment 
Parameters with units  
SAC 
3.14. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Flurbiprofen Plasma Pharmacokinetic 
Parameters (Non-Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.15. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Omeprazole and 5-
Hydroxyomeprazole Plasma Pharmacokinetic Parameters (Non-
Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.16. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Midazolam and 1-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters (Non-Transformed) Based on 
Actual Time by Treatment 
Parameters with units 
SAC 
3.17. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Digoxin Plasma Pharmacokinetic 
Parameters (Non-Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.18. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Pravastatin Acid and Pravastatin 
Lactone Plasma Pharmacokinetic Parameters (Non-Transformed) 
Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.19. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based on Actual 
Time 
Parameters with units 
SAC 
3.20. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Caffeine Plasma Pharmacokinetic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.21. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Metoprolol and Alpha-
hydroxymetoprolol Plasma Pharmacokinetic Parameters (Ln-
Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.22. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Montelukast and 36-
Hydroxymontelukast Plasma Pharmacokinetic Parameters (Ln-
Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.23. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Flurbiprofen Plasma Pharmacokinetic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.24. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Omeprazole and 5-
Hydroxyomeprazole Plasma Pharmacokinetic Parameters (Ln-
Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.25. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Midazolam and 1-Hydroxymidazolam 
Plasma Pharmacokinetic Parameters (Ln-Transformed) Based on 
Actual Time by Treatment 
Parameters with units 
SAC 
3.26. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Digoxin Plasma Pharmacokinetic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment 
Parameters with units 
SAC 
3.27. 
PK Parameter 
PKPT4 
Summary Statistics of Derived Pravastatin Acid and Pravastatin 
Lactone Plasma Pharmacokinetic Parameters (Ln-Transformed) 
Based on Actual Time by Treatment  
Parameters with units 
SAC 
3.28. 
PK Parameter 
PKPT4 
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on Actual 
Time 
Parameters with units 
SAC 
PK Analysis 
3.29. 
PK Parameter 
PKPT3 
Statistical Analysis of Caffeine Plasma Pharmacokinetic Parameters 
  
SAC 
3.30. 
PK Parameter 
PKPT3 
Statistical Analysis of Metoprolol and Alpha-hydroxymetoprolol 
Plasma Pharmacokinetic Parameters 
  
SAC 
3.31. 
PK Parameter 
PKPT3 
Statistical Analysis of Montelukast and 36-Hydroxymontelukast 
Plasma Pharmacokinetic Parameters 
  
SAC 
3.32. 
PK Parameter 
PKPT3 
Statistical Analysis of Flurbiprofen Plasma Pharmacokinetic 
Parameters 
  
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.33. 
PK Parameter 
PKPT3 
Statistical Analysis of Omeprazole and 5-Hydroxyomeprazole Plasma 
Pharmacokinetic Parameters 
  
SAC 
3.34. 
PK Parameter 
PKPT3 
Statistical Analysis of Midazolam and 1-Hydroxymidazolam Plasma 
Pharmacokinetic Parameters 
  
SAC 
3.35. 
PK Parameter 
PKPT3 
Statistical Analysis of Digoxin Plasma Pharmacokinetic Parameters 
  
SAC 
3.36. 
PK Parameter 
PKPT3 
Statistical Analysis of Pravastatin Acid and Pravastatin Lactone 
Plasma Pharmacokinetic Parameters 
  
SAC 
3.37. 
PK Parameter 
PKPT3 
Statistical Analysis of Predose (Trough) GSK3640254 Plasma 
Concentration Data (unit) 
 
SAC 


 
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11.9.8. 
Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PD Concentration Data 
4.1 
PD 
Concentration 
PKCT1 
Summary of CP-1 Baseline-adjusted Plasma Pharmacodynamic 
Concentration-Time Data (units) by Treatment 
 
SAC 
PD Derived Parameters 
4.2 
PD Parameter 
PKPT4 
Summary Statistics of Derived CP-1 Plasma Pharmacodynamic 
Parameters (Non-Transformed) Based on Actual Time by Treatment 
Parameters with units  
SAC 
4.3 
PD Parameter 
PKPT4 
Summary Statistics of Derived CP-1 Plasma Pharmacodynamic 
Parameters (Ln-Transformed) Based on Actual Time by Treatment 
Parameters with units  
SAC 
PD Analysis 
4.4 
PD Parameter 
PKPT3 
Statistical Analysis of CP-1 Plasma Pharmacodynamic Parameters 
  
SAC 


 
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11.9.9. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
3.1. 
PK 
Concentration 
PKCF1P 
Individual Caffeine Plasma Concentration-Time Plots by Participant 
(Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.2. 
PK 
Concentration 
PKCF2 
Individual Metoprolol and Alpha-hydroxymetoprolol Plasma 
Concentration-Time Plots by Participant (Linear and 
Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
3.3. 
PK 
Concentration 
PKCF2 
Individual Montelukast and 36-Hydroxymontelukast Plasma 
Concentration-Time Plots by Participant (Linear and 
Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.4. 
PK 
Concentration 
PKCF2 
Individual Flurbiprofen Plasma Concentration-Time Plots by 
Participant (Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.5. 
PK 
Concentration 
PKCF2 
Individual Omeprazole and 5-Hydroxyomeprazole Plasma 
Concentration-Time Plots by Participant (Linear and 
Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.6. 
PK 
Concentration 
PKCF2 
Individual Midazolam and 1-Hydroxymidazolam Plasma 
Concentration-Time Plots by Participant (Linear and 
Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.7. 
PK 
Concentration 
PKCF2 
Individual Digoxin Plasma Concentration-Time Plots by Participant 
(Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.8. 
PK 
Concentration 
PKCF2 
Individual Pravastatin Acid and Pravastatin Lactone Plasma 
Concentration-Time Plots by Participant (Linear and 
Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.9. 
PK 
Concentration 
PKCF2 
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant (Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.10. 
PK 
Concentration 
PKCF2 
Individual Caffeine Plasma Concentration-Time Plots by Treatment 
(Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.11. 
PK 
Concentration 
PKCF1P 
Individual Metoprolol and Alpha-hydroxymetoprolol Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.12. 
PK 
Concentration 
PKCF1P 
Individual Montelukast and 36-Hydroxymontelukast Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.13. 
PK 
Concentration 
PKCF1P 
Individual Flurbiprofen Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.14. 
PK 
Concentration 
PKCF1P 
Individual Omeprazole and 5-Hydroxyomeprazole Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.15. 
PK 
Concentration 
PKCF1P 
Individual Midazolam and 1-Hydroxymidazolam Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.16. 
PK 
Concentration 
PKCF1P 
Individual Digoxin Plasma Concentration-Time Plots by Treatment 
(Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.17. 
PK 
Concentration 
PKCF1P 
Individual Pravastatin Acid and Pravastatin Lactone Plasma 
Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
3.18. 
PK 
Concentration 
PKCF1P 
Individual GSK3640254 Plasma Concentration-Time Plots 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
Mean / Median Concentration Plots 
3.19. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Caffeine Plasma Concentration-Time 
Plots by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.20. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Metoprolol and Alpha-
hydroxymetoprolol Plasma Concentration-Time Plots by Treatment 
(Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.21. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Montelukast and 36-
Hydroxymontelukast Plasma Concentration-Time Plots by Treatment 
(Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.22. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Flurbiprofen Plasma Concentration-
Time Plots by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.23. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Omeprazole and 5-Hydroxyomeprazole 
Plasma Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.24. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Midazolam and 1-Hydroxymidazolam 
Plasma Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.25. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Digoxin Plasma Concentration-Time 
Plots by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.26. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Pravastatin Acid and Pravastatin 
Lactone Plasma Concentration-Time Plots by Treatment (Linear and 
Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.27. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) GSK3640254 Plasma Concentration-
Time Plots by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.28. 
PK 
Concentration 
PKCF1P 
Mean (± Standard Deviation) Predose (Trough) GSK3640254 
Plasma Concentration-Time Plots  (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.29. 
PK 
Concentration 
PKCF3 
Median (Range) Caffeine Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.30. 
PK 
Concentration 
PKCF3 
Median (Range) Metoprolol and Alpha-hydroxymetoprolol Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.31. 
PK 
Concentration 
PKCF3 
Median (Range) Montelukast and 36-Hydroxymontelukast Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.32. 
PK 
Concentration 
PKCF3 
Median (Range) Flurbiprofen Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.33. 
PK 
Concentration 
PKCF3 
Median (Range) Omeprazole and 5-Hydroxyomeprazole Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.34. 
PK 
Concentration 
PKCF3 
Median (Range) Midazolam and 1-Hydroxymidazolam Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
3.35. 
PK 
Concentration 
PKCF3 
Median (Range) Digoxin Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.36. 
PK 
Concentration 
PKCF3 
Median (Range) Pravastatin Acid and Pravastatin Lactone Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 


 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.37. 
PK 
Concentration 
PKCF3 
Median (Range) GSK3640254 Plasma Concentration-Time Plots  
(Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
3.38. 
PK 
Concentration 
PKCF1P 
Median (Range) Predose (Trough) GSK3640254 Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic) 
Treatments Overlaid 
SAC 
Statistical Figures 
3.39. 
PK Parameter 
Not available 
Geometric Mean Treatment Ratio (C/A) and 90% Confidence 
Interval of Pharmacokinetic Parameters for Probe Substrate 
Drugs 
GMR and 90% CI 
SAC 
 
 


 
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11.9.10. 
Pharmacodynamic Figures 
Pharmacodynamic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Individual Concentration Plots 
4.1 
PD 
Concentration 
PKCF1P 
Individual CP-1 Plasma Concentration-Time Plots by Participant 
(Linear and Semi-Logarithmic) 
Paginate by Participant 
Dashed line represents the LLQ 
Treatments Overlaid 
SAC 
4.2 
PD 
Concentration 
PKCF2 
Individual CP-1 Plasma Concentration-Time Plots by Treatment 
(Linear and Semi-Logarithmic) 
Paginate by Treatment 
Dashed line represents the LLQ 
Individual Overlaid 
SAC 
Mean / Median Concentration Plots 
4.3 
PD 
Concentration 
PKCF1P 
Mean (± Standard Deviation) CP-1 Plasma Concentration-Time Plots 
by Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
4.4 
PD 
Concentration 
PKCF3 
Median (Range) CP-1 Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic) 
Treatments Overlaid 
SAC 
 


 
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11.9.11. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1. 
Safety 
ES3 
Listing of Reasons for Study Withdrawal 
 
SAC 
2. 
Safety 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
 
SAC 
3. 
Screened 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
Protocol Deviations 
4. 
Safety 
DV2 
Listing of Important Protocol Deviations 
 
SAC 
5. 
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Populations Analyzed 
6. 
Safety 
SP3A 
Listing of Subjects Excluded from Any Population 
 
SAC 
Demographic and Baseline Characteristics 
7. 
Safety 
DM2 
Listing of Demographic Characteristics 
 
SAC 
8. 
Safety 
DM9 
Listing of Race 
 
SAC 
Prior and Concomitant Medications 
9. 
Safety 
CM5 
Listing of Concomitant Medications  
Based on GSK Drug Dictionary 
SAC 
Exposure and Treatment Compliance 
10. 
Safety 
EX4 
Listing of Exposure Data 
 
SAC 
11. 
Safety 
POP_L1 
Listing of Meal Data 
 
SAC 
Adverse Events 
12. 
Safety 
AE2 
Listing of Relationship Between System Organ Class and Verbatim 
Text 
 
SAC 
13. 
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
14. 
Safety 
AE9CP 
Listing of All Adverse Events 
 
SAC 


 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
15. 
Safety 
AE9CP 
Listing of Adverse Events of Special Interest 
 
SAC 
Serious and Other Significant Adverse Events 
16. 
Safety 
AE9CP 
Listing of Study Drug Related Adverse Events 
 
SAC 
17. 
Safety 
AE9CP 
Listing of Serious Adverse Events (Fatal & Non-Fatal) 
 
SAC 
18. 
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC 
19. 
Safety 
AE9CP 
Listing of Adverse Events Leading to Withdrawal from Study 
 
SAC 
Hepatobiliary (Liver) 
20. 
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping Events 
 
SAC 
21. 
Safety 
SU2 
Listing of Substance Use for Subjects with Liver Stopping Events 
 
SAC 
All Laboratory 
22. 
Safety 
LB5A 
Listing of Clinical Chemistry with any Toxicities  
 
SAC 
23. 
Safety 
LB5A 
Listing of All Clinical Chemistry Data for Subjects with any Toxicities  
 
SAC 
24. 
Safety 
LB5A 
Listing of Hematology with any Toxicities  
 
SAC 
25. 
Safety 
LB5A 
Listing of All Hematology Data for Subjects with any Toxicities  
 
SAC 
26. 
Safety 
LB5A 
Listing of Urinalysis with any Toxicities  
 
SAC 
27. 
Safety 
LB5A 
Listing of All Urinalysis Data for Subjects with any Toxicities  
 
SAC 
ECG 
28. 
Safety 
EG6 
Listing of All ECG Findings 
 
SAC 
29. 
Safety 
EG6 
Listing of All Abnormal ECG Findings 
 
SAC 
30. 
Safety 
EG4 
Listing of All ECG Values 
 
SAC 
Vital Signs 
31. 
Safety 
VS5 
Listing of All Vital Signs of Potential Clinical Importance 
 
SAC 
32. 
Safety 
VS5 
Listing of All Vital Signs for Subjects with any Value of Potential 
Clinical Importance 
 
SAC 


 
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11.9.12. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetics 
33. 
PK 
Concentration 
PKCL1P 
Listing of Caffeine Plasma Concentration-Time Data by Treatment 
 
SAC 
34. 
PK 
Concentration 
PKCL1P 
Listing of Metoprolol and Alpha-hydroxymetoprolol Plasma 
Concentration-Time Data by Treatment 
 
SAC 
35. 
PK 
Concentration 
PKCL1P 
Listing of Montelukast and 36-Hydroxymontelukast Plasma 
Concentration-Time Data by Treatment 
 
SAC 
36. 
PK 
Concentration 
PKCL1P 
Listing of Flurbiprofen Plasma Concentration-Time Data by Treatment 
 
SAC 
37. 
PK Parameter 
PKPL1P 
Listing of Omeprazole and 5-Hydroxyomeprazole Plasma 
Concentration-Time Data by Treatment 
 
SAC 
38. 
PK Parameter 
PKPL1P 
Listing of Midazolam and 1-Hydroxymidazolam Plasma 
Concentration-Time Data by Treatment 
 
SAC 
39. 
PK Parameter 
PKPL1P 
Listing of Digoxin Plasma Concentration-Time Data by Treatment 
 
SAC 
40. 
PK Parameter 
PKPL1P 
Listing of Pravastatin Acid and Pravastatin Lactone Plasma 
Concentration-Time Data by Treatment 
 
SAC 
41. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Concentration-Time Data by 
Treatment 
 
SAC 
42. 
PK Parameter 
PKPL1P 
Listing of Caffeine Plasma Pharmacokinetic Parameters Based on 
Actual Time by Treatment 
 
SAC 
43. 
PK Parameter 
PKPL1P 
Listing of Metoprolol and Alpha-hydroxymetoprolol Plasma 
Pharmacokinetic Parameters Based on Actual Time by Treatment 
 
SAC 
44. 
PK Parameter 
PKPL1P 
Listing of Montelukast and 36-Hydroxymontelukast Plasma 
Pharmacokinetic Parameters Based on Actual Time by Treatment 
 
SAC 


 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
45. 
PK Parameter 
PKPL1P 
Listing of Flurbiprofen Plasma Pharmacokinetic Parameters Based on 
Actual Time by Treatment 
 
SAC 
46. 
PK Parameter 
PKPL1P 
Listing of Omeprazole and 5-Hydroxyomeprazole Plasma 
Pharmacokinetic Parameters Based on Actual Time by Treatment 
 
SAC 
47. 
PK Parameter 
PKPL1P 
Listing of Midazolam and 1-Hydroxymidazolam Plasma 
Pharmacokinetic Parameters Based on Actual Time by Treatment 
 
SAC 
48. 
PK Parameter 
PKPL1P 
Listing of Digoxin Plasma Pharmacokinetic Parameters Based on 
Actual Time by Treatment 
 
SAC 
49. 
PK Parameter 
PKPL1P 
Listing of Pravastatin Acid and Pravastatin Lactone Plasma 
Pharmacokinetic Parameters Based on Actual Time by Treatment 
 
SAC 
50. 
PK Parameter 
PKPL1P 
Listing of GSK3640254 Plasma Pharmacokinetic Parameters Based 
on Actual Time by Treatment 
 
SAC 
Pharmacodynamic 
51. 
PD 
Concentration 
PKCL1P 
Listing of CP-1 Plasma Concentration-Time Data by Treatment 
 
SAC 
52. 
PD Parameter 
PKPL1P 
Listing of CP-1 Plasma Pharmacodynamic Parameters Based on 
Actual Time by Treatment 
 
SAC 
COVID-19 Related AE 
53. 
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom Assessment 
 
SAC 
54. 
Safety 
AE9CP 
Listing of Adverse Events of COVID-19 
 
SAC