Clinical trial NCT04604795
Conditions: Celiac Disease Coeliac Disease
Keywords: Celiac disease Itraconazole Grape fruit juice GSK3915393 Healthy Participants Pharmacokinetics First time into human
Sponsor: GlaxoSmithKline
Start date: 2020-11-04; Completion date: 2021-06-29
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a 3-part first time into human study (FTIH) study for GSK3915393. Parts A and B of the study will evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat oral doses of GSK3915393 in healthy adult participants. Part C will evaluate the impact of co-administration of GSK3915393 with grapefruit juice and itraconazole on the PK of GSK3915393.

Detailed description:

Arms: arm 1: In Part A, participants will receive dose levels (DLs) 1, 3, 4, IV microdose of GSK3915393, and placebo in a pre-determined sequence (Sequence A). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data. arm 2: In Part A, participants will receive dose levels 1, 2, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence B).

There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data. arm 3: In Part A, participants will receive dose levels 1, 2, 3, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence C).

There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data. arm 4: In Part A, participants will receive dose levels 2, 3, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence D).

There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data. arm 5: Participants will receive GSK3915393 dose level X twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A. arm 6: Participants will receive placebo matching GSK3915393 dose level X during Part B of the study. arm 7: Participants will receive GSK3915393 dose level Y twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B. arm 8: Participants will receive placebo matching GSK3915393 dose level Y twice daily during Part B of the study arm 9: Participants will receive GSK3915393 dose level Z twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B. arm 10: Participants will receive placebo matching GSK3915393 dose level Z twice daily during Part B of the study. arm 11: Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and itraconazole (ITZ) in period 2. Participants will then receive oral GSK3915393 plus water in period 3, oral GSK3915393 plus grape fruit juice (GFJ) in period 4 and oral GSK3915393 plus ITZ in period 5. arm 12: Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and ITZ in period 2. Participants will then receive oral GSK3915393 plus GFJ in period 3, oral GSK3915393 plus water in period 4 and oral GSK3915393 plus ITZ in period 5.
Interventions: intervention 1: GSK3915393 Capsules intervention 2: GSK3915393 Solution for Infusion intervention 3: Placebo capsules intervention 4: Itraconazole intervention 5: Water intervention 6: Grape fruit juice
Intervention descriptions: intervention 1: GSK3915393 capsules will be given orally. intervention 2: GSK3915393 solution for infusion will be administered intravenously. intervention 3: Placebo matching GSK3915393 capsules will be given orally. intervention 4: Participants will be administered with GSK3915393 along with ITZ orally intervention 5: Participants will be administered with GSK3915393 along with water orally intervention 6: Participants will be administered with GSK3915393 along with GFJ orally

Protocol documents:
Prot_000.pdf: 
TMF-11859187 
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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A Randomized, Placebo Controlled, Double Blind, Single and Repeat 
Dose Escalation Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of 
GSK3915393 in Healthy Participants and open label assessment of coadministration of 
GSK3915393 with grapefruit juice and itraconazole on the pharmacokinetics of 
GSK3915393 
Protocol Number: 213585/ Amendment 02 
Compound Number 
or Name: 
GSK3915393 
Brief Title: A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics 
of GSK3915393 in Healthy Participants and to evaluate the interaction between 
GSK3915393 and grapefruit juice and itraconazole  
Study Phase: Phase 1  
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual. 
Regulatory Agency Identifying Number(s) (EudraCT):  2020-003213-36 
Approval Date: 25 FEB 2021 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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SPONSOR SIGNATORY: 
Protocol Title: A Randomized, Placebo Controlled, Double Blind, Single and Repeat 
Dose Escalation Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of 
GSK3915393 in Healthy Participants and open label assessment of coadministration of 
GSK3915393 with grapefruit juice and itraconazole on the pharmacokinetics of 
GSK3915393 
Protocol Number: 213585/ Amendment 02 
Compound Number 
or Name: 
GSK3915393 
 
 
 
 
Geo Derimanov  
Discovery Medicine Physician Director 
GlaxoSmithKline 
 
 
Date 
The signed page is a separate document. 
 
 
Medical Monitor Name and Contact Information [will be provided separately OR can 
be found in the Study Reference Manual] 
 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 2 
25-FEB-2021 
TMF-11859187 
Amendment 1 
30-SEP-2020 
2020N440921_01 
Original Protocol 
05-AUG-2020 
2020N440921_00 
 
Amendment 2  
Overall Rationale for the Amendment: 
This amendment is to change Part C of the study from a Gluten Challenge in Celiac 
patients to a CYP3A4 interaction investigation in healthy participants.  Recent in-vitro 
studies have shown that GSK3915393 is a substrate for both intestinal (gut) and hepatic 
CYP3A4. The CYP3A4 interaction investigation will enable the impact of moderate 
CYP3A4 inhibitors and CYP3A4 inducers that may be included in future clinical trials to 
be modelled.  Since expression of intestinal CYP3A4 is altered in patients with Celiac 
Disease (CeD), it is important to understand the predicted pharmacological activity of 
GSK3915393 in patients. Therefore, this amendment will also determine the impact of 
intestinal CYP3A4 on the predicted exposure of GSK3915393 in the lamina propria (the 
site of TG2 activity in CeD).  
Owing to the rapid progress of the COVID-19 vaccination programme in the UK, a risk 
assessment for the concomitant use of a COVID-19 vaccine for subjects in the study has 
been conducted. There are no contraindications to vaccinating a participant while they are 
participating in the study as no interaction is expected between COVID-19 vaccinations 
and GSK3915393.  To avoid the risk of side effects from vaccination being captured in 
the study safety assessment, participants will not be eligible for the study if they have 
received a COVID-19 vaccination within 1 week of admission or readmission to the 
clinical unit or are demonstrating signs and symptoms following earlier vaccination. 
In addition, the risk management plan at the clinical unit has been updated. Local 
procedure no longer requires screening COVID-19 tests for studies. Therefore Covid-19 
test at screening has been removed from the protocol for all remaining study parts and 
participants must be negative at admission to the unit and are tested again on discharge.   
 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Protocol Title 
and Brief Title  
1.1 Synopsis  
1.2. Schema 
1.3.3. Part C 
SoA 
2.1. Study 
Rationale 
2.3.1. Risk 
Assessment. 
2.3.2. Benefit 
Assessment  
2.3.3. Overall 
Benefit:Risk 
Conclusion. 
3. Objectives 
and Endpoints 
4.1. Overall 
Design. 
4.1.1. Number 
of Participants 
4.1.2. Study 
Intervention 
Groups and 
Duration. 
4.2. Scientific 
Rationale for 
Study Design  
4.2.1 Participant 
input into 
Design. 
All sections have been 
updated to amend Part C of 
the study from a Gluten 
Challenge in Celiac patients 
to a CYP3A4 interaction 
investigation in healthy 
participants.  
Sponsor decision to remove the 
gluten challenge arm from the 
study.  
In-vitro data indicates that 
GSK3915393 is primarily 
metabolised by CYP3A4 in both 
hepatic and intestinal microsomes.  
A new cohort is added to the study 
to define the extent of metabolism 
by CYP3A4 in humans by studying 
the effect of grapefruit juice and 
itraconazole (ITZ) on the 
pharmacokinetics of GSK3915393 
in healthy volunteers. 
 


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Section # and 
Name 
Description of Change 
Brief Rationale 
4.3.4. Top 
Dose Selection 
for Part A 
4.3.7. Dose 
Selection for 
Part B. 
4.3.9 Dose 
Selection for 
Part C 
5. Study 
Population. 
6.1. Study 
Intervention(s) 
Administered 
6.3. Measures to 
Minimize Bias: 
Randomisation 
and Blinding. 
6.5. Dose 
Modification  
7.1.5. COVID-
19 
Discontinuation 
8.4.4. 
Itraconazole  
and Hydroxy 
Itraconazole PK 
Plasma 
collection. 
8.6. 
PD/Biomarkers 
9. Statistical 
Considerations 
10.6 Appendix 
6: Abbreviations 
and Trademarks. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2.1. Exclusion 
criteria. 
COVID-19 vaccination 
exclusion criteria has been 
added. 
 
To avoid the risk of side effects 
from vaccination being captured in 
the study safety assessment, 
participants will not be eligible for 
the study if they have received a 
COVID-19 vaccination within 1 
week of admission or readmission 
to the clinical unit or are 
demonstrating signs and symptoms 
following earlier vaccination.  
1.3.2. Part B 
SoA 
5.1.1. Inclusion 
Criteria  
COVID-19 test at screening 
has been removed from the 
protocol for all remaining 
study parts.  
 
The risk management plan at the 
clinical unit has been updated. 
Local procedure no longer requires 
screening COVID-19 tests for 
studies. Participants must be 
negative at admission.   
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) ........................................................................ 19 
1.3.1. 
Part A: Single Dose Administration in Healthy Participants .......... 20 
1.3.2. 
Part B: Repeat Dose Administration in Healthy 
Participants .................................................................................. 24 
1.3.3. 
Part C: CYP3A4 Victim Interaction. .............................................. 30 
2. 
INTRODUCTION .................................................................................................... 38 
2.1. 
Study Rationale .......................................................................................... 38 
2.2. 
Background ................................................................................................ 38 
2.3. 
Benefit/Risk Assessment ............................................................................ 40 
2.3.1. 
Risk Assessment ......................................................................... 40 
2.3.2. 
Benefit Assessment ..................................................................... 45 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 45 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 45 
4. 
STUDY DESIGN .................................................................................................... 48 
4.1. 
Overall Design ............................................................................................ 48 
4.1.1. 
Number of Participants ................................................................ 49 
4.1.2. 
Study Intervention Groups and Duration ...................................... 49 
4.2. 
Scientific Rationale for Study Design .......................................................... 52 
4.2.1. 
Participant Input into Design. ....................................................... 54 
4.3. 
Justification for Dose .................................................................................. 54 
4.3.1. 
Predicted Human Pharmacokinetics ............................................ 54 
4.3.2. 
Anticipated Pharmacological Dose Range of GSK3915393 ......... 54 
4.3.3. 
Starting Dose Selection for Part A ............................................... 55 
4.3.4. 
Top Dose Selection for Part A ...................................................... 56 
4.3.5. 
IV Microdose in Part A ................................................................. 56 
4.3.6. 
Safety Margins for Proposed Doses for Part A ............................. 57 
4.3.7. 
Dose Selection for Part B ............................................................. 57 
4.3.8. 
Dose Escalation in Parts A and B ................................................ 58 
4.3.9. 
Dose Selection for Part C ............................................................ 58 
4.4. 
End of Study Definition ............................................................................... 59 
5. 
STUDY POPULATION ........................................................................................... 59 
5.1. 
Inclusion Criteria ......................................................................................... 59 
5.1.1. 
Inclusion Criteria .......................................................................... 59 
5.2. 
Exclusion Criteria ........................................................................................ 61 
5.2.1. 
Exclusion Criteria ......................................................................... 61 
5.3. 
Lifestyle Considerations .............................................................................. 63 
5.3.1. 
Meals and Dietary Restrictions .................................................... 63 
5.3.1.1. 
Part A ......................................................................... 63 
5.3.1.2. 
Part B ......................................................................... 63 
5.3.1.3. 
Part C ......................................................................... 64 


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5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 64 
5.3.3. 
Activity ......................................................................................... 65 
5.4. 
Screen Failures........................................................................................... 65 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 65 
6.1. 
Study Intervention(s) Administered ............................................................. 65 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 67 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 68 
6.4. 
Study Intervention Compliance ................................................................... 69 
6.5. 
Dose Modification ....................................................................................... 69 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 70 
6.7. 
Treatment of Overdose ............................................................................... 70 
6.8. 
Concomitant Therapy.................................................................................. 71 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 71 
7.1. 
Discontinuation of Study Intervention .......................................................... 71 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 72 
7.1.2. 
QTc Stopping Criteria .................................................................. 73 
7.1.3. 
Vital signs Stopping Criteria ......................................................... 73 
7.1.4. 
Rechallenge ................................................................................. 73 
7.1.5. 
COVID-19 Discontinuation ........................................................... 73 
7.2. 
Study Stopping Criteria. .............................................................................. 74 
7.2.1. 
Safety Stopping Criteria ............................................................... 74 
7.2.2. 
Pharmacokinetic Stopping Criteria ............................................... 74 
7.3. 
Participant Discontinuation/Withdrawal from the Study ............................... 75 
7.4. 
Lost to Follow Up ........................................................................................ 75 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 76 
8.1. 
Efficacy Assessments ................................................................................. 76 
8.2. 
Safety Assessments ................................................................................... 76 
8.2.1. 
Physical Examinations ................................................................. 76 
8.2.2. 
Vital Signs .................................................................................... 77 
8.2.3. 
Electrocardiograms ...................................................................... 77 
8.2.3.1. 
Cardiodynamic assessment (ECGs extracted 
from Holter recordings) ............................................... 77 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................... 78 
8.2.5. 
COVID-19 testing ......................................................................... 78 
8.2.6. 
Pregnancy Testing ....................................................................... 79 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 79 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 79 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 80 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 80 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 80 
8.3.5. 
Pregnancy ................................................................................... 80 
8.3.6. 
Cardiovascular and Death Events ................................................ 81 
8.4. 
Pharmacokinetics ....................................................................................... 81 
8.4.1. 
GSK3915393 PK plasma collection. ............................................ 81 
8.4.2. 
Metabolite plasma collection. ....................................................... 82 
8.4.3. 
Urine Metabolite collection ........................................................... 82 


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8.4.4. 
Itraconazole and Hydroxy Itraconazole PK plasma 
collection...................................................................................... 82 
8.4.5. 
EnteroTracker: Bile Sample Collection ......................................... 82 
8.4.6. 
Plasma Sample for CYP3A4 Enzyme Activity .............................. 83 
8.5. 
Pharmacogenomics .................................................................................... 83 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 83 
9.1. 
Statistical Hypotheses................................................................................. 83 
9.2. 
Sample Size Determination ........................................................................ 83 
9.3. 
Analysis Sets .............................................................................................. 85 
9.4. 
Statistical Analyses ..................................................................................... 85 
9.4.1. 
Primary Endpoint(s) ..................................................................... 85 
9.4.2. 
Secondary Endpoint(s) ................................................................ 85 
9.4.3. 
Exploratory Endpoint(s) ............................................................... 88 
9.4.3.1. 
Modelling  Initiatives ................................................... 88 
9.4.3.2. 
Cardiodynamic ECG Evaluation ................................. 88 
9.5. 
Interim Analysis .......................................................................................... 88 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 90 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 90 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 90 
10.1.2. 
Financial Disclosure ..................................................................... 90 
10.1.3. 
Informed Consent Process .......................................................... 91 
10.1.4. 
Data Protection ............................................................................ 91 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 92 
10.1.6. 
Data Quality Assurance ............................................................... 92 
10.1.7. 
Source Documents ...................................................................... 93 
10.1.8. 
Study and Site Start and Closure ................................................. 93 
10.1.9. 
Publication Policy ......................................................................... 94 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 95 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 97 
10.3.1. 
Definition of AE ............................................................................ 97 
10.3.2. 
Definition of SAE .......................................................................... 98 
10.3.3. 
Definition of Cardiovascular Events ............................................. 99 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 99 
10.3.5. 
Reporting of SAE to GSK ........................................................... 101 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 103 
10.4.1. 
Definitions: ................................................................................. 103 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 105 
10.6. 
Appendix 6: Abbreviations and Trademarks .............................................. 107 
10.7. 
Appendix 7: COVID-19 Appendix .............................................................. 110 
10.7.1. 
Overall Rationale for this Appendix ............................................ 110 
10.7.2. 
Study Procedures During COVID-19 Pandemic ......................... 110 
10.7.3. 
Protocol Defined Procedures/Visits: ........................................... 110 
10.7.4. 
Data Management/Monitoring: ................................................... 111 
10.8. 
Appendix 8: Protocol Amendment History ................................................. 112 
11. REFERENCES ..................................................................................................... 114 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Placebo Controlled, Double Blind, Single and Repeat 
Dose Escalation Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of 
GSK3915393 in Healthy Participants and open label assessment of coadministration of 
GSK3915393 with grapefruit juice and itraconazole on the pharmacokinetics of 
GSK3915393 
Brief Title: A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics 
of GSK3915393 in Healthy Participants and to evaluate the interaction between 
GSK3915393 and grapefruit juice and itraconazole 
Rationale: 
Celiac Disease (CeD) is a common T cell-mediated disorder triggered by dietary gluten 
with a worldwide prevalence estimated at one percent.   
The only treatment currently available for CeD is strict adherence to a gluten-free diet 
(GFD), which improves mucosal villous atrophy and reduces symptoms in most patients.  
However, gluten cross-contamination has been demonstrated in the majority of patients 
adhering to a GFD as determined from gliadin immunogenic peptides in urine and feces.  
A significant number of patients continue to experience symptoms on a GFD and have 
incomplete mucosal healing.  
The enzyme transglutaminase 2 (TG2) is responsible for the generation of deaminated 
gluten peptides (dGP), the immunodominant antigen that triggers the inflammatory 
cascade in gastrointestinal tissue which drives mucosal injury.  By reducing the 
generation of dGP, treatment with a TG2 inhibitor should decrease the sensitivity of 
patients to gluten thereby reducing persistent mucosal damage and symptoms on a GFD 
and ensuring that inadvertent exposure to gluten will not invoke inflammation or 
symptoms. 
GSK3915393 is being developed as an orally administered inhibitor of TG2 for the 
treatment of patients with CeD.  This study is the first time into human study (FTIH) for 
GSK3915393.  Parts A and B of the study will evaluate the safety, tolerability and 
pharmacokinetics (PK) of single ascending and repeat oral doses of GSK3915393 in 
healthy adult participants.  In addition, during Part A, the PK following a single 
intravenous (IV) microdose of GSK3915393 will be evaluated and during Part B, the 
impact of food on the PK of GSK3915393 will be assessed. Part C will evaluate the 
impact of co-administration of GSK3915393 with grapefruit juice and itraconazole on the 
PK of GSK3915393.  
 
The results of this study are intended to identify well tolerated dose(s) of GSK3915393 to 
be used in further studies.  The victim drug interaction potential of GSK3915393 with the 
CYP3A4 inhibitors, grapefruit juice and itraconazole, will be evaluated. In addition, the 
results will also inform the anticipated pharmacological effect by enabling prediction of 


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the concentration of GSK3915393 at the target site of action in patients with Celiac 
Disease. 
 
 
 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Part A Dose Escalation Single Dose  
• To evaluate the safety and tolerability 
of single escalating oral doses of 
GSK3915393 administered in the fed 
state in healthy adult participants 
Part B Dose Escalation Repeat Dose 
• To evaluate the safety and tolerability 
of repeat escalating oral doses of 
GSK3915393 twice daily (BID) 
administered in the fed and fasted 
state in healthy adult participants  
 
Part C CYP3A4 Victim Interaction  
• To characterize the PK profile of IV 
GSK3915393 administered alone and 
when co-administered with 
itraconazole in healthy adult 
participants 
• To characterize the PK profile of oral 
GSK3915393 administered alone and 
when co-administered with grapefruit 
juice or with itraconazole in healthy 
adult participants 
 
Part A and B  
 
• Occurrence of serious adverse events 
(SAEs), adverse events (AEs) and 
treatment related AEs 
• Occurrence of clinically significant 
changes in physical examination, vital 
signs, laboratory parameters, and 12-
lead electrocardiogram (ECG) 
findings. 
 
 
 
Part C 
• Cmax, Tmax, AUC(0-t), (AUC(0-∞)) 
and (t1/2) as appropriate 
Secondary 
Part A Dose Escalation Single Dose  
• To characterize the PK profile of 
single oral doses of GSK3915393 in 
healthy adult participants 
• To characterize the PK profile of a 
single intravenous  dose of 
Part A 
• Maximum observed plasma drug 
concentration (Cmax), time to 
maximum observed plasma drug 
concentration (tmax), area under the 
plasma drug concentration versus time 
curve from time zero to last 
quantifiable concentration (AUC(0-t)), 


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Objectives 
Endpoints 
GSK3915393 in healthy adult 
participants 
• To evaluate the safety and tolerability 
of single microdose doses of 
GSK3915393 in healthy adult 
participants 
 
 
 
 
 
 
 
 
 
 
 
 
Part B Dose Escalation Repeat Dose 
• To characterize the PK profile of 
single doses and repeat oral doses of 
GSK3915393 in healthy adult 
participants 
• To assess the impact of food on the 
PK of GSK3915393 in healthy adult 
participants 
• To evaluate time to steady-state 
 
Part C CYP3A4 Victim Interaction 
• To evaluate the safety and tolerability 
of a single oral dose of GSK3915393 
when administered with grapefruit 
juice or with itraconazole in healthy 
adult participants 
• To evaluate the safety and tolerability 
of single intravenous dose of 
GSK3915393 when administered with 
AUC from time zero to infinity 
(AUC(0-∞)), and apparent terminal 
half-life (t1/2) as appropriate.   
• Clearance (CL) and volume of 
distribution (Vd) following IV 
administration and absolute 
bioavailability (F) of oral 
administration 
• Fraction of drug escaping hepatic 
metabolism (FH) and product of 
fraction of drug absorbed (FA) and 
fraction of drug escaping gut 
metabolism (FG) i.e., (FA*FG).  
• Clinical safety and tolerability data 
including adverse events (AEs) and 
serious adverse events (SAEs), 
clinically significant changes in 
laboratory values, vital signs and 12 
lead electrocardiogram (ECG) 
readings and physical examinations 
 
Part B 
• Cmax, Tmax, AUC(0-t), and AUC 
over the dosing interval AUC(0-) 
• Cmax, Tmax and AUC(0-) following 
1st dose of day 
• Pre-dose concentrations on Days 2, 3, 
5, 7 and 14 
 
 
Part C 
• Occurrence of serious adverse events 
(SAEs), adverse events (AEs) and 
treatment related AEs 
• Occurrence of clinically significant 
changes in physical examination, vital 
signs, laboratory parameters, and 12-
lead electrocardiogram (ECG) 
findings. 
• FA FG and FH 


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Objectives 
Endpoints 
itraconazole in healthy adult 
participants 
• To investigate absorption 
characteristics and first pass clearance 
of GSK3915393 
 
 
Overall Design: 
This FTIH study will be a randomized, , single centre trial in three parts. Parts A and B 
are double blind, placebo controlled and Part C is open label.   
1. Part A is a crossover design, single-dose (SD), dose escalation study in one 
cohort of healthy participants.  Participants will receive single ascending doses of 
GSK3915393 or matching placebo as an oral dose in periods 1, 2, 4 and 5 and as a 
single IV microdose dose of GSK3915393 in period 3.  The initial dosing for all 
periods in which the dose level has been escalated will be staggered so that 2 
participants will be dosed as sentinel participants, one with study drug and one 
with placebo.  After approximately 24 hours, and provided the investigator 
considers the safety and tolerability of the sentinels to be acceptable, the 
remainder of the participants scheduled for the period may be dosed. Sentinel 
dosing will not be required in period 3 for the open label IV microdose. 
2. Part B is a parallel group, 14-day, repeat oral dose, dose escalation study in 3 
cohorts of healthy participants.  Participants will receive GSK3915393 or 
matching placebo BID in each of the sequential cohorts.  The initial dosing for all 
periods in which the dose level has been escalated will be staggered so that 2 
participants will be dosed as sentinel participants, one with study drug and one 
with placebo.  After at least 4 days, provided the investigator considers the safety 
and tolerability of the sentinels to be acceptable, the remainder of the participants 
scheduled for the period may be dosed. 
3. Part C will be 5 SD periods in healthy adult participants.  In period 1 all 
participants will receive an IV microdose of GSK3915393.  In period 2, all 
participants will receive an IV microdose of GSK3915393 following prior dosing 
with itraconazole.   In periods 3 and 4, participants will receive oral GSK3915393 
with or without grapefruit juice in a randomized crossover design.  In period 5, all 
participants will receive oral GSK3915393 following prior dosing with 
itraconazole.   
Brief Summary: The purpose of this study is to assess the safety, tolerability and 
pharmacokinetics of escalating single and repeat doses of GSK3915393 compared to 
placebo in healthy participants and to determine the victim drug interaction potential of 
GSK3915393 with CYP3A4 inhibitors. 
 


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Number of Participants: 
A sufficient number of participants will be screened to ensure a minimum of 60 
participants are eligible to be randomised. Part A will have 12 randomized participants, 
part B will have 36 randomized participants and part C will have 12 randomized 
participants. Up to 12 additional participants in part A or part B may be enrolled to allow 
for evaluation of additional dose levels, up to a maximum 72 randomised participants, 
excluding replacements.   
Intervention Groups and Duration: 
Part A 
Participants in Part A will participate in 5 dosing periods and will receive 1 oral placebo 
dose and 4 active doses; 3 as an oral GSK3915393 dose and 1 as a single GSK3915393 
IV microdose dose in period 3.   
In each dosing period in which the dose level has been escalated and with the exception 
of period 3 where participants will be receiving the IV microdose, safety data from 
approximately the first 24 hours of sentinel dosing will be reviewed by the Principal 
Investigator (PI) prior to commencing dosing of the remainder of the cohort. The starting 
dose is 15 mg. The decision to proceed to the next dose level will be made by the Dose 
Escalation Committee based on safety, tolerability and available PK data (at a minimum 
data up to 24h post dose sample).  The IV dose will be 100 µg.   
Participants in Part A will be enrolled in the study for at least 14 weeks (up to 28 days 
screening, 5 in house dose assessment periods of up to 5 days each, 1 washout period 
between each dose of at least 7 days and up to 14 day follow up period).  
Part B 
Part B will investigate 3 repeat dose levels in 3 separate cohorts of participants who are 
not enrolled in part A of the study. Participants will be randomized to receive either 
GSK3915393 or placebo in each cohort.  The starting dose for part B will be selected 
after review of safety, tolerability and PK data from at least two oral dose levels in part A 
(IV dosing is not required to make the part B dose decision) and it will be selected such 
that the predicted maximum daily exposure does not exceed a daily exposure that has 
been well tolerated in part A. Safety data from at least the first 4 days of sentinel dosing 
will be reviewed by the PI prior to dosing the remainder of the cohort. Since the half-life 
of GSK3915393 is predicted to be <2h, PK steady state is expected to be achieved on day 
1. The 4 day time frame was selected to provide sufficient duration of dosing to assess 
safety data, however this duration may be increased based on emerging PK data. 
It is planned that participants will be dosed twice daily (approximately 10h and 14h 
dosing intervals).   
Preliminary safety and tolerability from 14 days of dosing and PK data from 7 days of 
dosing (up to 10h timepoint) for each cohort will be reviewed prior to dose escalation and 
will be used to determine the dose to be administered in the subsequent cohort.  The 


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decision to proceed to the next dose level will be made by the Dose Escalation 
Committee based on safety, tolerability and available PK data. 
Participants will be enrolled in the study for approximately 8 weeks (up to 28 days 
screening, approximately 16 days in-house assessment period, and up to 14 day follow up 
period).   
Part C 
Participants in Part C will participate in 5 single dosing periods of GSK3915393.  In 
period 1 all participants will receive an IV microdose of GSK3915393. In period 2 all 
participants will receive oral doses of itraconazole for 6 days and an IV microdose of 
GSK3915393 on the 4th day of itraconazole dosing.  In periods 3 and 4, participants will 
receive oral GSK3915393 with water or with grapefruit juice in a randomized crossover 
design.  In period 5, all participants will receive oral doses of itraconazole for 6 days and 
a single oral dose of GSK3915393 on the 4th day of itraconazole dosing. The IV 
microdose of GSK3915393 will be 100 μg and the oral dose of GSK3915393 will be 
selected after review of the IV PK data from periods 1 and 2  and will not exceed 20 mg. 
Since the half-life of GSK3915393 may be significantly extended upon coadministration 
with itraconazole, there is increased potential for carryover effects after these regimens 
compared to the other regimens. For this reason, the itraconazole regimens will be given 
in fixed periods (2 and 5) rather than in randomized sequence.  An extended washout 
period of at least 7 days is incorporated between periods 2 and 3.     
Participants in part C will be enrolled in the study for at least 10 weeks (up to 28 days 
screening, 5 in house dose assessment periods of  between 3 and 6 days each, 1 washout 
period between each dose and up to 14 day follow up period).  
Data Monitoring/ Other Committee: The decision to proceed to the next dose level of 
GSK3915393 in each Cohort and the oral dose to be used in Part C will be made by the 
Dose Escalation Committee. 
 


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1.2. 
Schema 
Figure 1 
Part A – Single Dose 
 
 
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post last 
dose)
DL1
N=12
9A:3P
DL2
N=12
9A:3P
100µg IV
N=12
12A
DL3
N=12
9A:3P
DL4
N=12
9A:3P
 A= Active
 P=Placebo
DL = Dose level
Data review - earliest decision point to proceed to Part B
Treatment period
Single dose (double-blinded) crossover 
     Washout and dose escalation committee (DEC) meeting 
(DEC at end of DL2 is to proceed to DL3)


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Figure 2 
Part B- Repeat Dose 
 
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post 
last dose)
Repeat DL1
14 days BID dosing 
N=12, 9A:3P
Cohort 1
Repeat DL2
14 days BID dosing
N=12, 9A:3P
Cohort 2
Repeat DL3
14 days BID dosing
N=12, 9A:3P
Cohort 3
DL=Dose level 
A= Active
P=Placebo
Treatment period
Dose escalation meeting
BID=Twice daily dosing 
    Data review - earliest decision point to proceed to Part C


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Figure 3 
Part C –CYP3A4 Victim Interaction  
  
 
Follow-up
(7-14 days post 
last dose)
Period 1
Period 2
Period 3
Period 4
Period 5
N=6
Single PO 
Dose 
GSK3915393
+
Water 
Single PO 
Dose 
GSK3915393
+
GFJ 
D-3 to D3 ITZ   
+
D1 Single PO 
Dose
GSK3915393
 N= 12
100µg IV 
GSK3915393
D-3 to D3 ITZ   
+
D1 100µg IV 
GSK3915393
N=6
Single PO 
Dose 
GSK3915393
+
GFJ 
Single PO 
Dose 
GSK3915393
+
Water 
D-3 to D3 ITZ   
+
D1 Single PO 
Dose
GSK3915393
D = Day 
PO GSK3915393
Treatment period
IV GSK3915393
Screening
(28 days prior to 1st 
dose)
      washout of at least 7 days and IV data review to select PO dose.
GFJ = Grapefruit Juice
ITZ = Itraconazole
N = Number of participants
NOTE: Washout periods represent the minimum duration required between each period and may be longer for operational purposes.
7 Days Washout
7 Days Washout
7 Days Washout
7 Days Washout
2 Days Washout


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1.3. 
Schedule of Activities (SoA) 
The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic and other biomarkers, may be altered during the course of the study 
based on emerging data or in-stream analyses (e.g., to obtain data closer to the time of 
peak plasma concentrations) to better characterize safety, PK, PD or efficacy.  
Any changes in the timing or addition of time points for any planned study assessments 
will be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF). 
Allowed time windows will be specified in the Study Reference Manual (SRM). 
• 
The Competent Authority (CA) and Ethics Committee (EC) will be informed of 
any safety issues that constitute a substantial amendment according to individual 
obligations including alteration of the safety monitoring scheme or amendment 
of the ICF. The changes will be approved by the CA and/or the EC before 
implementation as required. 


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1.3.1. 
Part A: Single Dose Administration in Healthy Participants 
Procedure (Part A) 
Screening (up 
to 28 days 
before Day 1) 
Sessions 1-5 
Follow-
up  
Early 
Withdrawal 
Notes 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Outpatient visit 
X 
  
  
  
  
X 
X 
  
Admission to clinical unit 
  
X 
  
  
  
  
  
  
Inpatient Stay at clinical unit 
  
<-----------------------> 
  
  
 
 
  
Discharge from clinical unit 
  
  
  
  
X 
  
  
  
Informed consent 
X 
  
  
  
  
  
  
  
Inclusion and exclusion criteria 
X 
X 
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
Physical examination  
X 
X 
  
  
X 
X 
X 
• 
Full Physical at screening with height and weight.  
• 
Brief physical on all other occasions. 
Medical/medication/drug/alcohol 
history 
X 
X 
  
  
  
  
  
  
Vital signs (BP, HR, temperature, 
respiratory rate) 
X 
 
X 
  
X 
X 
• 
Oral dosing - Pre-dose then 30mins, 1, 2, 4,12, 24, 36h post 
dose  
• 
IV dosing – Pre-dose then 30mins, 1, 2, 4,12, 24, 36h from the 
start of infusion  
• 
BP measurements in triplicate and average recorded in CRF. 


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Procedure (Part A) 
Screening (up 
to 28 days 
before Day 1) 
Sessions 1-5 
Follow-
up  
Early 
Withdrawal 
Notes 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
12-lead ECG 
X 
  
X 
  
X 
X 
• 
Oral dosing - Pre-dose then 30mins, 1, 2, 4,12, 24, 36h post 
dose 
• 
IV dosing – Pre-dose then 30mins, 1, 2, 4,12, 24, 36h from the 
start of infusion. 
• 
Triplicate ECGs will be obtained no more than 2 minutes apart 
at screening and pre-dose.  
• 
Single measurements will be obtained at all other timepoints.   
Telemetry 
  
  
<----------> 
  
  
  
 
 
• 
From 1h pre-dose to 24h. 
24h Holter ECG 
  
  
<---------> 
  
  
  
 
• 
Oral dosing - From 1h pre-dose to 24h. 
• 
IV dosing - 24h Holter ECG will not be recorded in IV dosing 
period. 
• 
ECG extractions at 3 time points prior to dosing and all post-
dose PK time points up to and including the 24h timepoint. 
• 
Participants will be resting in a semi-recumbent position for at 
least 15 min  at each PK time point for ECG extractions.  
• 
When ECG extractions and/or safety ECGs coincide with vital 
signs assessment and blood draws, procedures should occur 
in the following order; ECGs vital signs blood draws. 
Clinical laboratory (Chemistry, 
Hematology & UA) 
X 
X 
  
X 
  
X 
X 
• 
Day 2 clinical laboratory is at 24h post Day 1 dosing. 
• 
Sample collected following a fast of at least 8 hours. 
Serum Pregnancy test 
X 
X 
  
  
  
X 
  
• 
In women of childbearing potential (WOCBP) only  
Estradiol/FSH test   
X 
  
  
  
  
  
  
• 
If indicated  


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Procedure (Part A) 
Screening (up 
to 28 days 
before Day 1) 
Sessions 1-5 
Follow-
up  
Early 
Withdrawal 
Notes 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Covid-19 test 
X  
• 
Covid-19 testing to be performed according to local site 
procedures. 
• 
Minimum testing; screening (not required if subject had a 
negative SARS-CoV-2 test within 48 hours prior to date of 
informed consent signature), prior to admission to the unit and 
prior to discharge from the unit. 
Urine Cotinine, Drug & Alcohol test 
X 
X 
  
  
  
  
  
  
HIV, Hepatitis B and C screening 
X 
  
  
  
  
  
  
  
Study Treatment 
  
  
X 
  
  
  
  
Oral dosing – Capsules to be swallowed with 240ml of water  
IV dose to be infused over a 1h period. 
Local tolerability at the site of 
injection 
 
 
X 
 
 
 
IV dose only 5 mins, 20 mins, 1h (end of infusion), 2, 4, and 24h 
post start of infusion. 
Meals 
  
X 
X 
X 
X 
  
  
• 
Oral dosing - On Day 1 Participants will fast 8hr and a 
standard breakfast will be served approximately 30 minutes 
prior to dosing.   
• 
All other meals on Days -1, 1, and 2 will be served as per the 
site schedule. 
• 
IV dosing - All meals will be served as per the site schedule.  
• 
Water permitted on an ad lib basis. 
• 
Other decaffeinated drinks allowed by the protocol will be 
permitted except during fasting periods 


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Procedure (Part A) 
Screening (up 
to 28 days 
before Day 1) 
Sessions 1-5 
Follow-
up  
Early 
Withdrawal 
Notes 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Blood sample for PK  
  
  
X 
  
  
 
 
• 
Oral dosing - Pre-dose within 30 minutes prior to dose then at 
20mins, 40mins, 1, 1.5, 2, 3, 4, 6, 10, 12, 14, 24, 36h post 
dose.   
• 
IV dosing - Pre-dose within 30 minutes prior to dose then at 
the following timepoints post the infusion start time; 20mins, 
40mins, 1h (immediately before end of infusion), 1h 5mins, 1h 
10mins, 1h 20mins, 1h 40 mins, 2, 2.5, 3, 3.5, 4, 5, 6 h.   
Blood sample for Metabolites 
 
 
X 
 
 
 
• 
Oral dosing - Pre-dose within 30 minutes prior to dose then at 
20mins, 40mins, 1, 1.5, 2, 3, 4, 6, 10, 12, 14, 24, 36h post 
dose.   
• 
IV – No samples collected. 
Urine collection for Metabolites 
  
  
<----------> 
   
  
 
 
• 
Oral dosing - Urine samples will be collected pre-dose and 
over 0-24 hours for all cohorts. 
• 
IV – No samples collected 
AE review 
  
  
<--------------------------------> 
 
  
SAE review 
<--------------------------------------------------------> 
 
  
Concomitant medication review 
  
<-----------------------------------------> 
 
  
 


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1.3.2. 
Part B: Repeat Dose Administration in Healthy Participants 
FU= Follow up  
EW = Early withdrawal  
Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
Outpatient Visit 
X 
  
  
  
  
  
  
  
X 
X 
X 
  
Admission to Clinical Unit 
  
X 
  
  
  
  
  
  
  
  
  
  
Inpatient stay at Clinical Unit 
  
<--------------------------------------------------------->  
  
 
  
  
Discharge from unit 
  
  
  
  
  
  
  
X 
  
  
  
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Inclusion and exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
Medical/medication/drug/alcohol 
history 
X 
X 
  
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
  
  
X 
  
  
X 
  
X 
X 
• 
Full Physical at screening with height and 
weight.  
• 
Brief physical on all other occasions. 


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Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
Vital Signs (BP, HR, Temperature, 
respiratory rate) 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
• 
Days 1, 7 and 14; within 1 hour before the start 
of AM dose (pre-dose) and at 1, 2, 4, 12, and 
24 hours after AM dose. 
• 
Days, 3, 4, 5, 6, 9, 10, 11, 12, and 13; within 1 
hour before the start of AM dose (pre-dose). 
• 
BP measurements in triplicate and average 
recorded in CRF. 
12-Lead ECG 
X 
  
X 
X 
  
X 
X  
 
X 
X 
• 
Triplicate 12-lead safety ECGs will be obtained 
no more than 2 minutes apart at screening and 
within 1 hour before the start of AM dose (pre-
dose) on Days 1, 6, 10 and 14 
• 
Single measurements will be obtained at follow 
up/ EW and Days 1 & 14 at, 30min, 1hr, 2hr, 
4hr, 12hr, and 24hr post AM dose. 
Telemetry 
  
  
X 
  
  
  
X 
  
  
  
  
• 
Telemetry from -1h (i.e., 1h pre-dose) to 24h on 
Day 1 and Day 14 
24h Holter ECG 
  
  
X 
  
  
  
  
  
  
  
  
• 
From 1h pre-dose to 24h. 
• 
ECG extractions at 3 time points prior to dosing 
and all post-dose PK time points up to and 
including the 24 h timepoint. 
• 
Participants will be resting in a semi-recumbent 
position for at least 15 min  at each PK time 
point for ECG extractions. 
• 
When ECG extractions and/or safety ECGs 
coincide with vital signs assessment and blood 
draws, procedures should occur in the following 
order; ECGs vital signs blood draws. 


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Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
Clinical Labs (Chemistry, 
Hematology, and Urinalysis) 
X 
X 
  
X* 
X 
X* 
  
X 
X* 
X 
X 
• 
*Day 3, Day 11 and 1 visit only on any day 
between Day 18-20 
• 
Sample collected following a fast of at least 8 
hours. 
Serum Pregnancy test 
X 
X 
  
  
  
  
 
 X 
  
X 
 X 
• 
In WOCBP only   
• 
Day 14 test to be taken after PM dose.  
Estradiol/FSH 
X 
  
  
  
  
  
  
  
  
  
  
• 
If indicated  
Covid 19 test 
X 
• 
Covid-19 testing to be performed according to 
local site procedures. 
• 
Minimum testing; prior to admission to the unit 
and prior to discharge from the unit. 
Urine Cotinine, Drug & Alcohol 
Test 
X 
X 
  
  
  
  
  
  
  
  
  
  
HIV, Hep B, Hep C 
X 
  
  
  
  
  
  
  
  
  
  
  


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Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
Meals 
  
 X 
X 
X 
X 
X 
X 
 X 
  
  
  
Breakfast  
• 
Participants will fast 8hr and a standard 
breakfast will be given approximately 30 min 
pre dose (except on Day 3 and Day 5 (see 
below)).  On day 7 breakfast will be eaten within 
20 minutes. 
• 
Day 3 - Participants will fast 8hr and will be 
dosed fasted, a low-fat breakfast will be served 
approximately 2hr after dosing. 
• 
Day 5 - Participants will fast 8hr a high fat 
breakfast meal will be given approximately 30 
min. pre dose & eaten within 20 minutes. 
Lunch  
• 
Day 12 in the cohort undergoing bile sampling - 
A high fat small lunch meal will be served at 
approximately 5 hours post dose.  
• 
On all other day’s lunch and snacks will be 
served according to the sites schedule. 
Dinner  
• 
On D1 dinner will be served approximately 1 h 
before PM dose. On all other days the dinner 
meal will be given approximately 40 mins prior 
to the PM dose. 
Fluids 
• 
Water permitted on an ad lib basis  
• 
Other decaffeinated drinks allowed by the 
protocol will be permitted except during fasting 
periods and while the EnteroTracker is in place.   


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Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
Bile sampling 
  
  
  
  
  
X  
 
  
  
  
  
• 
Day 12 
• 
For the highest dose cohort only: EnteroTracker 
swallowed 2 h post-AM dose.   
• 
5 h post dose a food stimulus will be 
administered. 
• 
After 6 hr post dose the string will be removed. 
Dosing 
  
  
X 
X 
X 
X 
X 
  
  
  
  
• 
BID dosing PM dose to be administered 10 
hours after AM dose. 
Blood sample for PK  
  
  
X 
X 
X 
  
X 
 
  
  
• 
Days 1 and 14  - blood samples will be obtained 
predose within 30 minutes prior to AM  dose 
and then post AM dose at the following 
timepoints: 20mins, 40mins, 1h, 1.5h, 2h, 3h, 
4h, 6h, 10h (10 mins prior to PM dose), 10h 20 
min, 10h 40min, 12h, 12.5h, 13h, 14h, 16h, and 
24 h (within 10 minutes or less prior to next AM 
dose). 
• 
Days 3, 5, and 7 - blood samples will be 
obtained predose within 30 minutes prior to AM 
dose and then postdose at the following 
timepoints: 20mins, 40mins, 1h, 1.5h, 2h, 3h, 
4h, 6h, 10 (approximately 10 mins prior to PM 
dose).  
Blood sample for Metabolites  
  
  
X 
  
  
X 
  
 
 
• 
Blood samples for metabolite profiling will be 
collected at all PK timepoints up to 24h.  
Urine collection for Metabolites  
  
  
X 
  
  
  
X 
  
  
  
  
• 
Urine samples will be collected pre-dose and 
over 0-24 hours. 


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Procedure (Part B) 
Screening 
(up to 28 
days before 
Day 1) 
Day 
-1 
Day 
1 
Day 
2-6 
Day 
7 
Day 
8-13 
Day 
14 
Day 
15 
Day 
18-
20 
FU  EW  Notes 
4β-hydroxycholesterol sampling 
  
  
X 
  
  
  
  
X 
  
  
  
• 
Sample to be taken pre-dose on Day 1 in a 
fasted state. 
• 
Sample to be taken at 24hr post AM dose on 
Day 14. Sample should be in a fasted state. 
AE Assessment 
  
  
<----------------------------------------------------------------------> 
X 
  
SAE Assessment 
<----------------------------------------------------------------------------------------------------> 
X 
  
Concomitant Medication Review 
  
<-------------------------------------------------------------------------------> 
X 
  
 


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1.3.3. 
Part C: CYP3A4 Victim Interaction. 
FU= Follow up  
EW = Early withdrawal  
Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Outpatient visit 
X 
 
 
 
 
  
  
  
X 
X 
  
Inpatient Stay at clinical unit 
  
X 
X 
X 
X 
 X 
X 
X 
 
 
  
Informed consent 
X 
 
 
 
 
  
  
  
  
  
  
Inclusion and exclusion criteria 
X 
X 
 
 
 
  
  
  
  
  
  
Demography 
X 
 
 
 
 
  
  
  
  
  
  
Physical examination  
X 
X 
 
 
 
  
  
X 
X 
X 
• 
Full Physical at screening with 
height and weight.  
• 
Brief physical on all other 
occasions. 
Medical/medication/drug/alcohol 
history 
X 
X 
 
 
 
  
  
  
  
  
  


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Vital signs (BP, HR, temperature, 
respiratory rate) 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
• 
Periods 2 and 5 days -3 to -1 
assessment performed pre 
itraconazole dosing. 
• 
Day 1 IV GSK3915393 dosing – 
Pre-dose then 30mins, 1, 2, 4,12, 
24h from the start of GSK3915393 
infusion. 
• 
Day 1 oral GSK 3915393 dosing - 
Pre-dose then 30mins, 1, 2, 4,12, 
24h, post dose (timepoints relative 
to GSK 3915393 dosing) 
• 
Period 2 and 5 only  48h post oral 
GSK 3915393 dose or start of 
infusion.  
• 
BP measurements in triplicate and 
average recorded in CRF. 


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
12-lead ECG 
X 
 
X 
 
 
X 
 X 
 
X 
X 
• 
Day -3 ECG performed pre-ITZ 
dosing 
• 
Oral GSK 3915393 dosing - Pre-
dose then 30mins, 1, 2, 4,12, 24h, 
post dose 
• 
IV dosing – Pre-dose then 30mins, 
1, 2, 4,12, 24h from the start of 
infusion. 
• 
Triplicate ECGs will be obtained no 
more than 2 minutes apart at 
screening and pre-dose.  
• 
Single measurements will be 
obtained at all other timepoints.   
Clinical laboratory (Chemistry, 
Hematology & UA) 
X 
X 
 
 
X 
  
X 
X  
X 
X 
• 
Periods 1,3,4: D-1 and D2 (24h 
post D1 oral GSK 3915393  dose 
or start of infusion ) 
• 
Periods 2 and 5: D-4, D-1(pre 
itraconazole dose), and D3 (48h 
post D1 oral GSK 3915393  dose )  
• 
Sample collected following a fast of 
at least 8 hours. 
Serum Pregnancy test 
X 
X 
 
 
 
  
  
  
X 
X  
• 
In women of childbearing potential 
(WOCBP) only  
Estradiol/FSH test   
X 
 
 
 
 
  
  
  
  
  
• 
If indicated  


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Covid-19 test 
 
X 
 
 
 
 
X 
 
 
 
• 
Covid-19 testing to be performed 
according to local site procedures. 
• 
Minimum testing; prior to 
admission to the unit and prior to 
discharge from the unit. 
Urine Cotinine, Drug & Alcohol 
test 
X 
X 
 
 
 
  
  
  
  
  
  
HIV, Hepatitis B and C screening 
X 
 
 
 
 
  
  
  
  
  
  
GSK3915393 dosing 
  
 
 
 
 
X 
  
  
  
  
Periods 1 and 2: IV GSK 3915393 dose 
to be infused over a 1h period. 
 
Period 2: IV GSK 3915393 dose to start 
1 hour after Itraconazole dosing. 
 
Period 3 and 4: Capsules of GSK 
3915393 to be swallowed with water or 
with GFJ (volume to be defined in SRM) 
depending on randomisation. 
 
Period 5; Capsules of GSK 3915393 to 
be swallowed with water 1 hour after 
Itraconazole dosing. 
Local tolerability at site of  
injection. 
 
 
 
 
 
X 
X 
 
 
 
IV dose only 5 mins, 20 mins, 1h (end of 
infusion), 2, 4, and 24h post start of 
infusion. 


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Itraconazole dosing  
 
 
X 
X 
X 
X 
X 
X 
 
 
Periods 2 and 5 only: Itraconazole to be 
dosed 1 hr before oral GSK3915393 
dosing or start of GSK3915393 IV 
infusion on Day 1.  
 
 


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Meals 
  
X 
X 
X 
X 
X 
X 
X 
  
  
• 
On day 1 participants will fast 8hr 
prior to dosing (with Itraconazole or 
GSK3915393 depending on 
period) and a standard breakfast 
will be served approximately 2 
hours post GSK3915393 oral dose 
or start of IV infusion.   
(The Day 1 fasting requirements 
may be adjusted based on the 
emerging data from Part B.) 
• 
Itraconazole administration on 
Days -3 to -1 and Days 2 and 3 
may 
be administered following a 
standard meal. 
• 
All other meals will be served as 
per the site schedule. 
• 
Water permitted on an ad lib basis. 
• 
Other decaffeinated drinks allowed 
by the protocol will be permitted 
except during fasting periods 


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Blood samples for GSK3915393 
PK  
  
 
 
 
 
X 
 X 
X  
 
 
• 
IV dosing: - Pre-dose (within 30 
minutes prior to dose) then at the 
following timepoints post the 
infusion start time; 20mins, 40mins, 
1h (immediately before end of 
infusion), 1h 5mins, 1h 10mins, 1h 
20mins, 1h 40 mins, 2, 2.5, 3, 3.5, 
4, 5, 6, 7, 8, 10 h.   
• 
For Period 2, additional PK 
samples to be collected 12, 24, 36, 
48 and 60 h post-dose  
 
• 
Oral dosing - Pre-dose within 30 
minutes prior to dose then at 
20mins, 40mins, 1, 1.5, 2, 3, 4, 6, 
8, 10, 12, 14, 24h post dose.   
• 
For Period 5, additional PK 
samples to be collected  36, 48, 
and 60 h post-dose .  The PK 
sampling times and number of PK 
sample may be adjusted based on 
the observed half-life in period 2  
  


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Procedure (Part C) 
Screening 
(up to 28 
days before 
Day 1) 
On admission 
to unit (Day -4 
for periods 2 
and 5. Day -1 
for periods 1, 3 
and 4) 
Periods 2 and 5 
only 
Periods 1 – 5  
Early 
Withdrawal 
FU 
Notes 
 
 
 
Day 
-3 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
 
 
 
Blood sample for Itraconazole/ 
Hydroxy Itraconazole  PK 
 
 
 
 
 
X 
X 
 
 
 
• 
Periods 2 and 5 only  
• 
Pre-dose, 30 min, 1 h (prior to 
dosing GSK3915393), 1.5 h, 2 h, 3 
h, 4 h, 6 h, 8 h, 12 h and 24 h 
hours post itraconazole dose 
AE review 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
  
SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Concomitant medication review 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale  
GSK3915393 is being developed as an orally administered inhibitor of the enzyme 
transglutaminase 2 (TG2) for the treatment of patients with Celiac Disease (CeD).  This 
study is the first time into human study (FTIH) for GSK3915393.  Parts A and B of the 
study will evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending 
and repeat oral doses of GSK3915393 in healthy adult participants.  In addition, during 
Part A the PK following a single intravenous (IV) microdose of GSK3915393 will be 
evaluated and during Part B, the impact of food on the PK of GSK3915393 will be 
assessed.  Part C will evaluate the impact of co-administration of GSK3915393 with 
grapefruit juice and itraconazole on the PK of GSK3915393.  
The results of this study are intended to identify well tolerated dose(s) of GSK3915393 to 
be used in further studies.  The victim drug interaction potential of GSK3915393 with 
CYP3A4 inhibitors will be evaluated. In addition, the results will also inform the 
anticipated pharmacological effect by enabling prediction of the concentration of 
GSK3915393 at the target site of action in patients with Celiac Disease. 
 
2.2. 
Background 
CeD is a common T cell-mediated disorder triggered by dietary gluten with a worldwide 
prevalence estimated at one percent [Ludvigsson, 2014].  Presenting symptoms include 
abdominal pain, extreme weakness and tiredness, diarrhea, anemia, and vomiting while 
long-term complications include the development of cancer, such as small intestinal 
adenocarcinoma and enteropathy-associated T-cell lymphoma. 
The only treatment currently available for CeD is strict adherence to a gluten-free diet 
(GFD), which improves mucosal villous atrophy and reduces symptoms in most patients.  
However, gluten cross-contamination has been demonstrated in the majority of patients 
adhering to a GFD as determined from gliadin immunogenic peptides in urine and feces 
[Stefanolo, 2020] [Syage, 2018].  A significant number of patients continue to experience 
symptoms on a GFD and have incomplete mucosal healing [Pulido, 2013] [Silvester, 
2017].  A normal diet contains 5–15 g gluten/day while the average inadvertent exposure 
to gluten by celiac patients on a GFD is estimated to be 150–400 mg/day [Syage, 2018].  
However daily intake of 50 mg has been shown to be harmful to most patients [Catassi, 
2007] suggesting that inadvertent gluten exposure even on a GFD contributes to 
persistent enteropathy, continued symptoms, and a reduced quality of life [Leffler, 2007] 
[Hall, 2013] [Pulido, 2013].  Given the challenges in diet adherence and the persistence 
of mucosal injury and symptoms, there is an urgent need for the development of 
nondietary therapies for this widespread but overlooked disease.   
The ingestion of gluten in genetically predisposed patients leads to inflammation and 
damage of the small intestine. This is trigged by immunodominant gluten peptides that 
are deamidated by transglutaminase 2 (TG2) in the lamina propria and bind with very 
high affinity to disease-associated human leukocyte antigen (HLA) alleles, (DQ2, DQ8). 


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on antigen presenting cells.  This interaction results in activation of antigen specific CD4+ 
T cells, triggering an inflammatory cascade in gastrointestinal tissue which drives 
mucosal injury.   
By reducing the generation of deamidated gluten peptides (dGP), treatment with a TG2 
inhibitor should decrease the sensitivity of patients to gluten thereby reducing persistent 
mucosal damage and symptoms on a GFD and ensuring that inadvertent exposure to 
gluten will not invoke inflammation or symptoms. 
 


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2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention(s) 
Idiosyncratic hepatotoxicity 
Covalent binding in hepatic 
microsomes and the formation of 
glutathione adducts were 
observed in vitro. 4-week GLP 
rat and dog studies have not 
revealed any adverse effects on 
the liver. 
 
The in vitro findings suggest a 
potential for immune-mediated 
idiosyncratic hepatotoxicity. 
However, idiosyncratic 
hepatotoxicity is a rare event, 
and the risk to participants in 
early clinical trials of short 
treatment duration is low.   
Participants with hepatic disorders or liver 
laboratory abnormalities will be excluded 
from the study.  
 
Standard monitoring of LFTs will be 
implemented per Section 1.3, Section 
10.2, and Section 10.5. 
 
Liver chemistry stopping criteria will be 
used as per Section 7.1.1 and Section 
10.5. 
 
Paracetamol usage will be restricted (max 
2g/d, 500 mg at a time).  
 
Effect on vital signs (HR and BP) 
Increased blood pressure and/or 
heart rate have been observed in 
rats and dogs. These changes in 
vital signs were mild and 
transient, and the risk of 
significant changes in heart rate 
Monitoring of vital signs will be conducted 
as per Section 1.3. 
Stopping criteria related to changes in vital 
signs will be implemented as per Section 
7.1.3. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
or blood pressure in humans is 
considered low.  
 
Effect on human embryo/fetus 
Preliminary animal embryofetal 
studies suggest minimal risk for 
the developing human embryo or 
fetus. Females of reproductive 
potential (FRP) can receive 
GSK3915393 in a clinical study if 
they use proper contraception as 
required by the study protocol to 
avoid pregnancy while taking 
part in the study. 
 
Pregnant women will not be eligible to 
participate. 
Participating FRPs will agree to comply 
with the study contraception requirements. 
Participants will be withdrawn from the 
study if the participants become pregnant 
during the study 
Pregnancy tests will be done at screening, 
before dosing, and after completion of 
dosing. 
Drug Drug Interaction (DDI) (perpetrator) 
(risk of CYP3A4 induction and CYP3A4 metabolism dependent 
inhibition)  
In vitro, GSK3915393 is a weak 
CYP3A4 inducer and a CYP3A4 
metabolism dependent inhibitor 
(MDI).  
 
Physiologically based 
pharmacokinetic [PBPK] 
modelling integrating the in vitro 
CYP3A4 parameters with the 
predicted human 
pharmacokinetics predicts that 
the risk of significant CYP3A4 
inhibition is low at the 
GSK3915393 doses planned in 
Co-medications are prohibited in FTIH 
except for paracetamol and hormonal 
contraceptives.,  


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
FTIH (<1.6-fold change in AUC 
with doses up to 160 mg BID 
with a sensitive CYP3A4 
substrate). The risk of loss of 
efficacy of oral contraceptives 
due to induction of CYP3A4 is 
also low (<0.96-fold change in 
AUC with doses up to 160 mg 
BID with a sensitive CYP3A4 
substrate). 
DDI (victim) in Part C 
 
In vitro, GSK3915393 is 
metabolised by intestinal and 
hepatic CYP3A4. Administration 
of itraconazole, a potent inhibitor 
of both gut and hepatic CYP3A4, 
could result in a substantial 
increase in systemic exposure to 
GSK3915393 when administered 
orally due to inhibition of 1st pass 
CYP3A4 (gut and liver) as well 
as by inhibition of hepatic 
CYP3A4 metabolism of 
systemically available 
GK3915393.   
 
 
 
An IV microdose (100ug) of GSK3915393 
will be used to evaluate the impact of 
itraconazole hepatic inhibition of CYP3A4 
on the systemic exposure to 
GSK3915393.   Any  observed fold-
increase in systemic exposure when IV 
GSK3915393 is administered with 
itraconazole, compared to IV 
GSK3915393 alone, will be used to predict 
the potential increase in exposure for oral 
GSK3915393 with the addition of inhibition 
of first-pass clearance.   
 
The oral dose of GSK3915393 in the 
victim drug interaction study (Part C) will  
not exceed 20 mg. The oral dose selection 
will be based on maintaining the predicted 
exposure to GSK3915393 in the presence 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
of itraconazole to within the systemic 
exposures already achieved in Parts A 
and B of the study.   
 
Study Procedures 
Bile Sampling (Entero-Tracker) 
Streaks of blood on the string 
due to local irritation have been 
infrequently noted. Rarely, a 
patient will be unable to swallow 
the capsule because of gagging 
or will vomit after doing so. 
Gagging upon retrieval of the 
string can occur. On a few 
occasions, an entire string has 
been swallowed without ill effects 
and passes from the gut in the 
feces.   
The string will be securely taped to the 
side of the participants face during the 
collection time to minimize risk of 
swallowing the entire string.  
Participants undergoing bile-sampling 
should not be exposed to magnetic 
resonance imaging (MRI) for at least 72 
hours after swallowing of the capsule 
device – such time will allow the stainless-
steel ball to be expelled into the feces.  
 
Other  
 
COVID-19  
Participation within an inpatient 
environment may increase risk of 
contracting COVID-19. 
Exposure to other participants 
and staff may increase risk of 
exposure. 
Monitoring of clinical presentation of 
COVID-19 signs/symptoms. 
Conduct study at sites which have 
appropriate mitigation strategies in place. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Itraconazole 
Risk of hepatotoxicity. Rare 
cases of severe hepatotoxicity 
have been observed with ITZ. 
 
Subjects with liver disease or abnormal 
liver enzyme tests will be excluded from 
the study. 
Subjects with history of liver toxicity from 
other drugs will be excluded. 
LFTs will be monitored in the periods 
when ITZ is administered. 
Liver chemistry stopping criteria will be 
used as per Section 7.1.1 and Section 
10.5. 
 
 
 


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2.3.2. 
Benefit Assessment 
The proposed study with GSK3915393 will be conducted in healthy participants; no 
medical benefit will be derived by volunteer’s participation.   
2.3.3. 
Overall Benefit: Risk Conclusion 
The potential risks associated with GSK3915393 in study 213585 can be appropriately 
mitigated by the careful selection of study participants and the proposed safety monitoring 
procedures. As such, the risk to potential participants is considered low. Safety and 
tolerability will be evaluated from reported AEs, scheduled physical examinations, vital 
sign measurements, 12-lead ECGs, and clinical laboratory test results as well as continued 
observation by clinical staff.   
The study will be conducted in an accredited unit set up for dealing with medical 
emergencies. The in-house periods as detailed in the SoA will allow for continuous medical 
monitoring for all participants following first dose until discharge. Participants will only 
be discharged from the unit if the Investigator deems it safe to do so. 
Considering the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with GSK3915393 are justified by the anticipated benefits 
that may be afforded by the future development of a new therapy in an area of unmet need. 
3. 
OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
Part A Dose Escalation Single 
Dose  
• To evaluate the safety and 
tolerability of single 
escalating oral doses of 
GSK3915393 administered 
in the fed state in healthy 
adult participants 
 
Part B Dose Escalation Repeat 
Dose 
• To evaluate the safety and 
tolerability of repeat 
escalating oral doses of 
GSK3915393 twice daily 
(BID) administered in the 
fed and fasted state in 
healthy adult participants  
Part A and B  
• Occurrence of serious adverse events (SAEs), 
adverse events (AEs) and treatment related AEs 
• Occurrence of clinically significant changes in 
physical examination, vital signs, laboratory 
parameters, and 12-lead electrocardiogram 
(ECG) findings. 
 
 
 
 
 
 
 
 
 


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Objectives 
Endpoints 
 
Part C CYP3A4 Victim 
Interaction  
• To characterize the PK 
profile of IV GSK3915393 
administered alone and when 
co-administered with 
itraconazole in healthy adult 
participants 
• To characterize the PK 
profile of oral GSK3915393 
administered alone and when 
co-administered with 
grapefruit juice or with 
itraconazole in healthy adult 
participants 
Part C 
• Cmax, Tmax, AUC(0-t), (AUC(0-∞)) and (t1/2) 
as appropriate 
 
Secondary 
Part A Dose Escalation Single 
Dose  
• To characterize the PK 
profile of single oral doses of 
GSK3915393 in healthy 
adult participants 
• To characterize the PK 
profile of a single 
intravenous dose of 
GSK3915393 in healthy 
adult participants 
• To evaluate the safety and 
tolerability of single 
microdose doses of 
GSK3915393 in healthy 
adult participants 
 
 
 
 
 
Part B Dose Escalation Repeat 
Dose 
Part A 
• Maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma 
drug concentration (tmax), area under the 
plasma drug concentration versus time curve 
from time zero to last quantifiable concentration 
(AUC(0-t)), AUC from time zero to infinity 
(AUC(0-∞)), and apparent terminal half-life 
(t1/2) as appropriate.   
• Clearance (CL) and volume of distribution (Vd) 
following IV administration and absolute 
bioavailability (F) of oral administration 
• Fraction of drug escaping hepatic metabolism 
(FH) and product of fraction of drug absorbed 
(FA) and fraction of drug escaping gut 
metabolism (FG) i.e., (FA*FG).  
• Clinical safety and tolerability data including 
adverse events (AEs) and serious adverse 
events (SAEs), clinically significant changes in 
laboratory values, vital signs and 12 lead 
electrocardiogram (ECG) readings and physical 
examinations 
 
Part B 


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Objectives 
Endpoints 
• To characterize the PK 
profile of single doses and 
repeat oral doses of 
GSK3915393 in healthy 
adult participants 
• To assess the impact of food 
on the PK of GSK3915393 
in healthy adult participants 
• To evaluate time to steady-
state 
 
Part C CYP3A4 Victim 
Interaction 
• To evaluate the safety and 
tolerability of a single oral 
dose of GSK3915393 when 
administered with grapefruit 
juice or with itraconazole in 
healthy adult participants 
• To evaluate the safety and 
tolerability of single 
intravenous dose of 
GSK3915393 when 
administered with 
itraconazole in healthy adult 
participants 
• To investigate absorption 
characteristics and first pass 
clearance of GSK3915393 
 
• Cmax, Tmax, AUC(0-t), and AUC over the 
dosing interval AUC(0-) 
• Cmax, Tmax and AUC(0-) following 1st dose 
of day 
• Pre-dose concentrations on Days 2, 3, 5, 7 and 
14 
 
 
 
 
Part C 
• Occurrence of serious adverse events (SAEs), 
adverse events (AEs) and treatment related AEs 
• Occurrence of clinically significant changes in 
physical examination, vital signs, laboratory 
parameters, and 12-lead electrocardiogram 
(ECG) findings. 
• FA FG and FH  
Exploratory 
• To investigate metabolites of 
GSK3915393 in plasma and 
urine following oral dosing 
(Part A and B) 
• To investigate metabolites of 
GSK3915393 in duodenal 
bile following oral dosing 
(Part B, highest dose only) 
• Metabolites of GSK3915393 in plasma and 
urine. The analyses will be conducted and 
reported separately  
• Metabolites of GSK3915393 in duodenal bile. 
The analyses will be conducted and reported 
separately  


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Objectives 
Endpoints 
• To assess potential effect of 
repeat doses of GSK3915393 
on Cytochrome P450 3A4 
(CYP3A4) enzyme activity 
(Part B). 
• To assess the effect of single 
dose GSK3915393 on Holter 
ECG in healthy volunteers. 
Waveforms will be stored for 
potential future analysis. 
• Plasma 4β-hydroxycholesterol to cholesterol 
ratio at pre-treatment and following repeat 
dosing of GSK3915393 
• If analyses conducted: Centrally read ECG 
parameters and correlation between plasma 
levels of GSK3915393 and QTc changes 
 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This FTIH study will be a randomized, single centre trial in three parts. Parts A and B are 
double blind and placebo controlled and Part C is open label.  Please see Section 4.2 for 
scientific rationale for study design.   
1. Part A is a crossover design, single-dose (SD), dose escalation study in one 
cohort of healthy participants.  Participants will receive single ascending doses of 
GSK3915393 or matching placebo as an oral dose in periods 1, 2, 4 and 5 and as a 
single IV microdose dose in period 3.  The initial dosing for all periods in which 
the dose level has been escalated will be staggered so that 2 participants will be 
dosed as sentinel participants, one with study drug and one with placebo.  After 
approximately 24 hours, and provided the investigator considers the safety and 
tolerability of the sentinels to be acceptable, the remainder of the participants 
scheduled for the period may be dosed. Sentinel dosing is not required in the IV 
dosing period. 
2. Part B is a parallel group, 14-day, repeat oral dose, dose escalation study in 3 
cohorts of healthy participants.  Participants will receive GSK3915393 or 
matching placebo BID in each of the sequential cohorts.  The initial dosing for all 
periods in which the dose level has been escalated will be staggered so that 2 
participants will be dosed as sentinel participants, one with study drug and one 
with placebo.  After at least 4 days of dosing, and provided the investigator 
considers the safety and tolerability of the sentinels to be acceptable, the 
remainder of the participants scheduled for the period may be dosed. 
3. Part C consists of 5 SD periods in healthy adult participants.  In period 1 all 
participants will receive an IV microdose of GSK3915393. In period 2 all 
participants will receive oral doses of itraconazole for 6 days and an IV microdose 
of GSK3915393 on the 4th day of itraconazole dosing.  In periods 3 and 4, 
participants will receive oral GSK3915393 with or without grapefruit juice in a 
randomized crossover design.  In period 5, all participants will receive oral doses 


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of itraconazole for 6 days and a single oral dose of GSK3915393 on the 4th day of 
itraconazole dosing  
The participants, investigator, and study staff are all blinded in parts A and B. The 
schematic of each part is provided in Section 1.2. 
4.1.1. 
Number of Participants 
A sufficient number of participants will be screened to ensure a minimum of 60 
participants are eligible to be randomized.  It is estimated that Part A will have 12 
randomized participants, Part B will have 36 randomized participants and Part C will 
have 12 randomized participants.   
 
Up to 12 additional participants in Part A or Part B may be enrolled to allow for 
evaluation of additional dose levels, i.e. up to a maximum of 72 randomised participants 
in total in the study, excluding replacements.   
4.1.2. 
Study Intervention Groups and Duration 
Part A 
Part A will be a double-blind, single dose, dose-escalating, placebo controlled, 
randomized (with respect to placebo allocation) study.  A sufficient number of healthy 
participants will be screened to enroll 12 participants. Participants will be randomized to 
one of the sequences shown in Table 1  Participants will participate in 5 dosing periods 
and will receive 1 oral placebo dose and 4 active doses; 3 as an oral GSK3915393 dose 
and 1 as a single GSK3915393 IV microdose dose in period 3.  Participants will be dosed 
in the fed state.    
Table 1 
Part A Treatment Sequences 
Number of 
Participants 
Period 1 
 
Period 2 
 
Period 3 
 
Period4 
Period 5 
3 
P 
D2 
IV 
D3 
D4 
3 
D1 
P 
IV 
D3 
D4 
3 
D1 
D2 
IV 
P 
D4 
3 
D1 
D2 
IV 
D3 
P 
 
Each dosing period where the dose is escalated will be staggered so that only 2 
participants will be administered study drug initially, 1 active and 1 placebo.  Once 
approximately 24 hours have elapsed, and provided there are no safety concerns, the 
remainder of participants scheduled for that dosing period may be dosed. Sentinel dosing 
is not required in period 3 when the IV microdose is administered.  A review of safety, 
tolerability, and PK will occur prior to administration of the next oral dose level.  
Participants will return for their next scheduled dosing period once at least 5 half lives 
have elapsed and once all information for dose adjustment/ escalation has been received 


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and reviewed, which is anticipated to be at least 7 days after administration of the study 
drug from the prior dosing period. Review of PK data is not required prior to proceeding 
to the IV dose. 
The actual doses to be administered may be adjusted based on emerging safety, 
tolerability and PK data; these dose adjustments may involve either an increase or a 
decrease in the planned dose or to repeat a dose level.  Sentinel dosing will not be 
required should the dose be equivalent to, or lower than a dose already given in Part A. 
The decision to proceed to the next oral dose level will be made by the Dose Escalation 
Committee based on safety, tolerability and available PK data.  The IV dose will be 100 
µg. 
Participants in part A will be enrolled in the study for at least 11weeks (up to 28 days 
screening, 5 in house dose assessment periods of up to 5 days each, 1 washout period 
between each dose of at least 7 days and up to 14 days follow up period).   
If a participant withdraws prematurely from Part A of the study, additional participants 
may be recruited and assigned to the same treatment sequence, starting from the current 
dosing period of the early withdrawal at the discretion of the sponsor in consultation with 
the investigator. 
Part B 
Part B will be a double-blind, 14 day repeat oral dosing, placebo controlled, randomized 
(with respect to placebo allocation,) dose escalation study with 3 repeat dose levels in 3 
separate cohorts of participants who are not enrolled in part A of the study.  A sufficient 
number of healthy participants will be screened to enroll approximately 36 participants 
(12 participants/cohort).   Participants will be randomized to receive either GSK3915393 
(9 participants) or placebo (3 participants) in each cohort.  Each cohort will be staggered 
so that only 2 of the 12 participants will be administered study drug initially, 1 active and 
1 placebo.  After at least 4 days and provided the investigator considers the safety and 
tolerability of the sentinels to be acceptable, the remainder of the participants scheduled 
for the period may be dosed.  Since the half-life of GSK3915393 is predicted to be <2h, 
PK steady state is expected to be achieved on day 1 (see dose justification section, 
Section 4.3). The 4 day (120 h) time frame was selected to provide sufficient duration of 
dosing to assess safety data, however this duration may be increased based on emerging 
PK data. 
It is planned that participants will be dosed twice daily (approximately 10h and 14h 
dosing intervals).  The impact of food on the PK of GSK3915393 will be investigated 
following the AM dose on three days in all cohorts (day 3 = fasted, day 5 = high fat meal, 
day 7 = standard meal). Timings of meals are detailed in Section 5.3.1. The BID dosing 
regimen and the timing of meals relative to dosing may be adjusted based on emerging 
PK data.  
Blood samples for PK analysis will be collected following both the morning and evening 
dose on days 1 and 14 following administration of standard meals in order to evaluate 
any diurnal changes on the rate or extent of absorption and to evaluate the extent of 
accumulation upon repeat dosing.  Additional blood samples for PK analysis will be 
collected for 10 hours following the first dose on days 3 (fasted), 5 (high-fat), 7 (standard 
breakfast) to evaluate the impact of food by comparing day 5 and day 7 PK profiles with 


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day 3.  The study days for food effect evaluation may change if emerging PK data 
suggests that steady-state is not predicted to be achieved by day 3.   
The starting dose for part B will be selected after review of safety, tolerability and PK 
data from at least two oral dose levels in part A (IV dosing is not required to make the 
part B dose decision. The actual doses to be administered may be adjusted based on 
emerging safety, tolerability and PK data; these dose adjustments may involve either an 
increase or a decrease in the planned dose or to repeat a dose level.  Sentinel dosing will 
not be required in a Cohort should the dose be equivalent to, or lower than a dose already 
given in Part B. Preliminary safety and tolerability from 14 days of dosing and PK data 
from 7 days of dosing for each cohort will be reviewed prior to dose escalation and will 
be used to determine the dose to be administered in the subsequent cohort.  The decision 
to proceed to the next dose level will be made by the Dose Escalation Committee based 
on safety, tolerability and available PK data. 
Participants will be enrolled in the study for approximately 8 weeks (up to 28 days 
screening, approximately 16 days in-house assessment period, and up to 14 day follow up 
period).  
If a participant withdraws prematurely from Part B of the study, additional participants 
may be recruited and assigned to the same repeat dose level, starting from baseline at the 
discretion of the sponsor in consultation with the investigator. 
Part C 
Part C consists of 5 single dose periods of GSK3915393.  In period 1, all participants will 
receive an IV microdose of GSK3915393. In period 2 all participants will receive oral 
doses of itraconazole for 6 days and an IV microdose of GSK3915393 on the 4th day of 
itraconazole dosing.  In periods 3 and 4, participants will receive oral GSK3915393 with 
water or with grapefruit juice in a randomized crossover design.  In period 5, all 
participants will receive oral doses of itraconazole for 6 days and a single oral dose of 
GSK3915393 on the 4th day of itraconazole dosing. A sufficient number of healthy 
participants will be screened to enroll 12 participants. Participants will be randomized to 
one of the 2 sequences shown in Table 2.  Participants will participate in 5 dosing periods 
and will receive an IV microdose of GSK3915393 in periods 1 and 2 and three active oral 
doses of GSK3915393 in periods 3, 4 and 5; either dosed alone, with grapefruit juice or 
with itraconazole.  Participants will be dosed in the fasted state.    
Table 2 
Part C Treatment Sequences 
Number of 
Participants 
Period 1 
 
Period 2 
 
Period 3 
 
Period 4 
Period 5 
6 
IV microdose 
GSK3915393  
IV microdose 
GSK3915393 
+ ITZ 
GSK3915393 
+ water 
GSK3915393 
+ GFJ 
GSK3915393 
+ ITZ 
6 
IV microdose 
GSK3915393  
IV microdose 
GSK3915393 
+ ITZ 
GSK3915393 
+ GFJ 
GSK3915393 
+ water 
GSK3915393 
+ ITZ 
 


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The IV microdose of GSK3915393 will be 100 μg. The oral dose of GSK3915393 to be 
given in periods 3-5 will be selected after review of the IV PK data from periods 1 and 2 
and will not exceed 20 mg (see Section 4.3.9 for more details on oral dose selection in 
Part C).   
Participants in part C will be enrolled in the study for at least 10 weeks (up to 28 days 
screening, 5 in house dose assessment periods of between 3 and 6 days each, 1 washout 
period between each dose (see Section 1.2 Schema for minimum duration of washout 
periods) and up to 14 days follow up period).  
If a participant withdraws prematurely from Part C of the study, additional participants 
may be recruited and assigned to the same treatment sequence, at the discretion of the 
sponsor in consultation with the investigator. The treatment period in which a 
replacement volunteer will start from will be at the discretion of the sponsor in 
consultation with the investigator. 
 
4.2. 
Scientific Rationale for Study Design 
The study design is based on well-established and published methods to evaluate the first 
single and repeat dose administration of experimental drugs including the use of sentinel 
dosing.  This study includes a placebo arm to allow for a valid evaluation of adverse 
events attributable to treatment versus those independent of treatment.  
A cross-over design is preferred for part A where each participant receives placebo as it 
allows assessment of safety in the same individual thus reducing the influence of inter-
individual variability. 
An IV microdose arm has been included Part A in order to determine the absolute 
bioavailability of GSK3915393 at clinically relevant doses.   
Initial evaluation of safety, tolerability, and PK of GSK3915393 in the single ascending 
dose and multiple ascending dose phases of the study will be conducted in healthy 
participants.  It is prudent to examine safety in participants for 14 days in part B to inform 
future clinical studies. 
Because the solubility of GSK3915393 is pH dependent (high solubility at low pH and 
low solubility at higher pH), it is likely that the absorption of GSK3915393 will be higher 
when administered with food particularly at higher doses due to longer retention time in 
the stomach which will allow greater dissolution time for GSK3915393.  For the single 
ascending dose phase GSK3915393 will therefore be administered in the fed state, 
following a standard breakfast.  In part B, the impact of prandial state (high-fat meal, 
standard meal and fasted) on the PK of GSK3915393 will be determined at each dose 
level to determine the appropriate dosing conditions for future clinical studies 
Recent in-vitro studies have shown that GSK3915393 is a substrate for both intestinal 
(gut) and hepatic CYP3A4. The impact of moderate CYP3A4 inhibitors and CYP3A4 
inducers that may be included in future clinical trials can be modelled based on data from 


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a strong inhibitor such as itraconazole therefore coadministration of GSK3915393 with 
itraconazole will be evaluated in part C. Initially an IV microdose (100 µg) of 
GSK3915393 will be used in Periods 1 and 2 to evaluate the impact of itraconazole 
inhibition of hepatic CYP3A4 on the systemic exposure to GSK3915393.   This data will 
be used to select the oral dose of GSK3915393 to be used in Periods 3 to 5 (Section 
4.3.9). The oral dose to be used in Part C will not exceed 20 mg.   
 
Since expression of intestinal CYP3A4 is altered in patients with CeD, determining the 
impact of intestinal CYP3A4 on the predicted exposure of GSK3915393 in the lamina 
propria (the site of TG2 activity in CeD) is important to understand the predicted 
pharmacological activity of GSK3915393 in patients. Grapefruit juice administered as a 
single dose has been shown to inhibit CYP3A4 gut metabolism but not CYP3A4 hepatic 
metabolism, so in Periods 3 and 4 of Part C, GSK3915393 will be administered with and 
without coadministration of grapefruit juice (GFJ) to determine the fraction of 
GSK3915393 which escapes gut metabolism by CYP3A4 in healthy volunteers. 
Coadministration of GSK3915393 with GFJ will occur in either period 3 or 4, per the 
randomization schedule, to minimize impact of period effects to the GFJ interaction 
assessments. 
Itraconazole 200mg will be dosed for 6 days with GSK3915393 dosed on Day 4.  The 3-
day lead-in of ITZ dosing allows for accumulation of ITZ to maximise the degree of 
CYP3A4 inhibition.  Continuing to dose ITZ on Days 5 and 6 will maintain maximal 
CYP3A4 inhibition to fully characterise the impact of ITZ on the elimination of 
GSK3915393. Since the half-life of GSK3915393 may be significantly extended upon 
coadministration with itraconazole, there is increased potential for carryover effects after 
these regimens compared to the other regimens. For this reason, the itraconazole 
regimens will be given in fixed periods (2 and 5) rather than in randomized sequence, An 
extended washout period of at least 7 days is incorporated between periods 2 and 3.   
Holter monitor data will be collected and stored for future evaluation of the correlation 
between plasma levels of GSK3915393 and changes in the QTc interval, if appropriate. 
Emerging literature suggests that frequent QT evaluation early in development may 
mitigate the need for a formal thorough QT/QTc (TQT) study [Darpo, 2014]. Therefore, 
Holter monitor data will be collected during Parts A and B of this study. This data will be 
held by ERT and may be analysed in the future, if necessary, for a potential TQT waiver 
in further development of the compound. This will not be reported in the primary clinical 
study report (CSR). 
In order to characterize potential biliary elimination pathways, this study will also employ 
the Entero-Tracker for sampling of duodenal bile to conduct qualitative assessment of drug 
metabolites in this matrix.  The Entero-Tracker is based on a similar device, Entero-Test 
which has been shown to be an easy-to-use and minimally invasive method for sampling 
bile from the duodenum. The Entero-Tracker is a recent replacement device for Entero-
Test which is a FDA 510k exempt device. Information on the biliary disposition of drug-
related material derived in the current study may avoid the need for invasive methods of 
bile collection in future studies. The specific cohort and dose level (aiming for the highest 


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dose level) in part B that will undergo bile sampling will be determined based upon 
emergent pharmacokinetic data as agreed by the Dose Escalation Committee (DEC). The 
Entero-Tracker bile sample collected from placebo-dosed participants will be considered 
as the control. In addition, urine will be collected and used to investigate the urinary 
elimination of parent drug and any metabolites alongside bile analysis as well as analysis 
of residual PK plasma samples for drug and metabolites. The results of the metabolite 
investigations in these matrices will be reported under a separate GSK protocol.   
4.2.1. 
Participant Input into Design. 
Participants in this study are healthy volunteers and therefore input into design is not 
applicable.   
4.3. 
Justification for Dose 
The dose justification provided below is based on the supporting information from the 
first time in human dose justification report [GlaxoSmithKline Document Number 
2020N445405_00]. 
4.3.1. 
Predicted Human Pharmacokinetics  
The predicted human therapeutic dose of GSK3915393 is based on PBPK modelling 
[GlaxoSmithKline Document number 2020N441210_00]. This approach is 
mechanistically robust and allows the utilisation of the predicted time course of 
GSK3915393 concentrations in the human lamina propria. The PBPK model predicts 
complete absorption of GSK3915393 (100%) with high first pass extraction (FPE) 
resulting in a low overall bioavailability of 4%.   
The human pharmacokinetic (PK) concentration-time profiles and PK exposure 
parameters (Cmax and AUC) of GSK3915393 were also predicted using in vitro to in 
vivo extrapolation (IVIVE) and allometric scaling to evaluate the range of likely 
exposures and predicted maximum TG2 inhibition following a range of single doses of 
GSK3915393 [GlaxoSmithKline Document number 2020N445405_00]. 
For both the IVIVE and allometric scaling approaches, human clearance and volume of 
distribution values were estimated assuming a weight of 70 kg and the bioavailability was 
assumed to be 10% (based on the range of mouse, rat and dog bioavailability values from 
2 to 20%).  The absorption rate constant (ka) was assumed to be 2 h-1.  For all methods 
the human half-life (t½) of GSK3915393 is predicted to be short (<2h).  
4.3.2. 
Anticipated Pharmacological Dose Range of GSK3915393 
The site of action for TG2 inhibition for the treatment in CeD is in the lamina propria of 
the gut.  The predicted GSK3915393 concentration-time profile in the lamina propria 
from the PBPK model was used to predict TG2 inhibition. 
The predicted human PK parameters along with the experimentally obtained human in 
vitro kinetics values of Ki (244 nM) and kinact (0.13 min-1) were incorporated into a 
mechanistic pharmacokinetics/pharmacodynamics (PKPD) model to predict levels of 


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TG2 inhibition at various dose levels. The rate of regeneration of TG2 activity in the 
tissue was assumed to be 2.5x slower than that observed in mouse (i.e. t½=93h).  
Based on the predicted percentage inhibition of TG2, for the same total daily dose, twice 
daily dosing (BID) provided improved trough TG2 inhibition over QD dosing whereas 
increasing the frequency to three times daily dose (TID) did not provide additional 
improvement on the trough   TG2 inhibition.  Therefore, the anticipated pharmacological 
dose range of GSK3915393 is based on a BID dosing regimen.  It is anticipated that 
GSK3915393 would be dosed prior to or at the same time as breakfast and evening meal, 
therefore the BID dosing regimens were simulated assuming 10 h and 14 h dosing 
intervals (e.g. dosing at 8am and 6 pm). Based on these simulations a dose of 20 mg BID 
is predicted to provide a mean of 90% TG2 inhibition over a 24 hour period 
[GlaxoSmithKline Document number 2020N441210_00]. 
4.3.3. 
Starting Dose Selection for Part A 
Although, TG2 is not expected to be activated in the small intestine of healthy 
participants, it is proposed that the starting dose is based on using the ‘Minimal 
Anticipated Biological Effect Level’ (MABEL) approach.  Based on the average 
predicted maximum TG2 inhibition across the 4 human PK prediction methods, a starting 
dose of 15 mg is predicted to provide a maximum of approximately 46% inhibition of 
TG2 in the lamina propria and 5% inhibition systemically following single dose 
administration of GSK3915393 (Table 3). 
Table 3 
Predicted maximum percentage TG2 inhibition in the gut lamina 
propria (LP) and blood following single dose administration of 
GSK3915393   
Dose 
PBPK 
IVIVE lower CL 
IVIVE higher 
CL 
Allometric 
scaling 
Average Across 
Human 
Prediction 
Methods 
 
LP 
Blood 
LP 
Blood 
LP 
Blood 
LP 
Blood 
LP 
Blood 
10 mg 
35 
1 
48 
5 
35 
4 
21 
2 
35 
3 
15 mg  
47 
2 
61 
8 
47 
6 
30 
3 
46 
5 
20 mg 
57 
3 
71 
10 
57 
7 
37 
4 
56 
6 
 
Safety margins are calculated using the Cmax and AUC values from the scaling approach 
predicting the highest exposure for a given dose level. At the 15 mg dose, the highest 
predicted mean plasma Cmax (12.6 ng/mL) and AUC(0-inf) (50.7 ng.h/mL) values are 
expected to have 763-fold and 669-fold safety cover, respectively, based on Day 28 
gender averaged mean Cmax (9620 ng/mL) and AUC(0-t) (33900 ng/mL) values observed 
at the NOAEL in dog [60 mg/kg BID] in the 4 week safety assessment study.  Thus, a 
starting dose of 15 mg in human provides sufficient safety margins against the preclinical 
toxicological findings to ensure the safety of study participants. 


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4.3.4. 
Top Dose Selection for Part A 
GSK3915393 can generate reactive metabolites in the liver, which has the potential to 
cause idiosyncratic hepatoxicity in a small number of people. Although generally a rare 
event, the risk of this occurring is greatly reduced if the dose is less than 100 mg/day 
[Sakatis, 2012].  The highest dose intended to be taken into Phase 2 for chronic dosing is 
40 mg BID (80 mg/day).  In part B it is proposed to evaluate a dose of 160 mg BID (320 
mg/day) [see Dose Selection for Part B for rationale].  To support dosing of 160 mg BID 
dose in part B, it is proposed to administer 320 mg as the top dose in part A. 
The top dose of 320 mg is predicted to provide up to a 16-fold higher Cmax than the 
anticipated therapeutic unit dose of 20 mg which supports supratherapeutic 
concentrations for evaluation of QT.  However, if intestinal CYP3A4 plays a significant 
role in the metabolism of GSK3915393, these margins may be narrower due to higher 
Cmax in CeD patients compared with healthy individuals. 
At the 320 mg dose, the predicted highest mean plasma Cmax (268 ng/mL) and AUC(0-) 
(1082  ng.h/mL) values are expected to have approximately 36-fold and 31-fold safety 
cover, respectively, based on gender averaged Day 28 Cmax and AUC(0-t) values observed 
at the NOAEL in the dog  (60 mg/kg BID) in the 4 week safety assessment study (Table 
4). 
4.3.5. 
IV Microdose in Part A 
Predictions of human GSK3915393 PK following IV administration were based on the 
PBPK model. Human PK estimates derived assuming a weight of 70 kg were; clearance 
= 72.2 L/h, volume = 106 L. 
The IV dose of GSK3915393 to be administered is a microdose of 100 μg, which will be 
infused over 1 h.  The predicted Cmax and AUC(0-inf) have greater than 5000 and 
15000-fold safety margins compared with the gender averaged Day 28 Cmax and AUC 
values observed at the NOAEL in the dog 4 week safety assessment study (Table 4). 
A 100 µg total dose of GSK3915393A will be formulated as a 0.1 mg/mL solution 
(prepared in 20mM Acetate buffer). In an in vitro hemolysis assay using human 
erythrocytes, GSK3915393 IV Solution for Infusion at concentrations 0.1 mg/mL 
(prepared in a 20mM acetate buffer) did not produce hemolysis when added to human 
blood.   


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4.3.6. 
Safety Margins for Proposed Doses for Part A 
Table 4 
Proposed doses for Part A, with predicted exposure and safety 
cover. 
Dose Level  Dose 
Predicted 
Cmax (ng/mL) 
Predicted fold 
below NOAEL1 
 
Predicted 
AUC 
(ng.h/mL) 
Predicted fold 
below NOAEL2 
1 
15 mg PO 
12.6 
763 
50.7 
669 
2 
60 mg PO 
50.1 
 192 
203 
167 
3 
160 mg PO 
133 
72.3 
541 
62.7 
4 
320 mg PO 
268 
36.2 
1082 
31.3 
 
100 ug IV 
1.4 
6871 
2.14 
15841 
1 Calculated based on gender averaged Week 4 toxicokinetic Cmax (9620 ng/mL) in dogs 
following oral dosing at NOAEL of 60 mg/kg BID  
2 Calculated based on gender averaged Week 4 toxicokinetic AUC(0-t) (33900 ng.h/mL) in dogs 
following oral dosing at NOAEL of 60 mg/kg BID         
 
4.3.7. 
Dose Selection for Part B  
The dose level of GSK3915393 selected to be administered in Part B will not exceed the 
maximum daily dose investigated in Part A of the study. Twice-daily (BID) dosing of 
GSK3915393 for 14 days is currently planned for Part B.  Dose selection for Part B is 
based on providing safety cover for the dose to be used in future studies in patients with 
CeD.   It is proposed that three dose levels will be evaluated in part B (e.g. 20, 60 and 160 
mg BID).  Since t½ of GSK3915393 is predicted to be <2h, a BID regimen is not 
expected to result in any accumulation of GSK3915393 upon repeat dosing.  The safety 
margins for the proposed top dose of 160 mg BID in part B are the same as for the 320 
mg (for AUC) and 160 mg (for Cmax) single dose margins in part A.   
In-vitro data has shown that GSK3915393 is a substrate for intestinal and hepatic 
CYP3A4. Patients with CeD have reduced intestinal CYP3A4 activity, therefore drugs 
which are subject to intestinal CYP3A4 metabolism may have increased systemic 
exposure compared to healthy subjects.  This has been observed for felodipine which is 
completely absorbed but has an oral bioavailability of 16% as a result of intestinal and 
hepatic first pass clearance.  Approximately 50% of an administered dose of felodipine is 
cleared via CYP3A4 intestinal metabolism [Xie, 2016].  A study in patients with CeD 
showed that the systemic exposure (AUC) to felodipine was approximately 1.7-fold 
higher in patients with mild mucosal abnormalities compared to healthy controls and was 
approximately 2.3-fold higher in patients with moderate to severe mucosal abnormalities 
[Chretien, 2020].  This suggests that the majority of felodipine that is cleared by intestinal 
CYP3A4 in healthy controls is not cleared in patients with CeD.  A review of 15 orally 
administered CYP3A4 substrate drugs showed that the majority had between 35 to 55% 
eliminated by intestinal metabolism [Xie, 2016].  However, buspirone has 78% of 
administered drug elimination via intestinal CYP3A4 metabolism.  If GSK3915393 were 
to have a similar proportion of drug eliminated via intestinal CYP3A4, the systemic 
exposure in patients CeD could be around 4.5-fold higher than in healthy subjects 


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(i.e.100% available for absorption vs 22%).   Therefore, it is proposed to evaluate higher 
doses in the healthy participants in Part B of the study than the highest dose that is 
planned to be evaluated in future studies in CeD: e.g. upto 160 mg BID in Part B to cover 
for 40 mg BID in CeD. As described above in Section 4.3.4, the highest dose which may 
be evaluated in future studies in CeD is 40 mg BID.  
 
 
4.3.8. 
Dose Escalation in Parts A and B 
Dose escalation will be guided by the principles listed below, the criteria in Section 6.5 
and the stopping criteria detailed in Section 7.2  
Part A 
The following rules will guide dose selection in Part A: 
1. The highest dose escalation step to the next dose will be 5-fold. 
2. Once the dose exceeds 80 mg (the planned maximum daily dose to be taken into 
Phase 2), any further dose escalation will be no higher than 3-fold in order to 
minimize the risk of adverse events. 
3. The highest dose in part A will not exceed 320 mg.  
 
Part B 
The following rules will guide dose selection in Part B: 
1. The starting daily dose in part B will be selected after review of safety, tolerability 
and PK data from at least two dose levels in Part A. 
2. The highest dose escalation step to the next dose will be 4-fold; Once the dose is ≥ 
80 mg/d (the planned maximum daily dose to be taken into phase 2), any further 
dose escalation will be no higher than 3-fold.  
3. The highest daily dose in part B will not exceed 320 mg/day (160 mg BID). 
 
4.3.9. 
Dose Selection for Part C  
There is a potential of substantial increase in exposure to GSK3915393 following oral 
administration of GSK3915393 with itraconazole, therefore the interaction of 
itraconazole will initially be evaluated with an IV micro-dose of GSK3915393 (100 µg). 
This will allow the impact of itraconazole inhibition of hepatic CYP3A4 on systemic 
exposure to GSK3915393 to be evaluated and inform the selection of the oral dose of 
GSK3915393 to be administered in periods 3 to 5   
Preliminary PK data from Part A of the study showed that following administration of the 
IV micro-dose (100 µg), the observed mean Cmax and AUC values (5 ng/mL and 5  


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ng.h/mL, respectively) have approximately 1900 and 6800-fold safety margins compared 
with the gender averaged Day 28 Cmax (9620 ng/mL) and AUC (33900 ng.h/mL) values 
observed at the NOAEL in the dog 4 week safety assessment study. Therefore there is no 
risk that the exposures observed in the presence of itraconazole will approach the 
specified PK stopping criteria.  
All available PK data, including information from the IV microdose in the presence of 
itraconazole will be used to set the oral dose for periods 3-5. The selection of the oral 
dose will be based on maintaining the predicted exposure to GSK3915393 in the presence 
of itraconazole in accordance with the defined PK stopping criteria and within the 
systemic exposures already achieved in Parts A and B of the study and will not exceed 20 
mg.  See Section 6.5 for further details on dose selection for Part C.  
4.4. 
End of Study Definition 
The end of the study is defined as the date of last scheduled procedure at FU (LSLV) 
shown in the Schedule of Activities for the last participant in the trial globally. 
A participant is considered to have completed the study if he/she has completed all 
phases of the study part including the last scheduled procedure shown in the Schedule of 
Activities. 
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 
5.1.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Study Specific Criteria:  
AGE 
1. Between 18 and 50 years of age inclusive, at the time of signing the informed 
consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Healthy Participants who are overtly healthy as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and cardiac 
monitoring.  
3. Negative COVID-19 test on admission.  


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WEIGHT 
4. Body weight 40 kg and body mass index (BMI) within the range 18.5-29.9 kg/m2 
(inclusive). 
SEX 
5. Male or females  
a. Male participants: 
• 
No restrictions for male participants. 
b. Female participants: 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and one of the following conditions applies: 
o Is a woman of non-childbearing potential (WONCBP) as defined in Section 
10.4 Contraception and Barrier Guidance. 
OR 
o Is a woman of childbearing potential (WOCBP) and using an acceptable 
contraceptive method as described in Section 10.4 from 30 days prior to 
first dose until follow up visit. The investigator should evaluate the 
potential for contraceptive method failure (e.g., noncompliance, recently 
initiated in relationship to the first dose of study intervention). 
• A WOCBP must have a negative highly sensitive pregnancy test (serum) at 
screening and on admission to the clinical unit, see Section 8.2.6 Pregnancy 
Testing. 
• Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.2.6. 
• 
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 
6. Capable of giving signed informed consent 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 
5.2.1. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
 
MEDICAL CONDITIONS 
1. History or current evidence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal (Irritable bowel syndrome [IBS], Gastroesophageal reflux disease 
[GERD], nausea, vomiting or dysphagia), endocrine, hematological, neurological, 
or psychiatric disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; constituting a risk when taking the study 
treatment; or interfering with the interpretation of data. 
2. Current evidence of active infection.  
3. Participants with signs/symptoms suggestive of COVID-19 (i.e. fever, cough, etc) 
within the past 14 days prior to screening and admission to clinical unit. 
4. Participants with known COVID-19 positive contacts in the past 14 days prior to 
screening and admission to clinical unit. 
5. Any history of suicidal behavior within the past 6 months or any history of 
attempted suicide in a participant’s lifetime. 
6. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).  
7. Bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
8. Current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
9. History of GI surgery (with exception of appendectomy). 
10. Average QTcF >450 msec at screening  
11. Any clinically relevant abnormality on the screening medical assessment, 
laboratory examination, or ECG 
12. History of QTc prolongation, symptomatic cardiac arrhythmias or cardiac arrest. 
13. For Part C only, history of liver toxicity resulting from drug administration. 
14. For Part C only, history of intolerance to itraconazole. 
 
PRIOR/CONCOMITANT THERAPY 
15. History of sensitivity to any of the study medication, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or GSK 
Medical Monitor, contraindicates their participation.  


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16. Use of any immunosuppressive medications within 6 months prior to entry. 
17. Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, probiotics, antacids, 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 medication for each 
dosing, unless in the opinion of the Investigator and GSK Medical Monitor the 
medication will not interfere with the study procedures or compromise participant 
safety.  (Paracetamol is acceptable at a dose of no more than 500 mg at a time and 
no more than 2 grams per day). 
18. Participants who have received a COVID-19 vaccine within 7 days of admission 
(or readmission) to the clinical unit or who are demonstrating signs/symptoms 
attributed to a COVID-19 vaccination that occurred greater than 7 days earlier.  
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
19. Recent donation of blood or blood products such that participation in the study 
would result in loss of blood in excess of 500 mL within 56 days. 
20. The participant has participated in a clinical trial and has received an 
investigational product within the following time period 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 investigational product (whichever is longer). 
21. Exposure to more than 4 investigational medicinal products within 12 months prior 
to the first dosing day 
22. Unwillingness or inability to follow the procedures outlined in the protocol or any 
other type of medical research within 30 days of randomization. 
 
DIAGNOSTIC ASSESSMENTS 
23. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study treatment 
24. Positive hepatitis C antibody test result at screening or within 3 months prior to 
first dose of study treatment.  NOTE: Participants with positive Hepatitis C 
antibody due to prior resolved disease can be enrolled, only if a confirmatory 
negative Hepatitis C ribonucleic acid (RNA) test is obtained 
25. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.  NOTE: Test is optional and participants with negative 
Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing 
26. A positive pre-study drug/alcohol screen 
27. Positive human immunodeficiency virus (HIV) antibody test 
 


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OTHER EXCLUSIONS 
28. History of drug abuse (as defined by the current version of the Diagnostic and 
Statistical Manual [DSM]) within 2 years before dosing, or a positive drug screen 
reflecting consumption of illicit drugs.  
29. Regular alcohol consumption within 6 months prior to screening:  
• An average weekly intake of >21 units for males or >14 units for females. 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. 
30. Urinary cotinine levels indicative of smoking or use of tobacco or nicotine-
containing products (e.g. nicotine patches or vaporizing devices) at screening or on 
admission to the unit. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or citrus fruit juices from 7 
days before the start of study intervention until after the final dose. 
5.3.1.1. 
Part A 
• On Day 1 in all oral dosing periods participants will fast for 8hr and a standard 
breakfast will be served approximately 30 minutes prior to dosing. 
• All other meals will be served as per the site schedule. 
• In the IV dosing period all meals will be served as per the site schedule. 
• 8 fl oz (240 mL) of water to be taken after dosing and water permitted on an ad lib 
basis. 
• Other decaffeinated drinks will be permitted except during fasting periods 
5.3.1.2. 
Part B 
• Breakfast  
• Participants will fast 8hr and a standard breakfast will be given approximately 30 
min pre dose (except on Day 3 and Day 5 (see below)).  On day 7 breakfast will 
be eaten within 20 minutes. 
• Day 3 - Participants will fast 8hr and will be dosed fasted, a low-fat breakfast will 
be served approximately 2hr after dosing. 
• Day 5 - Participants will fast 8hr and a high fat breakfast meal will be given 
approximately 30 min. pre dose & eaten within 20 minutes. 
• Lunch  


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• Day 12 in the cohort undergoing bile sampling - A high fat small lunch meal will 
be served at approximately 5 hours post dose.  
• On all other day’s lunch and snacks will be served according to the sites schedule. 
• Dinner  
• On D1 dinner will be served approximately 1 h before PM dose. On all other days 
the dinner meal will be given approximately 40 mins prior to the PM dose. 
• Fluids 
• Water permitted on an ad lib basis  
• Other decaffeinated drinks allowed by the protocol will be permitted except 
during fasting periods and while the EnteroTracker is in place.   
 
5.3.1.3. 
Part C 
• On day 1 participants will fast 8hr prior to dosing (with Itraconazole or 
GSK3915393 depending on period and day) and a standard breakfast will be 
served approximately 2 hours post GSK3915393 oral dose or start of IV infusion  
o The day 1 fasting requirements may be adjusted based on the emerging 
food effect data in Part B. Changes will be documented in a note to file. 
• Itraconazole administration on Days -3 to -1 and Days 2 and 3 may 
be administered following a standard meal. 
• All other meals will be served as per the site schedule. 
• Water or GFJ (volume to be defined in SRM) to be taken with GSK3915393 
dosing (depending on period) and water permitted at other times on an ad lib 
basis. 
• Other decaffeinated drinks will be permitted except during fasting periods 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing (with itraconazole or GSK3915393 depending on 
period) until after collection of the final PK and/or pharmacodynamic sample. 
• During each dosing session, participants will abstain from alcohol for 24 hours before 
the start of dosing (with itraconazole or GSK3915393 depending on period) until after 
collection of the final PK and/or pharmacodynamic sample.  
• Use of tobacco products will not be allowed from screening until after the final 
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5.3.3. 
Activity 
• Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading, walking). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study may be rescreened. 
Rescreened participants should be assigned a new participant number. Screening 
assessments that yield aberrant results (e.g., safety laboratory samples) may be repeated 
once within the screening window at the discretion of the investigator. Individuals who 
failed initial screening but passed rescreening may be admitted into the study based upon 
clinical judgement and after consultation with the GSK medical monitor.  
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
The following products will be received by the participant as per the protocol design. 
Part A - Participants will receive GSK3915393 extemporaneous formulations: API filled 
capsules and placebo capsules according to the treatment sequence to which they are 
assigned.  For the IV dose, participants will receive GSK3915393 at a dose of 100 µg 
within 24 hours from compounding. 
Part B - Participants will receive GSK3915393 extemporaneous formulations: API filled 
capsules and placebo capsules according to the treatment to which they are assigned. 
Part C - Participants will receive GSK3915393 extemporaneous formulations: API filled 
capsules for 3 Periods.  For the IV dose, participants will receive GSK3915393 at a dose 
of 100 µg within 24 hours from compounding. In periods 2 and 5, 200 mg Itraconazole 
will be given as an oral solution or tablets (depending on emerging data from Part B). In 
periods 3 or 4 participants will receive GFJ according to the randomisation.


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Intervention 
Name 
GSK3915393 
Solution for 
Infusion 
GSK3915393 
Capsules 
GSK3915393 
Placebo to 
Match 
Capsules 
Itraconazole 
Grapefruit 
Juice  
Type  
Drug  
Drug 
Drug 
Drug 
Food Stuff 
Dose 
Formulation  
IV  
Capsule 
Capsule 
Solution or 
capsule 
Drink  
Unit Dose 
Strength(s)  
IV infusion to 
be prepared 
by 
extemporaneo
us 
compounding 
to 100 µg. 
API alone in 
capsule to be 
prepared by 
extemporaneo
us 
compounding 
to required 
weight. 
Multiple 
Capsules can 
be used as 
required. Fill 
weight can 
span from 
2mg to 100mg 
as required  
To match oral 
active.  (No 
placebo for IV 
infusion arm.) 
Solution 10  
mg/ml or 100 
mg capsule 
Volume to 
be defined 
in SRM  
Dosage 
Level(s) 
100 µg once 
Starting dose 
single dose of 
15 mg 
subsequent 
doses to be 
determined at 
dose 
escalation 
meetings   
To match oral 
active.  (No 
placebo for IV 
infusion arm.) 
200 mg 
Volume to 
be defined 
in SRM  
Route of 
Administrati
on 
IV infusion 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Experimental 
Placebo 
Experimental 
Experiment
al  
IMP and 
NIMP 
IMP  
IMP  
IMP  
NIMP 
NIMP 


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Intervention 
Name 
GSK3915393 
Solution for 
Infusion 
GSK3915393 
Capsules 
GSK3915393 
Placebo to 
Match 
Capsules 
Itraconazole 
Grapefruit 
Juice  
Sourcing 
 
Extemporaneo
us 
compounding 
facility to 
provide, 
labelled, 
solution for 
injection via 
Extemporaneo
us 
Compounding 
Extemporaneo
us 
compounding 
facility to 
provide 
blinded, 
labelled, API 
in Capsule 
and Placebo 
capsules via 
Extemporaneo
us 
Compounding 
TBC 
Extemporaneo
us 
compounding 
facility to 
provide 
blinded, 
labelled, API 
in Capsule 
and Placebo 
capsules via 
Extemporaneo
us 
Compounding 
Kleva 
Pharmaceutic
als (Generic 
substitution is 
permitted) 
Provided 
by GSK 
Packaging 
and 
Labelling 
 
Syringe which 
is capped 
Capsules 
provided in 
labelled HDPE 
bottles 
Capsules 
provided in 
labelled HDPE 
bottles 
N/A 
N/A 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual. 
5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 


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unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
6. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
On Day 1 of the first dosing period for each cohort, participants will be assigned a unique 
randomisation number in ascending numerical order. In parts A and B, the randomisation 
number encodes the participant’s assignment to either GSK3915393 or placebo, 
according to the randomisation schedules generated prior to the study by the Statistics 
Department at GSK, using validated internal software. The PI or delegated responsible 
person will assign the randomisation numbers as described above and the randomisation 
number will be entered in the case report form (CRF).  Subjects will receive 
GSK3915393 in all periods in Part C, and the randomisation schedule defines the period 
in which GFJ will be co-administered with GSK3915393.  
The unblinded pharmacist will receive a copy of the randomisation schedules from the 
GSK randomisation co-ordinator to enable dispensing of study medication.  
Parts A and B of the study are double blind. Investigators will remain blinded to each 
participant’s assigned study intervention throughout the course of the study. In order to 
maintain this blind, an unblinded pharmacist will be responsible for the reconstitution and 
dispensation of all study intervention. 
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
Code break envelopes, which contain the treatment codes if required in an emergency, 
will be prepared by the unblinded pharmacist/unblinded site personnel. Code break 
envelopes will be stored in a secure fire-proof environment that is inaccessible to blinded 
personnel, but can be directly accessed 24 hrs a day by the investigator in case emergency 
unblinding is required.   
The investigator or treating physician may unblind a participant’s treatment assignment, 
using the code break envelopes, only in the case of an emergency OR in the event of a 
serious medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
investigator. 
It is preferred (but not required) that the investigator first contacts the Medical Monitor or 
appropriate GSK study personnel to discuss options before unblinding the participant’s 
treatment assignment.  


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If GSK personnel are not contacted before the unblinding, the investigator must notify 
GSK as soon as possible after unblinding, but without revealing the treatment assignment 
of the unblinded participant, unless that information is important for the safety of 
participants currently in the study.  
The date and reason for the unblinding must be fully documented in the CRF. A 
participant will be withdrawn if the participant’s intervention code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
Part C is being conducted open label as placebo-to-match ITZ and GFJ are not currently 
available.  The time periods for ITZ coadministration are fixed as opposed to randomised 
(see Section 4.2). The primary endpoint for Part C is pharmacokinetic, and there is no 
risk of bias with this objective measure. There is however potential for carry over/period 
effects to confound the safety evaluation within Part C, but since safety is a secondary 
objective in Part C and the exposures within Part C are expected to remain within the 
range studied in the randomised double blind phases of the study (Parts A and B), there is 
minimal risk to the overall integrity of the study by adopting this approach in Part C. 
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.  In oral dosing periods study site staff will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
6.5. 
Dose Modification 
Dose justification and stopping criteria are detailed in Section 4.3 and Section 7.1 
respectively. 
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum daily dose will not exceed 320mg in parts A and B. 
The decision to proceed to the next dose level of GSK3915393 (either an increase, a 
decrease or to repeat a dose level) during parts A and B will be made by a DEC 
consisting of the Principal Investigator (or appropriate designee), Medical Monitor, GSK 


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Study Team Leader, GSK Clinical Pharmacology Modelling and Simulation (CPMS) 
representative, a GSK GCSP representative and a GSK Statistician (or appropriate 
designees for GSK DEC members).   The DEC will review blinded data.  Unblinded data 
may be reviewed by the GSK Medical Monitor, GSK CPMS representative, and a GSK 
Biostats representative.  The decision to progress from part A to part B and the oral dose 
to be used in Part C will also be made by the DEC.  
In parts A and B, dose escalation or adjustment decisions will be based on data review 
which includes at least 6 participants on active treatment (two thirds of planned 9 
participants on active treatment) at the prior dose level.  The review data set will at 
minimum consist of AE listings, safety labs, vital signs and ECG and PK results up to 24 
h post-dose in part A, and up to 10 h post-Day 7 dose in part B. Laboratory findings will 
also be reviewed. 
In Part C, data review will be conducted prior to initiating period 3 and will comprise a 
minimum of 8 subjects dosed with GSK3915393 IV + ITZ and GSK3915393 IV to 
enable the selection of the oral dose of GSK3915393 to be co-administered with GFJ and 
ITZ in periods 3-5.  The review data set will comprise of PK data and AE listings, safety 
labs, vital signs and ECG from periods 1 and 2 in conjunction with available safety data 
from Parts A and B. 
In parts A and B the dosing schedule may also be adjusted to expand a dosing cohort to 
further evaluate safety and/or PK findings at a given dose level to add cohorts to evaluate 
up to 1-2 additional dose levels. The study procedures for these additional 
participant(s)/cohort(s) will be the same as those described for other study 
participants/cohorts. Additional dose levels will not exceed the doses described in Section 
4.3.8. 
The Dose Escalation Plan will outline how the study team will ensure data integrity is 
maintained in dose selection decisions by performing clinical data review and appropriate 
quality control of data prior to making dose selection decisions or decisions to transition 
into a subsequent part of the study. 
The DEC charter will also outline the responsibilities of the investigators and site staff for 
reporting safety data, participation during dose escalation/ adjustment meetings and 
confirmation that the data used for dose escalation/ adjustment are accurate and complete. 
 
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
Participants will not receive any additional treatment from GSK, or with GSK3915393, 
after completion of the study because this is a Phase 1 study 
6.7. 
Treatment of Overdose 
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat an overdose. 


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In the event of an overdose, the investigator or treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities for at least 
4 days. 
3. Obtain a plasma sample for PK analysis immediately unless a PK sample has already 
been obtained after the overdose. 
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. 
6.8. 
Concomitant Therapy 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days 
if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the 
start of study intervention until completion of the follow-up visit, unless, in the opinion of 
the investigator and sponsor, the medication will not interfere with the study.  
Paracetamol, at doses of 2 grams/day, 500mg at a time is permitted for use any time 
during the study. Other concomitant medication may be considered on a case-by-case 
basis by the investigator in consultation with the Medical Monitor if required. 
Oral contraception as detailed in Section 10.4 are permitted.  
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study until the end of that treatment period to be evaluated for safety and 
tolerability. See the SoA (Section 1.3) for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that 
need to be completed. 
A participant may be withdrawn from the study if: 
a) A participant experiences a serious or severe clinically significant non-serious AE 
that in the clinical judgement of the Investigator, is at least possibly related to 
investigational product. 
b) The participant initiates treatment with any prohibited medications. 
c) If any of the protocol individual stopping criteria are met. 


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• 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
a) Deviation(s) from the protocol 
b) Withdrawal of consent by participant (or proxy) 
c) Discretion of the Investigator 
d) Participant is lost to follow-up 
 
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. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm or  
•  in the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, if the investigator believes that it is in the best interest of the 
participant.  
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met: 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal. 


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Refer to Section 10.5 for required Liver Safety Actions and Follow up Assessments.  
7.1.2. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion below will be withdrawn from the study.   
• QTcF >500 msec, 
• Change from baseline in healthy volunteer participants: QTcF >60 msec 
The QTcF correction formula must be used for each participant to determine eligibility 
for and discontinuation from the study.  This formula may not be changed or substituted 
once the participant has been enrolled. If an ECG demonstrates a prolonged QT interval, 
two more ECGs should be obtained over 5-10 mins and the average QTcF value of the 
three ECGs should be used to determine if the participant meets the QTc stopping criteria 
see Section 8.2.3. 
7.1.3. 
Vital signs Stopping Criteria 
A subject will be withdrawn if any of the following cardiovascular changes are detected 
up to 24 h post last dose in each session.    
• 
Clinically significant and sustained (i.e., for greater than 2 hours) increase in 
systolic or diastolic blood pressure, for example: 
• 
- systolic blood pressure >160 mmHg or >30 mmHg increase from baseline or, 
• 
- diastolic blood pressure >100 mmHg or >20 mmHg increase from baseline 
• 
Clinically significant and sustained increase in resting heart rate (for example, 
>120 beats/minute for more than 2 hours) 
Withdrawal is to be based on an average value from triplicate blood pressure or heart rate 
readings.  If any blood pressure or heart rate readings are flagged as clinically significant, 
they are to be repeated in triplicate and checked every 20 minutes until they are no longer 
clinically significant. 
7.1.4. 
Rechallenge 
If any stopping criteria are met by any participant in this study, study treatment restart or 
rechallenge is not allowed. 
7.1.5. 
COVID-19 Discontinuation 
• If a participant develops COVID-19 like symptoms during the study the following 
actions should be taken: 
o During Part A and C, participants who develop signs/symptoms highly 
suggestive of COVID-19 disease should be isolated and tested for 
COVID-19 in accordance with site procedures. 


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o During Part B, study treatment should be halted for any participants who 
develop signs/symptoms highly suggestive of COVID-19 disease; they 
should be isolated and tested for COVID-19 in accordance with site 
procedures. 
o In both cases, assessments should be continued as per the protocol where 
possible; withdrawal of participants from the study will be at the 
discretion of the Principal Investigator but should first be discussed and 
agreed with the GSK Medical Monitor. 
7.2. 
Study Stopping Criteria. 
7.2.1. 
Safety Stopping Criteria  
In the event of any of the following, ongoing dosing will be halted. 
• 
Two or more participants in the same dose group/cohort experience non-serious 
severe adverse events considered at least possibly related to the administration of 
GSK3915393. 
• 
Any participant experiences a serious adverse event considered at least possibly 
related to the administration of GSK3915393. 
The dosing will be temporarily halted, and no further participants will be dosed until a 
full safety review of the study has taken place. Relevant reporting and discussion with the 
GSK medical monitor, relevant GSK personnel, and with the CA and IRB / IEC will then 
take place prior to any resumption of dosing, which may also include the evaluation of 
lower doses. If following an internal safety review, it is appropriate to restart the trial, a 
substantial amendment will be submitted to the MHRA and REC.  The trial will not 
restart until the amendment has been approved by the MHRA and REC. 
7.2.2. 
Pharmacokinetic Stopping Criteria 
The following dose adjustment / PK stopping criteria will apply:   
• 
If exposure in an individual subject and/or mean cohort exposure exceeds or is 
predicted to exceed the gender averaged PK exposures in dogs following oral 
dosing at the NOAEL of 60 mg/kg BID (Cmax of 9620 ng/mL or total daily 
AUC(0-24) of 33900 ng.h/mL), dose escalation will be stopped 
• 
If the PK stopping criteria is reached with initial doses, the dose escalation will 
be stopped. The GSK team will decide based on safety and PK whether to 
evaluate any lower doses or repeat doses already evaluated in remaining periods 
to collect additional safety and PK data. Throughout all parts of the study, 
noncompartmental PK analysis will be used to help inform the choice of the 
next dose level as part of dose escalation discussions. 


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7.3. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA (Section 1.3). 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/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
7.4. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods).  These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• Protocol waivers or exemptions are not allowed  
• Immediate safety concerns will be managed by the investigator with discussions 
with the GSK Medical Monitor as required to determine if the participant should 
continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
• 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 
Efficacy assessments will not be performed in this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A full physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
 


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8.2.2. 
Vital Signs 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed in the semi-recumbent 
position with a completely automated device.  Manual techniques will be used only if 
an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 
pulse and 3 blood pressure measurements (3 consecutive blood pressure readings will 
be recorded at intervals of at least 1 minute).  The average of the 3 blood pressure 
readings will be recorded. 
 
8.2.3. 
Electrocardiograms 
• Triplicate OR Single 12-lead ECG will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.  Refer to Section 7.1.2 for QTc 
withdrawal criteria. 
• At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 
2 minutes apart.  
• If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a 
brief period of time and then use the mean QTcF values of the 3 ECGs. 
• Safety ECGs will be printed and interpreted on-site by the Investigator to ensure 
participant safety. Refer to Section 7.1.2 for QTc withdrawal criteria.  
• Continuous cardiac telemetry will be performed at time points indicated in the SoA 
(Section 1.3).  Full disclosures will be reviewed in detail and the review maintained 
as part of the subject’s source documents. 
 
8.2.3.1. 
Cardiodynamic assessment (ECGs extracted from Holter recordings) 
The 12-lead Holter/ECG equipment will be supplied and supported by ERT. All continuous 
ECG (Holter) data will be collected using a Global Instrumentation (Manlius, NY, USA) 
M12R ECG continuous 12 lead digital recorder. The continuous 12-lead digital ECG data 
will be stored onto SD memory cards. In case the cardiodynamic evaluation is undertaken, 
12-lead ECGs will be extracted in replicates from the continuous ECG recording at pre-
determined time points as defined in the SoA and will be read centrally by ERT. If a 
decision is taken to undertake cardiodynamic evaluations, details will be outlined in a 
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8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency.  
• The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the source documents.  
• All laboratory tests with values considered clinically significantly abnormal 
during participation in the study including at follow up should be repeated until 
the values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor.  
o If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, further investigations to determine 
the etiology should be undertaken in coordination with the sponsor. 
• All protocol-required laboratory tests, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
• If laboratory values from non-protocol specified laboratory tests require a change 
in participant management or are considered clinically significant by the 
investigator, the results must be recorded. 
 
8.2.5. 
COVID-19 testing  
Participants will be tested for Covid-19 according to local site procedures, at a minimum 
participant will be tested at the timepoints in the SoA.  
Subjects who report symptoms suggestive of COVID-19 while in the research unit should 
be isolated according to local site procedures in the unit or at home and tested for 
COVID-19 infection using an approved molecular test.  


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8.2.6. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• 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. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AE or SAEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention or study (see 
Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
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 follow-up visit at the 
time points specified in the SoA (Section 1.3).  
• All AEs will be collected from the start of intervention until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
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8.3.2. 
Method of Detecting AEs and SAEs 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.4). Further information on follow-up procedures is given in 
Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of 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 CA 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 CA, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 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 Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• 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. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until completion of the final follow up visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant pregnancy. 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. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
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• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular (CV) events detailed in Section 10.3 and all deaths, whether or 
not they are considered SAEs, specific CV and Death sections of the CRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.4. 
Pharmacokinetics 
Instructions for the collection, handling and shipping of biological samples will be 
provided in the SRM. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Samples collected for analyses of GSK3915393 plasma concentration may also be 
used to evaluate safety aspects related to concerns arising during or after the study. 
8.4.1. 
GSK3915393 PK plasma collection.  
Blood samples will be collected at all timepoints in Parts A, B and C for measurement of 
plasma concentrations of GSK3915393.  
GSK3915393 concentration analysis will be performed under the control of In 
Vitro/In Vivo Translation (IVIVT).  Plasma concentrations of GSK3915393 will be 
determined using approved bioanalytical methodology.   
The bioanalytical site will be detailed in the SRM and raw data will be archived in 
the GSK R&D GLP archives.  


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8.4.2. 
Metabolite plasma collection.  
Plasma will also be analysed for other compound-related metabolites and the results 
reported separately.  
Blood samples will be collected in part A and part B (Days 1 and 14), as specified in the 
SoA (Section 1.3) to assess for GSK3915393 metabolites. 
8.4.3. 
Urine Metabolite collection  
Urine samples for analysis of GSK3915393 and its metabolites will be collected at 
the time-points listed in the SoA (Section 1.3). These samples may then be analysed 
for compound-related material and the results reported separately.  
Details of urine sample processing, storage and shipping procedures are provided in 
the SRM.  
8.4.4. 
Itraconazole and Hydroxy Itraconazole PK plasma collection.  
Blood samples will be collected at specified timepoints in Part C for measurement of 
plasma concentrations of Itraconazole and Hydroxy Itraconazole.  
Itraconazole and Hydroxy Itraconazole concentration analysis will be performed 
under the control of In-Vitro/In-Vivo Translation (IVIVT).  Plasma concentrations of 
Itraconazole and Hydroxy Itraconazole will be determined using approved 
bioanalytical methodology.   
The bioanalytical site will be detailed in the SRM and raw data will be archived in 
the GSK R&D GLP archives.  
The concentrations of itraconazole and hydroxy itraconazole will be used as part of 
the drug interaction modelling initiative (Section 9.4.3.1).   
8.4.5. 
EnteroTracker: Bile Sample Collection 
Duodenal bile samples will be collected at the time-points listed in the SoA for the 
analysis of GSK3915393 and its metabolites for participants in the highest dose part B 
cohort only. 
Bile fluid is recovered on a highly absorbent nylon line which is contained within a 
weighted gelatin capsule. The 90 cm line unwinds after capsule swallowing as the 
capsule dissolves in the stomach and the line then passes into the duodenum. During 
withdrawal, the weighted section of the capsule separates from the line and passes in the 
stool.  
Additional details of the bile EnteroTracker sample collection, processing, storage and 
shipping procedures are provided in the SRM. These samples may then be analysed for 
compound-related material and the results reported separately. 


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8.4.6. 
Plasma Sample for CYP3A4 Enzyme Activity 
Plasma derived from select PK blood samples in Part B (as in the SoA Table, see Section 
1.3), will be analyzed for 4β-hydroxycholesterol and cholesterol as a potential in vivo 
marker of CYP3A4 enzyme activity.  Samples collected pre-treatment and at steady-state 
will be compared to evaluate this potential marker. 
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM. 
Baseline and Day 14, post-treatment plasma samples will be analyzed using a validated, 
specific, and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) method 
to determine concentrations of 4β-hydroxycholesterol and total cholesterol.  A 
comparison will be made between the ratio of 4β-hydroxycholesterol: cholesterol at 
baseline and on Day 14 to assess potential changes in CYP3A4 enzyme activity 
following GSK3915393 treatment. 
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline. 
8.5. 
Pharmacogenomics 
Pharmacogenomics are not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GlaxoSmithKline. 
Reporting of study data will be performed in accordance with applicable GSK and/or 
contract research organization (CRO) standards. 
Complete details of the planned statistical analyses will be provided in the statistical 
analysis plan (SAP).  Any deviations from the planned analyses will be described in a 
SAP addendum and justified in the final integrated clinical study report. 
 
9.1. 
Statistical Hypotheses 
The primary objectives of parts A and B of this study are to assess the safety and 
tolerability of single and repeat ascending doses of GSK3915393 in healthy participants.  
The primary objective of Part C is to assess the victim drug interaction potential of 
GSK3915393 with the CYP3A4 inhibitors, grapefruit juice and itraconazole. No formal 
hypotheses will be tested.    
9.2. 
Sample Size Determination 
Twelve, 36 and 12  participants are planned to be randomised to study intervention in 
parts A, B and C respectively.  A further 12 healthy volunteers may be randomised in 


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parts A or B if additional dose levels are required to be studied. The sample sizes for 
parts A and B were selected to support the planned assessments of safety and tolerability, 
the primary objective of parts A and B of the study. 
 
In parts A and B, 9 subjects will receive each active oral dose.  If 0/9 subjects experience 
a particular adverse event, the upper limit of the exact 95% CI indicates that a true 
incidence rate of 33.6% could not be ruled out.  Whereas if 1/9 subjects experienced an 
event, the upper limit of the exact 95% CI indicates that a true incidence rate of 48.2% 
could not be ruled out. 
The sample size for Part C was selected taking into consideration the precision of 
estimation of the ratios of AUC and Cmax for the following comparisons of interest.   
• GSK3915393 PO + GFJ vs GSK3915393 PO + water    
• GSK3915393 IV + ITZ vs GSK3915393 IV  
• GSK3915393 PO + ITZ vs  GSK3915393 PO + water 
 
Assuming a within subject coefficient of variation of 35%, with 12 subjects the upper and 
lower limits of the 90% CI for the AUC and Cmax ratios will be 0.78 and 1.28 times the 
point estimate respectively. Increases in AUC and Cmax are expected to be observed 
when GSK3915393 is dosed in combination with GFJ or ITZ and it is expected that FG 
(ratio of AUC for GSK3915393 PO + water: GSK3915393 PO + GFJ) will be less than 1. 
The resulting confidence intervals for a range of ratio scenarios are illustrated in Table 5. 
 
Table 5 
Precision of estimation of AUC and Cmax Ratios in Part C  
Ratio Estimate 
90% CI with N=12 and 
CVW=35% 
0.2 
(0.16, 0.26) 
0.4 
(0.31, 0.51) 
0.6 
(0.47, 0.77) 
1 
(0.78, 1.28) 
2.5 
(1.95, 3.21) 
5 
(3.90, 6.42) 
10 
(7.79, 12.83) 
20 
(15.59. 25.66) 
 


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9.3. 
Analysis Sets 
The populations for the study are detailed below. 
Population 
Description 
Screened  
All participants who were screened for eligibility 
Randomized  
  
All participants who were randomly assigned to treatment in the study. 
This population will be based on the treatment the participant was 
randomized to. 
Safety 
All randomized participants who received at least one dose of study 
treatment. 
This population will be based on the treatment the participant actually 
received. 
  
PK 
All participants in the Safety population who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-missing 
values). 
This population will be based on the treatment the participant actually 
received. 
9.4. 
Statistical Analyses 
The statistical analysis plan will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned 
statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.4.1. 
Primary Endpoint(s) 
In parts A and B, the primary endpoints are the safety assessments as detailed in Section 
3. 
 
Safety data will be summarised in tabular and/or graphical form by dose regimen over 
time for the safety population.  Data for each study part will be summarised separately. 
 
In part C, the primary endpoints are GSK3915393 pharmacokinetic parameters AUC, 
Cmax, Tmax and t1/2  and these are outlined alongside the pharmacokinetic endpoints for 
parts A and B within Section 9.4.2. 
 
9.4.2. 
Secondary Endpoint(s) 
Pharmacokinetic Endpoints 
All pharmacokinetic analyses will be performed on the Pharmacokinetic Population.  


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Plasma concentration-time data of GSK3915393 will be analysed by non-compartmental 
methods. Calculations will be based on the actual sampling times recorded during the 
study. Full details will be described in the reporting and analysis plan.  
GSK3915393 pharmacokinetic parameters, including but not limited to the following will 
be determined from the plasma concentration-time data, as data permit: 
Part A 
• Maximum observed plasma concentration (Cmax) 
• Time to Cmax (Tmax)  
• Area under the plasma concentration-time curve (AUC) from time zero to the last 
quantifiable concentration (AUC(0-t)) 
• AUC from time zero to infinity (AUC(0-∞))  
• Apparent terminal phase half-life (t1/2)   
• Plasma clearance (CL) (iv only)  
• Plasma volume of distribution (Vd) (iv only) 
• Absolute bioavailability (F) 
o Where F=[AUC(0-∞) po /dose po ]/[AUC(0-∞) iv/dose iv]) 
• Fraction of drug escaping hepatic metabolism (FH) 
o Where, FH = (1-EH) (EH = hepatic extraction ratio) 
o EH = CLH,b ÷ QH,b    
o CLH,b= hepatic blood clearance; QH,b  = hepatic blood flow (1.26 L/h/kg) 
o CLH,b (Dose IV ÷ Plasma AUC(0-inf)) IV  ÷ 0.64 (Blood : Plasma) 
• Fraction of drug absorbed intact * Fraction of drug escaping gut metabolism (FA*FG) 
o Where (FA*FG) = F ÷ FH 
 
Part B repeat dose comparison day 1 and day 14 
• Cmax after 1st and 2nd dose  
• Tmax after 1st and 2nd dose  
• AUC over the 1st and 2nd dosing interval (AUC(0-Ƭ)) 
• AUC over 24 hours (AUC(0-24)) 
• Trough concentrations CƬ 
• AUC(0-∞) after 1st dose on Day 1, if data allow  
• t1/2 after 1st dose on Day 1, if data allow  
• Cmax accumulation CmaxD14/CmaxD1 
• Observed accumulations ratio Ro (AUC(0-Ƭ)D14 / AUC(0-Ƭ)D1) 
• Steady-state accumulations ratio Rs (AUC(0-Ƭ)D14 / AUC(0-∞)D1), if data permit 
 
Part B food effect comparison (high fat meal v fasted and standard meal v fasted) 
• Cmax after 1st dose  
• Tmax after 1st dose  


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• AUC over 1st dosing interval (AUC(0-Ƭ)) 
 
Part B time to steady-state  
• 
 Pre-dose concentrations on days 2, 3, 5, 7 and 14. 
 
Part C (CYP3A4 victim assessment) 
 
• Cmax  
• Tmax  
• AUC(0-t) 
• AUC(0-∞)  and t1/2, if data allow   
• FG = AUCH2O ÷ AUCGFJ  (oral administration of GSK3915393) 
• F, FA, FH: 
o F and FH are defined as above under Part A 
o FA = (F ÷ FH) ÷ FG 
 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. 
Statistical Analyses of Pharmacokinetic Data 
Dose linearity (Part A): Single dose linearity will be assessed by visual inspection of dose 
normalised AUC (0-∞) [or if not available AUC(0-t) or AUC (0-t’)] and Cmax values 
versus dose. Analysis of loge-transformed parameters may be carried out, using the 
power model. 
Food effect (Part B): The ratio of fed state to fasted state will be assessed for parameters 
Cmax and AUC (0‑Ƭ) after 1st dose. 
Repeat vs Single dose (Part B): The extent of accumulation after repeat dosing will be 
determined based on the observed Cmax accumulation, Ro.  An assessment of time to 
achieve steady state will be made based on visual inspection of the trough concentrations 
by day. Dose proportionality may be assessed using similar methods to the single dose.  
Impact of Grapefruit Juice (Part C) Log transformed AUC(0-∞) [or if not available 
AUC(0-t) or AUC (0-t’)] for periods 3 and 4 will be analysed using a mixed model with 
fixed regimen and period effects and random subject effect. Between regimen differences 
will be computed and back transformed to provide point estimates and 90% CI for the 
ratio of AUC for GSK3915393 PO with GFJ: GSK3915393 PO + water, and an estimate 
of FG defined as the ratio of AUC GSK3915393 PO with water: GSK3915393 PO + GFJ    
Similar analysis will be conducted for log transformed Cmax to provide an estimate of 
the ratio of  Cmax for GSK3915393 PO with GFJ: GSK3915393 PO + water.   
 


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Impact of itraconazole (Part C): Log transformed AUC(0-∞) [or if not available AUC(0-
t) or AUC (0-t’)] will be analysed for periods 1 and 2 utilising a mixed model with 
regimen fixed effect and subject random effect.  Between regimen differences will be 
computed and back transformed to provide point estimates and 90% CI for the ratios of 
AUC for GSK3915393 IV + ITZ:  GSK3915393 IV:  A similar mixed model analysis 
utilizing period 3-5 data will be conducted to provide point estimates and 90% CI for 
ratio of AUC for GSK3915393 PO + ITZ:  GSK3915393 PO + water.   These analyses 
will also be conducted for log transformed Cmax to derive point estimates and 90% CI 
for the Cmax ratios of interest.  
Safety – Part C (CYP3A4 victim assessment) 
The Part C safety data will be summarised by regimen.    
 
9.4.3. 
Exploratory Endpoint(s) 
9.4.3.1. 
Modelling  Initiatives 
Pharmacokinetic data from the current study are being used to support the modelling 
initiatives outlined below.   
• Assess risk for GSK3915393 to be a victim or perpetrator of drug-drug interaction 
(DDI) to support any restrictions on concomitant drug administration in Phase 2 
study 
• FG determined from healthy participants in the current study will be used in 
conjunction with gut CYP3A4 expression in Celiac Disease subjects to predict 
exposure to GSK3915393 in the lamina propria (site of action in CeD). 
• A population PBPK model will be developed using IV and oral data along with 
information from predicted exposure to GSK3915393 in lamina propria to assess 
probability of pharmacological success for Phase 2.    
• Tablet formulation development work for Phase 2. 
Further information on these modelling approaches are described in the data 
dissemination plan located in the study Trial Master File. These modelling initiatives will 
be reported separately from the main CSR. Abbreviated reports may be generated if 
GSK3915393 does not progress into Phase 2. 
9.4.3.2. 
Cardiodynamic ECG Evaluation 
Cardiodynamic ECG evaluation may be performed in the future for Part A (SAD all 
periods excluding the micro dose period) and Part B (MAD all cohorts). Cardiodynamic 
ECG evaluation will be described in a separate statistical analysis plan (SAP). 
9.5. 
Interim Analysis 
The decision to proceed to higher dose strengths in parts A and B will be made by the 
DEC (see Section 6.5) based on assessment of safety, tolerability and pharmacokinetic 
data at the preceding doses.  In part C, an interim evaluation of the pharmacokinetic and 
safety data in periods 1 and 2 (IV GSK3915393 + ITZ or water) in conjunction with 


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available safety data from parts A and B will be conducted by the DEC to support the 
selection of the GSK3915393 oral dose to be administered in periods 3-5.     
The DEC will review blinded outputs for Parts A and B of the study which may include 
individual participant data, tabular summaries, graphical presentations and statistical 
analysis. GSK members of the DEC may additionally review unblinded data in a GSK 
only closed session of the DEC. Unblinded data will not be shared with the 
investigators/site who will remain blinded throughout.  
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
▪ Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
▪ Applicable ICH Good Clinical Practice (GCP) Guidelines 
▪ Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
▪ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
▪ Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
▪ Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), 
and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
• A participant who is rescreened is not required to sign another ICF. 
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised 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 signature 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. 
10.1.4. 
 Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant 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/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 
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10.1.5. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
patients’ received.  The investigator(s) is/are encouraged to share the summary 
results with the study subjects, as appropriate. 
• Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-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. 
Requests for access may be made through www.clinicalstudydatarequest.com. 
• GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
10.1.6. 
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 in the QTL plan 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 permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 


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• 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 
CSR/ equivalent summary unless local regulations or institutional policies require 
a longer retention period. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred 
to another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
• Definition of what constitutes source data and its origin can be found in Source 
Data Agreement. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• 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.  
10.1.8. 
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. 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
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For site termination: 
• 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 or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate 
participant therapy and/or follow-up 
10.1.9. 
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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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 6 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. 
Table 6 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose (fasting) Calcium 
Alkaline 
phosphatase2 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• Highly sensitive Serum human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential) 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
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Laboratory 
Assessments 
Parameters 
• Urine alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody 
• COVID-19 testing (performed at additional time noted in the SoA tables 
and as required) 
NOTES : 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Section 10.5. All events of ALT 3 × upper limit of normal 
(ULN) and total 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 to 
GSK in an expedited manner (excluding studies of hepatic impairment or cirrhosis). 
2. 
If alkaline phosphatase is elevated, consider fractionating. 
 


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


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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 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. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 


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medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias,  
convulsions, or development of intervention dependency or intervention 
abuse. 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
10.3.4. 
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. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 


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• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
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• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.  
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 


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SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o 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 
prior to randomisation is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen contraception methods listed below if they wish to 
continue their HRT during the study.  
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), 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. 
 
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. 
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. 


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


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase I liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the subject until liver chemistries 
resolve, stabilise, or return to within 
baseline (see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within 24 hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and 
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, within 48 hours of last 
dose4  
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5: 


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Liver Chemistry Stopping Criteria  
perform liver event follow up assessments 
within 24-72 hrs 
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants 
3. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
subject’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: Abbreviations and Trademarks 
Abbreviation 
Explanation 
(AUC(0-∞)) 
AUC from time zero to infinity 
(AUC(0-t)) 
Area under the plasma drug concentration versus time curve from time zero to 
last quantifiable concentration 
µg 
Microgram 
AE 
Adverse event 
BID 
Twice daily  
BMI 
Body Mass Index 
CA 
Competent authority 
CeD 
Celiac Disease 
Cl 
Clearance 
Cmax 
Maximum observed plasma drug concentration  
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTFG 
Clinical trial facilitation group  
DDI 
Drug Drug Interaction 
DEC 
Dose Escalation Commitee 
dGP 
Deamidated Gluten Peptide 
DL 
Dose Level 
DSM 
Diagnostic and Statistical Manual  
EC 
Ethics committee 
ECG 
Electrocardiogram 
EMA 
Endomysial Antibodies 
EW 
Early Withdrawal 
F 
Bioavailability 
FA 
Product of fraction of drug absorbed 
FG 
Fraction of drug escaping gut metabolism 
FH 
Fraction of drug escaping hepatic metabolism  
FPE 
First pass extraction  
FRP 
Female Reproductive Potential 
FTIH 
First time into human 
FU 
Follow Up 
GC 
Gluten challenge  
GDP 
Gliadin-derived peptides 
GERD 
Gastroesophageal reflux disease 
GFD 
Gluten-free diet  
GFJ 
Grapefruit Juice 
GSK 
GlaxoSmithKline 
HLA 
Human Leukocyte Antigen 
IBS 
Irritable bowel syndrome 
ICF 
Informed consent form 
IL2 
Interleukin-2 
ITZ 
Itraconazole  


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Abbreviation 
Explanation 
IV 
Intravenous 
IVIVE 
In vitro to in vivo extrapolation 
LFT 
Liver Function Tests 
LSLV 
Last Subject Last Visit 
MABEL 
Minimal Anticipated Biological Effect Level 
MDI 
Metabolism Dependent Inhibitor 
MSDS 
Material safety data sheet  
NOAEL 
No Observed Adverse Event Level 
PBMC 
Peripheral blood mononuclear cell 
PBPK 
Physiologically based pharmacokinetic 
PK 
Pharmacokinetics 
PKPD 
Pharmacokinetics/pharmacodynamics 
QC 
Quality control 
QTcF 
QT interval corrected using Bazett's formula 
QTL 
Quality tolerance limits  
RAP 
Reporting and analysis plan 
RBC 
Red blood cells 
REC 
Research Ethics Committee  
RNA 
Ribonucleic acid 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan  
SD 
Single-dose 
SGOT 
Serum glutamic-oxaloacetic transaminase  
SGPT 
Serum glutamic-pyruvic transaminase  
SoA 
Schedule of Activities  
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2 
Terminal half-life 
TBD 
To be determined 
TG2 
Transglutaminase 2 
TID 
Three times daily dose  
tmax 
Maximum observed plasma drug concentration  
TQT 
Thorough QT/QTc 
tTG 
Tissue Transglutaminase 
ULN 
Upper limit of normal  
Vd 
Volume of distribution  
WBC 
White Blood Cells 
WOCBP 
Woman of Childbearing Potential  
WONCBP 
Woman of Non-Childbearing Potential  
 


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Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
EnteroTracker 


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10.7. 
Appendix 7: COVID-19 Appendix 
10.7.1. 
Overall Rationale for this Appendix  
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
 
These measures will remain in place until study completion. 
 
10.7.2. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants. 
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants. 
• 
Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study 
conduct and duration of those changes and indicate which trial participants were 
impacted and how those trial participants were impacted (as per the current local 
COVID-19 related regulatory guidance). 
• 
Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. 
 
10.7.3. 
Protocol Defined Procedures/Visits: 
• The protocol defined interval for the collection of  samples during the follow-up 
visit (see Section 1.3 Schedule of Activities), may be extended up to a maximum 
length of 14 days.  


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10.7.4. 
Data Management/Monitoring: 
• 
If a situation arises where on-site monitoring is no longer permitted, GSK will 
consider remote Source Data Verification/Source Document Review (SDV/SDR) 
where permitted by the clinical site/institution. Remote SDV/SDR will be proposed 
to study sites to meet a participant and/or critical quality need, e.g., to assess 
participant safety or to ensure data integrity. In case of remote SDV/SDR, GSK will 
work with the site to ensure participant privacy. 
• 
eCRF/CRF Final or Interim Sign off Process: The PI is responsible for ensuring that 
the data within the eCRF casebook and any other data sources utilized during the 
study for each study participant is complete and consistent with source documents 
throughout the study (ICH GCP 4.9.1 4.9.2). The PI may sign/re-sign the eCRF from 
any computer/location by accessing InForm (or other eDC platform) using his/her 
unique eCRF log-in credentials. The PI may delegate this activity to another 
medically qualified and trained sub-investigator and this must be documented on the 
Delegation of Responsibilities (DoR) Log. It is recommended that the PI identifies a 
sub-investigator as a back-up for eCRF signatures. The sub-investigator must be 
appropriately trained on the protocol and eCRF requirements (with training 
documented), and the DoR log updated accordingly. 
• 
Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK 
 


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10.8. 
Appendix 8: Protocol Amendment History 
Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC) 
Amendment 1 Dated 30-SEP-2020 
Overall Rationale for the Amendment: This amendment is in response to questions 
raised in the MHRA’s Grounds for non-acceptance letter dated 23 Sep 2020 (also 
including ethics committee comments under a Combined Ways of Working process) and 
includes revisions to the data required for making dose escalation decisions, the threshold 
for smaller does escalation increments, the process for investigator unblinding, update to 
contraception guidelines and removal of different nonclinical exposure data thresholds 
for individual and mean pharmacokinetic stopping criteria.  
Section # and 
Name 
Description of Change 
Brief Rationale 
4.3.8 Dose 
escalation. 
The threshold for smaller 
escalation increments reduced 
to 80 mg/day.  
 
The threshold for smaller escalation 
increments has been aligned to the 
planned maximum daily therapeutic 
dose. 
6.3 Measures to 
Minimize Bias: 
Randomisation 
and Blinding  
Unblinding process has been 
added. 
To describe the process by which 
the investigator can access the 
treatment allocation for an 
individual subject to facilitate 
emergency unblinding, if required. 
6.5 Dose 
Modification  
Increase in the minimum 
number of subjects required 
to make a dose escalation 
decision and the minimum 
safety data to be reviewed has 
been updated to clarify it 
includes all vital signs and 
ECG data. 
To ensure data from at least two-
thirds of subjects dosed with 
GSK3915393 is available for dose 
escalation decisions and to enable 
the identification of trends safety 
data in the absence of any flagged 
abnormalities.  
7.1 
Discontinuation 
of Study 
Intervention.  
Removed the requirement for 
the Investigator to consult 
with the Medical Monitor 
prior to withdrawing a 
participant who experiences a 
serious or severe clinically 
significant non-serious AE 
that is at least possibly related 
to investigational product. 
  
To permit the investigator to make 
the judgement based on the treating 
investigator’s opinion alone. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
7.2.2 
Pharmacokinetic 
Stopping 
Criteria  
Removed the different 
criteria for individual and 
group pharmacokinetic 
stopping criteria.    
To apply the agreed stopping limits 
at the individual level in addition to 
the mean cohort exposure. 
10.4.1 
Definitions. 
Removed reference to 
effective methods of 
contraception that are not 
considered to be highly 
effective (failure rate ≥1% 
per year).  
To align with the Clinical Trial 
Facilitation Group document for 
clarification of effective 
contraception in a clinical trial. 
 
 


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11. 
REFERENCES 
Anderson RP, van Heel DA, Tye-Din JA, Barnardo M, Salio M, Jewell DP, et.al. T cells 
in peripheral blood after gluten challenge in coeliac disease. Gut. 2005;54(9):1217‐1223. 
Catassi C, et al. Am J Clin Nutr. 2007 Jan; 85(1):160-6. A prospective, double-blind, 
placebo-controlled trial to establish a safe gluten threshold for patients with celiac 
disease. 
Chretien ML, Bailey DG, Asher L, Parfitt J, Driman D, Gregor J.  Severity of coeliac 
disease and clinical management study when using a CYP3A4 metabolised medication: a 
phase I pharmacokinetic study. BMJ Open 2020;10:e034086. doi: 10.1136/bmjopen-
2019-034086. 
Darpo B., Garnett C., Benson C.T., Keirns J., Leishman D., Malik M. Cardiac safety 
research consortium: Can the thorough QT/QTc study be replaced by early QT 
assessment in routine clinical pharmacology studies? Scientific update and a research 
proposal for a path forward. Am Heart J 2014; 168:262-72. 
GlaxoSmithKline Document number 2020N441210_00 Efficacious human clinical dose 
prediction for GSK3915393 in celiac disease (CeD), incorporating physiologically based 
pharmacokinetic (PBPK) and PKPD modelling. 
GlaxoSmithKline Document number 2020N445405_00 Dose Justification for 
GK3915393 First Time in Human Study (213585) based on predicted human 
pharmacokinetic profile and TG2 inhibition. 21 July 2020. 
Goel G, Daveson AJM, Hooi CE, Tye-Din JA, Wang S, Szymczak E, et.al. Serum 
cytokines elevated during gluten-mediated cytokine release in coeliac disease. Clin Exp 
Immunol. 2020;199(1):68‐78. 
Hall, NJ, Rubin GP, Charnock A. Appetite. 2013 Sep; 68:56-62.  Intentional and 
inadvertent non-adherence in adult coeliac disease. A cross-sectional survey. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et.al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Klöck C, Diraimondo TR, Khosla C. Role of transglutaminase 2 in celiac disease 
pathogenesis. Semin Immunopathol. 2012;34(4):513-522. 
Leffler, DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Clinical 
Gastroenterology and Hepatology 2007; 5: 445–450.  Etiologies and Predictors of 
Diagnosis in Nonresponsive Celiac Disease. 
Ludvigsson JF, Bai j, Biagi F, Card T, Ciacci C, Ciclitira P. Gut 2014; 63:1210–1228. 
Diagnosis and management of adult coeliac disease:  guidelines from the British Society 
of Gastroenterology. 


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Pulido O, Zarkadas M, Dubois S, Maclsaac K, Cantin I, La Vieille S et al. Clinical 
features and symptom recovery on a gluten-free diet in Canadian adults with celiac 
disease. Can J Gastroenterol. 2013;27(8):449-453.  
Sakatis MZ, Reese MJ, Harrell AW, Taylor MA, Baines IA, Chen L, et.al. Preclinical 
Strategy to Reduce Clinical Hepatotoxicity Using in Vitro Bioactivation Data for >200 
Compounds.  Chem. Res. Toxicol., 2012, 25 (10), pp 2067-2082. 
Silvester JA, Kurada S, Szwajcer A, Kelly CP, Leffler DA, Duerksen DR, 
Gastroenterology (2017) 153(3): 689-701 Tests for Serum Transglutaminase and 
Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent 
Villous Atrophy on Gluten-free Diets: a Meta-analysis. 
Stefanolo JP, Tálamo M, Dodds S, de la Paz Temprano M, Florencia Costa A, Moreno 
ML et al. Real-world Gluten Exposure in Patients With Celiac Disease on Gluten-Free 
Diets, Determined From Gliadin Immunogenic Peptides in Urine and Fecal Samples. Clin 
Gastroenterol Hepatol. 2020;S1542-3565(20)30350-5. 
Syage, J.A. Kelly CP, Dickason MA, Ramirez AV, Leon F, Dominguez R et al., 
Determination of gluten consumption in celiac disease patients on a gluten-free diet. 
American Journal of Clinical Nutrition, 2018. 107(2): p. 201-207. 
Tye-Din, J.A, Daveson JM, C. Ee H, Goel G, MacDougall J, Acaster S, et al., Elevated 
serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic 
biomarker for coeliac disease. Alimentary Pharmacology and Therapeutics, 2019. 50(8): 
p. 901-910. 
Xie F, Ding X, Zhang QY. An update on the role of intestinal cytochrome P450 enzymes 
in drug disposition. Acta Pharm Sin B. 2016;6(5):374-383. 
doi:10.1016/j.apsb.2016.07.012. 
Zühlke S, Risnes LF, Dahal-Koirala S, Christophersen A, Sollid LM, Lundin KE. CD38 
expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac 
disease. United European Gastroenterol J. 2019 Dec;7(10):1337-1344. 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
Study ID:  213585 
 
Official Title of Study: A Randomized, Placebo Controlled, Double Blind, Single and 
Repeat Dose Escalation Phase 1 Study to Evaluate Safety, Tolerability, and 
Pharmacokinetics of GSK3915393 in Healthy Participants and open label assessment of 
coadministration of GSK3915393 with grapefruit juice and itraconazole on the 
pharmacokinetics of GSK3915393 
 
EudraCT Identifier:  2020-003213-36 
 
Date of Document: 06-APR-2021 (The date is redacted on page 33) 
 
 


C O N FI D E N TI A L  
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 5 8 5  
 
 
1  
 
Di visi o n  
: W orl d wi de De vel o p me nt  
I nf or m ati o n T y pe 
: Statistical A nal ysis Pla n ( S A P)  A me n d me nt 0 1  
TI T L E P A G E  
Pr ot oc ol Title: A R a n d o mize d, Place b o C o ntr olle d, D o u ble Bli n d, Si n gle a n d Re peat 
D ose Escalati o n P hase 1 St u d y t o E v al uate Safet y, T olera bilit y, a n d P har mac o ki netics of  
G S K 3 9 1 5 3 9 3 i n Healt h y Partici pa nts  a n d o pe n la bel assess me nt of c o a d mi nistrati o n of 
G S K 3 9 1 5 3 9 3 wit h gra pefr uit j uice a n d itrac o naz ole o n t he p har mac o ki netics of 
G S K 3 9 1 5 3 9 3  
Pr ot oc ol N u m ber : 2 1 3 5 8 5  / A me n d me nt 0 2  
C o m p o u n d N u m ber : G S K 3 9 1 5 3 9 3  
S h ort Title : A P hase 1 St u d y t o E val uate t h e Safet y, T olera bilit y, a n d P har mac o ki netics 
of G S K 3 9 1 5 3 9 3 i n Healt h y Partici pa nts  a n d t o e val uate t he i nteracti o n bet wee n 
G S K 3 9 1 5 3 9 3 a n d gra p efr uit j uice a n d  itrac o n az ole. 
S p o ns or N a me: Gla x o S mit h Kli ne Researc h & De vel o p me nt Li mite d  
Re g ul at or y A ge nc y I de ntifier N u m ber(s)  
Re gistr y  
I D 
E u dra C T  
2 0 2 0 -0 0 3 2 1 3 -3 6  
 
S A P  A ut h or(s):  
A ut h or  
  
Lea d Statisticia n , De v Bi ostats Stats I n dia 
 
Statistics Lea der, De v Bi ostats Stats De v  
 
 
 
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d.  
P P D
P P D


C O N FI D E N TI A L  
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 5 8 5  
 
 
2  
 
S A P  Te a m Re vie w C o nfir m ati o ns  ( E-m ail C o nfir m ati o n) : 
Re vie wer  
 
Gl o bal Cli nical De vel o p me nt, R & D G C S D  
 
, Disc o ver y Me dici ne 
 
, Disc o ver y Me dici n e 
 
S E R M Ma na ger , Earl y P hase Gr o u p, Gl o b al Safet y   
 
Pr o gra m mer/ A nal yst , De v Bi ostats Pr o g De v 
 
Ma na ger, Cli nical D ata Ma na ge m e nt  
 
, Cli nical P har mac ol o g y, Cli nical P har mac ol o g y M o delli n g & 
Si m ulati o n  
 
E D L, E arl y D e vel o p me nt Lea ders  
S A P Bi os t atistics Li ne A p pr o v al (e Si g n at ure): 
A p pr o ver  
 
 Bi ost atistics 
O n be half of 
 (
 - Statistic, Bi ostatistics I n dia ) 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Objectives, Endpoints and Estimands ........................................................... 6 
1.1.1. 
Objectives and Endpoints .............................................................. 6 
1.1.2. 
Estimands ...................................................................................... 9 
1.2. 
Study Design .............................................................................................. 14 
2. 
STATISTICAL HYPOTHESES ............................................................................... 18 
3. 
ANALYSIS SETS ................................................................................................... 19 
4. 
STATISTICAL ANALYSES ..................................................................................... 19 
4.1. 
General Considerations .............................................................................. 19 
4.1.1. 
General Methodology .................................................................. 19 
4.1.2. 
Baseline Definition ....................................................................... 20 
4.2. 
Safety Analyses .......................................................................................... 20 
4.2.1. 
Adverse Events Analyses ............................................................ 20 
4.2.2. 
Clinical Laboratory Analyses ........................................................ 21 
4.2.3. 
Other Safety Analyses ................................................................. 21 
4.3. 
Pharmacokinetic Analyses .......................................................................... 21 
4.3.1. 
Pharmacokinetic Parameters ....................................................... 21 
4.3.2. 
Single Dose Pharmacokinetics (part A) ........................................ 24 
4.3.2.1. 
Endpoints/Variables .................................................... 24 
4.3.2.2. 
Main Analytical Approach ........................................... 24 
4.3.3. 
Repeat Dose Pharmacokinetics (part B) ...................................... 24 
4.3.3.1. 
Endpoints/Variables .................................................... 24 
4.3.3.2. 
Main Analytical Approach ........................................... 25 
4.3.4. 
Assessment of Food Effect (Part B) ............................................. 26 
4.3.4.1. 
Endpoints/Variables .................................................... 26 
4.3.4.2. 
Main Analytical Approach ........................................... 26 
4.3.5. 
CYP3A4 victim assessment – Impact of Grapefruit Juice (Part C) 27 
4.3.5.1. 
Endpoints/Variables .................................................... 27 
4.3.5.2. 
Main Analytical Approach ........................................... 27 
4.3.6. 
CYP3A4 victim assessment – impact of itraconazole (part C) ...... 27 
4.3.6.1. 
Endpoints/Variables .................................................... 27 
4.3.6.2. 
Main Analytical Approach ........................................... 27 
4.3.7. 
Additional Part C Assessments .................................................... 28 
4.3.7.1. 
Endpoints/Variables .................................................... 28 
4.3.7.2. 
Summary Measure ..................................................... 28 
4.3.8. 
Other Endpoints ........................................................................... 28 
4.3.8.1. 
Endpoints/Variables .................................................... 28 
4.3.8.2. 
Summary Measure ..................................................... 28 
4.4. 
Interim Analyses ......................................................................................... 28 
4.5. 
Changes to Protocol Defined Analyses ....................................................... 28 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 28 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 30 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 30 


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6.1.1. 
List of Abbreviations .................................................................... 30 
6.1.2. 
Trademarks ................................................................................. 31 
7. 
REFERENCES ....................................................................................................... 32 
 


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Version history 
Table 1 
SAP Version History Summary 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
1 
22 OCT 
2020 
1.0 
Not Applicable 
Original version 
2 
24 MAR 
2021 
2.0 
Revised Part C 
study design and 
related sections 
and minor 
modifications in 
part B 
Updated to align with Part 
C study design change 
and other minor changes 
covered in protocol 
amendment 2 and 
“213585 File 
Note_Changes to feeding 
regimen and add 
additional pre dose PK 
samples in Part B Cohort 
2” 
 


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213585 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses for study parts A, B and C to 
be included in the Clinical Study Report for Protocol 213585. All details of the dose 
escalation process and associated data review is outlined in the dose escalation plan.  
Metabolite evaluations will be conducted by DMPK and is not covered in this SAP.  
Descriptive study population analyses such as summary of demography and baseline 
characteristics and additional detail with regards to data handling conventions and the 
specification of data displays will be provided in the Output and Programming 
Specification (OPS) document. 
1.1. 
Objectives, Endpoints and Estimands 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
Part A HV Dose Escalation Single 
Dose  
• To evaluate the safety and 
tolerability of single escalating 
oral doses of GSK3915393 
administered in the fed state in 
healthy adult participants 
Part B HV Dose Escalation Repeat 
Dose 
• To evaluate the safety and 
tolerability of repeat escalating 
oral doses of GSK3915393 twice 
daily (BID) administered in the fed 
and fasted state in healthy adult 
participants 
Part C CYP3A4 Victim Interaction  
• To characterize the PK profile of 
IV GSK3915393 administered 
alone and when co-administered 
with itraconazole in healthy adult 
participants 
• To characterize the PK profile of 
oral GSK3915393 administered 
Part A and B 
• Occurrence of serious adverse events 
(SAEs), adverse events (AEs) and 
treatment related AEs 
• Occurrence of clinically significant 
changes in physical examination, vital 
signs, laboratory parameters, and 12-lead 
electrocardiogram (ECG) findings. 
 
 
 
 
 
 
Part C 
• Cmax, tmax, AUC(0-t), AUC (0-∞) and 
(t1/2) as appropriate 


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Objectives 
Endpoints 
alone and when co-administered 
with grapefruit juice or with 
itraconazole in healthy adult 
participants 
Secondary Objectives 
Secondary Endpoints 
Part A HV Dose Escalation Single 
Dose  
• To characterize the PK profile of 
single oral doses of GSK3915393 
in healthy adult participants 
• To characterize the PK profile of a 
single intravenous dose of 
GSK3915393 in healthy adult 
participants 
• To evaluate the safety and 
tolerability of single microdose 
doses of GSK3915393 in healthy 
adult participants 
 
 
 
 
 
 
 
 
 
Part B HV Dose Escalation Repeat 
Dose 
• To characterize the PK profile of 
single doses and repeat oral doses 
of GSK3915393 in healthy adult 
participants 
Part A 
• Maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(tmax), area under the plasma drug 
concentration versus time curve from 
time zero to last quantifiable 
concentration (AUC(0-t)), AUC from 
time zero to infinity (AUC(0-∞)), and 
apparent terminal half-life (t1/2) as 
appropriate. 
• Clearance (CL) and volume of 
distribution (Vd) following IV 
administration and absolute 
bioavailability (F) of oral administration 
• Fraction of drug escaping hepatic 
metabolism (FH) and product of fraction 
of drug absorbed (FA) and fraction of 
drug escaping gut metabolism (FG) i.e., 
(FA*FG).  
Clinical safety and tolerability data 
including adverse events (AEs) and 
serious adverse events (SAEs), clinically 
significant changes in laboratory values, 
vital signs and 12 lead electrocardiogram 
(ECG) readings and physical 
examinations 
 
Part B 
• Cmax, tmax, AUC(0-t), and AUC over 
the dosing interval AUC (0-τ) 


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Objectives 
Endpoints 
• To assess the impact of food on the 
PK of GSK3915393 in healthy 
adult participants  
• To evaluate time to steady-state 
Part C CYP3A4 Victim Interaction 
• To evaluate the safety and 
tolerability of a single oral dose of 
GSK3915393 when administered 
with grapefruit juice or with 
itraconazole in healthy adult 
participants 
• To evaluate the safety and 
tolerability of single intravenous 
dose of GSK3915393 when 
administered with itraconazole in 
healthy adult participants 
• To investigate absorption 
characteristics and first pass 
clearance of GSK3915393 
• Cmax, tmax and AUC (0-τ) following 1st 
dose of day 
• Pre-dose concentrations on Days 2, 3, 5, 
7 and 14 
 
 
Part C 
• Occurrence of serious adverse events 
(SAEs), adverse events (AEs) and 
treatment related AEs 
• Occurrence of clinically significant 
changes in physical examination, vital 
signs, laboratory parameters, and 12-lead 
electrocardiogram (ECG) findings. 
• FA, FG and FH 
 
Exploratory Objectives 
Exploratory Endpoints 
• To investigate metabolites of 
GSK3915393 in plasma and urine 
following oral dosing (Part A and 
B) 
• To investigate metabolites of 
GSK3915393 in duodenal bile 
following oral dosing (Part B, 
highest dose only) 
• To assess potential effect of repeat 
doses of GSK3915393 on 
Cytochrome P450 3A4 (CYP3A4) 
enzyme activity (Part B).  
• To assess the effect of single dose 
GSK3915393 on Holter ECG in 
healthy volunteers. Waveforms 
will be stored for potential future 
analysis. 
• Metabolites of GSK3915393 in plasma 
and urine. The analyses will be conducted 
and reported separately. 
• Metabolites of GSK3915393 in duodenal 
bile. The analyses will be conducted and 
reported separately. 
• Plasma 4β-hydroxycholesterol to 
cholesterol ratio at pre-treatment and 
following repeat dosing of GSK3915393 
• If analyses conducted: Centrally read 
ECG parameters and correlation between 
plasma levels of GSK3915393 and QTc 
changes.  These analyses if conducted 
will be detailed in a separate analysis 
plan.   
 


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1.1.2. 
Estimands 
In Table 2, the possible intercurrent events and the rationale for relating them to treatment or otherwise is described. Individual participant 
data will be included in data listings regardless of the strategies followed for the analyses. 
Table 2 
Estimands 
The following two attributes apply to all estimands: 
• 
Treatment condition: GSK3915393 vs Placebo  
• 
Population: Healthy Volunteers. 
Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Intercurrent Event Strategy 
Population Level 
Summary Measure 
Primary Objective (1): To evaluate the safety and tolerability of single escalating oral doses of GSK3915393 administered in the fed state in 
healthy adult participants. 
Primary 1 
(Part A) 
• 
Adverse events  
• 
Clinically significant changes 
from baseline in laboratory data  
• 
Clinically significant changes 
from baseline in vital signs  
• 
Clinically significant changes 
from baseline in 12 lead 
electrocardiograms (ECGs)  
• 
Clinically significant changes 
from baseline in physical 
examination 
 
• 
All Intercurrent Events - All data will be reported 
as captured  
 
• 
(Treatment policy strategy, where we are 
interested in evaluating all adverse events including 
clinically significant other safety findings occurring 
after the start of treatment) 
Descriptive Statistics 


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Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Intercurrent Event Strategy 
Population Level 
Summary Measure 
Primary Objective (2): To evaluate the safety and tolerability of repeat escalating oral doses of GSK3915393 twice daily (BID) administered in the 
fed and fasted state in healthy adult participants. 
Primary 2 
(Part B) 
As defined for Primary Objective 1 
As Defined for Primary Objective 1 
As Defined Primary for 
Objective 1  
Primary Objective (3): To characterize the PK profile of IV GSK3915393 administered alone and when co-administered with itraconazole in 
healthy adult participants 
Primary 3 
(Part C) 
• 
Cmax, 
• 
tmax,   
• 
AUC(0-t),  
• 
AUC(0-∞) and  
• 
t1/2 
• 
All Intercurrent Events – a treatment policy 
approach will be applied such that all available data 
will be included in analyses. For subjects with 
partial concentration-time data on a given study 
period, derived parameters such as AUC will be 
available on that study period provided there are 
sufficient concentration data to enable their 
estimation 
Descriptive statistics 
 
Point estimates  
and 90% CI for ratios of 
AUC or Cmax for 
GSK3915393 IV with ITZ 
vs GSK3915393 IV. 
 
Primary Objective (4): To characterize the PK profile of oral GSK3915393 administered alone and when co-administered with grapefruit juice or 
with itraconazole in healthy adult participants 
Primary 4 
(Part C) 
As defined for Primary Objective 3 
As Defined for Primary Objective 3 
As Defined Primary for 
Objective 3 
 
Point estimates  
and 90% CI for ratios of 
AUC or Cmax for 
GSK3915393 PO with GFJ 
vs GSK3915393 PO with 
water and GSK3915393 PO 
with ITZ vs GSK3915393 
PO with water  


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Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Intercurrent Event Strategy 
Population Level 
Summary Measure 
Secondary Objective (1): To characterize the PK profile of single oral doses of GSK3915393 in healthy adult participants 
Secondary 1 
(Part A) 
• 
 AUC (0-∞) 
• 
 AUC (0-t)  
• 
 Cmax  
• 
 tmax  
• 
 t1/2 
• 
Absolute bioavailability (F) 
• 
FH 
• 
FA*FG 
 
As Defined for Primary Objective 3 
Descriptive Statistics 
 
 
 
 
 
 
 
 
Secondary Objective (2): To characterize the PK profile of single intravenous doses of GSK3915393 in healthy adult participants 
Secondary 2  
(Part A) 
• 
AUC (0-∞) 
• 
AUC (0-t) 
• 
Cmax  
• 
Tmax 
• 
t1/2 
• 
Clearance (CL) (IV only)  
• 
Volume of distribution (Vd)  
(IV only)  
As Defined for Primary Objective 3 
Descriptive Statistics 
 
Secondary Objective (3): To evaluate the safety and tolerability of single microdose doses of GSK3915393 in healthy adult participants. 
Secondary 3 
(Part A) 
As defined for Primary Objective 1 
 
As defined for Primary Objective 1 
As defined for Primary 
Objective 1  
Secondary Objective (4): To characterize the PK profile of single doses and repeat oral doses of GSK3915393 in healthy adult participants. 
Secondary 4 
(Part B) 
• 
AUC (0-24) 
• 
AUC over the dosing interval 
AUC (0-τ) 
• 
Cmax after 1st and 2nd dose 
As defined for Primary Objective 3 
 
Descriptive Statistics 
 
Geometric mean & 90% CI 
for accumulation ratios 


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Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Intercurrent Event Strategy 
Population Level 
Summary Measure 
• 
tmax after 1st and 2nd dose 
• 
Trough concentrations Cτ  
• 
t1/2 after 1st dose on day 1 
• 
Accumulation ratios (Cmax 
accumulation, Ro) 
 
 
 
 
 
 
 
Secondary Objective (5): To access the impact of food on the PK of GSK3915393 in healthy adult participants 
Secondary 5 
(Part B) 
• 
AUC over the dosing interval 
AUC (0-τ) after 1st dose 
• 
Cmax after 1st dose 
• 
tmax after 1st dose 
As defined for Primary Objective 3 
 
Descriptive statistics 
Geometric mean ratio and  
90% CI for AUC and Cmax 
Median difference and 90% 
CI for tmax  
Secondary Objective (6): To evaluate time to steady-state 
Secondary 6 
(Part B) 
• 
Pre-dose concentrations on Days 
1-14 (days 2, 3, 5, 7 and 14 only 
in cohort 1)  
As defined for Primary Objective 3 
 
Descriptive statistics 
Point estimate and 90% CI 
for day effect  
 
Secondary Objective (7): To evaluate the safety and tolerability of a single oral dose of GSK3915393 when administered with grapefruit juice or 
with itraconazole in healthy adult participants 
Secondary 7 
(Part C) 
As defined for Primary Objective 1 
As defined for Primary Objective 1 
As defined for Primary 
Objective 1 
Secondary Objective (8): To evaluate the safety and tolerability of single intravenous dose of GSK3915393 when administered with itraconazole 
in healthy adult participants 
Secondary 8 
(Part C) 
As defined for Primary Objective 1 
As defined for Primary Objective 1 
As defined for Primary 
Objective 1 
Secondary Objective (9): To investigate absorption characteristics and first pass clearance of GSK3915393 


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Estimand 
Category 
Estimand 
Variable/ 
Endpoint 
Intercurrent Event Strategy 
Population Level 
Summary Measure 
Secondary 9 
(Part C) 
• 
F 
• 
FA FG and FH 
As defined for Primary Objective 3 
Descriptive statistics 
 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
Part A – Single Dose 
 
Part B – Repeat Dose 
 
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post last 
dose)
DL1
N=12
9A:3P
DL2
N=12
9A:3P
100µg IV
N=12
12A
DL3
N=12
9A:3P
DL4
N=12
9A:3P
 A= Active
 P=Placebo
DL = Dose level
Data review - earliest decision point to proceed to Part B
Washout and dose escalation meeting
Treatment period
Single dose (double-blinded) crossover 
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post 
last dose)
Repeat DL1
14 days BID dosing 
N=12, 9A:3P
Cohort 1
Repeat DL2
14 days BID dosing
N=12, 9A:3P
Cohort 2
Repeat DL3
14 days BID dosing
N=12, 9A:3P
Cohort 3
DL=Dose level 
A= Active
P=Placebo
Treatment period
Dose escalation meeting
BID=Twice daily dosing 
    Data review - earliest decision point to proceed to Part C


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Overview of Study Design and Key Features 
Part C – CYP3A4 Vicitim Interaction 
 
Design 
Features 
This FTIH study will be a randomized, double-blind, placebo 
controlled, single center trial in two parts.   
Part A is a crossover design, single dose (SD), dose escalation study in 
one cohort of healthy participants.  Participants will receive single 
ascending doses of GSK3915393 or matching placebo as an oral dose 
in periods 1, 2, 4 and 5 and as a single IV microdose dose in period 3.  
The initial dosing for all periods in which the dose level has been 
escalated will be staggered so that 2 participants will be dosed as 
sentinel participants, one with study drug and one with placebo.  After 
approximately 24 hours, and provided the investigator considers the 
safety and tolerability of the sentinels to be acceptable, the remainder 
of the participants scheduled for the period may be dosed. Sentinel 
dosing is not required in the IV dosing period. 
Part B is a parallel group,14-day, repeat oral dose, dose escalation 
study in 3 cohorts of healthy participants.  Participants will receive 
GSK3915393 or matching placebo BID in each of the sequential 
cohorts.  The initial dosing for all periods in which the dose level has 
been escalated will be staggered so that 2 participants will be dosed as 
sentinel participants, one with study drug and one with placebo.  After 
at least 4 days of dosing, and provided the investigator considers the 
safety and tolerability of the sentinels to be acceptable, the remainder 
of the participants scheduled for the period may be dosed. The impact 
of food on the PK of GSK3915393 will be investigated following the 
Follow-up
(7-14 days post 
last dose)
Period 1
Period 2
Period 3
Period 4
Period 5
N=6
Single PO 
Dose 
GSK3915393
+
Water 
Single PO 
Dose 
GSK3915393
+
GFJ 
D-3 to D3 ITZ   
+
D1 Single PO 
Dose
GSK3915393
 N= 12
100µg IV 
GSK3915393
D-3 to D3 ITZ   
+
D1 100µg IV 
GSK3915393
N=6
Single PO 
Dose 
GSK3915393
+
GFJ 
Single PO 
Dose 
GSK3915393
+
Water 
D-3 to D3 ITZ   
+
D1 Single PO 
Dose
GSK3915393
D = Day 
      washout of at least 7 days and IV data review to select PO dose.
GFJ = Grapefruit Juice
ITZ = Itraconazole
N = Number of participants
NOTE: Washout periods represent the minimum duration required between each period and may be longer for operational purposes.
PO GSK3915393
Treatment period
IV GSK3915393
Screening
(28 days prior to 1st 
dose)
7 Day Washout
7 Day Washout
7 Day Washout
7 Day Washout
2 Day Washout


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Overview of Study Design and Key Features 
AM dose on three days in all cohort (day 3=fasted, day 5= high fat 
breakfast, day 7=standard breakfast).  
The participants, investigator, and study staff are all blinded.  
Part C is a 5 Single Dose periods in healthy adult participants.  In 
period 1 all participants will receive an IV microdose of GSK3915393.  
In period 2, all participants will receive an IV microdose of 
GSK3915393 following prior dosing with itraconazole.  In periods 3 
and 4, participants will receive oral GSK3915393 with or without 
grapefruit juice in a randomized crossover design.  In period 5, all 
participants will receive oral GSK3915393 following prior dosing with 
itraconazole.   
Study 
Intervention 
Part A – Participants will receive GSK3915393 extemporaneous 
formulations: API filled capsules and placebo capsules according to the 
treatment sequence to which they are assigned. For the IV dose, 
participants will receive GSK3915393 at a dose of 100 µg within 24 
hours from compounding. 
Part B – Participants will receive GSK3915393 extemporaneous 
formulations: API filled capsules and placebo capsules according to the 
treatment to which they are assigned.  
Part C – The IV microdose of GSK3915393 will be 100 µg. The oral 
dose of GSK3915393 to be given in periods 3-5 will be selected after 
review of the IV PK data from periods 1 and 2 and will not exceed 20 
mg. Participants would be either dosed GSK3915393 alone, with 
grapefruit juice or with itraconazole. Participants will be dosed in the 
fasted state.  
Study 
Intervention 
Assignment 
Part A Cohort 1 participants will be randomized to one of the 4 
treatment sequences and will receive 1 oral placebo dose and 4 active 
doses (3 as an oral GSK3915393 dose and 1 as a single GSK3915393 
IV microdose): 
In each cohort in Part B, 9 participants on active versus 3 participants 
in placebo (i.e., in a 3:1 ratio)  
In Part C, twelve participants will be randomized to one of the 2 
sequences and will receive 2 IV microdose of GSK3915393 and 3 


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Overview of Study Design and Key Features 
active oral doses of GSK3915393 either alone, with grapefruit juice or 
with itraconazole. 
Interim 
Analysis 
The decision to proceed to higher dose strengths in parts A and B will 
be made by the Data Escalation Committee (DEC) based on 
assessment of safety, tolerability and pharmacokinetic data at the 
preceding doses.  In part C, an interim evaluation of the 
pharmacokinetic and safety data in periods 1 and 2 (IV GSK3915393 + 
ITZ or water) in conjunction with available safety data from parts A 
and B will be conducted by the DEC to support the selection of the 
GSK3915393 oral dose to be administered in periods 3-5.     
The DEC will review blinded outputs which may include individual 
participant data, tabular summaries, graphical presentations and 
statistical analysis. GSK members of the DEC may additionally review 
unblinded data in a GSK only closed session of the DEC. Unblinded 
data will not be shared with the investigators/site who will remain 
blinded throughout.  Further details are provided in the dose escalation 
plan. 
 


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2. 
STATISTICAL HYPOTHESES  
The primary objectives of parts A and B of this study are to assess the safety and 
tolerability of single and repeat ascending doses of GSK3915393 in healthy participants 
and the primary objective of part C is to evaluate the pharmacokinetic interaction 
between GSK393153 and grapefruit juice and itraconazole.  
No formal hypotheses will be tested. However, wherever appropriate, an estimation 
approach has been used, and point estimates and confidence intervals (CIs) will be 
constructed. 


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3. 
ANALYSIS SETS 
For the purposes of analysis, the following analysis sets are defined. 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who were screened 
for eligibility. 
• Study Population 
Randomised 
 
• All participants who were randomly 
assigned to treatment in the study. 
• This population will be based on the 
treatment the participant was 
randomized to. 
• Study Population 
Safety 
• All randomized participants who 
received at least one dose of study 
treatment. 
• This population will be based on the 
treatment the participant actually 
received. 
• Safety 
• Study Population 
COVID-19 
• All participants in the Safety set who 
had a confirmed, probably or 
suspected COVID-19 case diagnosis. 
• Study Population 
• Safety 
Pharmacokinetic 
(PK) 
• All participants in the Safety 
population who had at least 1 non-
missing PK assessment.  
(Non-quantifiable [NQ] values will 
be considered as non-missing values). 
• This population will be based on the 
treatment the participant actually 
received. 
• PK 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
The study population analyses will be based on the Safety set, unless otherwise specified. 
Safety analyses will also be based on the safety set and PK analyses will be based on the 
PK set. 
4.1.1. 
General Methodology 
Safety evaluations are planned to be descriptive in nature. Statistical modelling will be 
performed for Pharmacokinetic data, and point estimates with 90% CIs will be 
constructed. 


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Unless otherwise specified, summary tables will provide the following descriptive 
statistics as a minimum: 
• Continuous data:  
n, mean, standard deviation (SD), median, minimum and maximum. 
• Log transformed PK parameters:  
n, geometric mean, 95% confidence interval for geometric mean, SD on the log 
scale (SD (log)), Between subject coefficient of variation (%CVb). 
• Categorical data: 
number and percentage of participants in each category. 
4.1.2. 
Baseline Definition 
Baseline is defined as the last non-missing assessment prior to first dose.   
For some ECG and Vital Signs parameters, the pre-dose data is captured as triplicate. In 
these cases, the baseline will be defined as the mean of the triplicate assessments.   
For Part A and B and periods 1, 3 and 4 in part C, the day 1 pre-dosing assessment will 
be the baseline. However, if there are no pre-dose assessment collected at Day 1, the last 
available data from either Day -1 or screening (as schedule of assessment in each Cohort 
permits) will be defined as baseline. If there are no valid assessments from day 1, day -1 
or screening, the baseline will be set to missing.   
In part A & C, period baselines will be defined utilising the assessments taken in the 
specific period. Participant level baselines will also be computed and will be the means of 
the available period level baselines for each participant. 
For Part C in periods 2 and 5, the day 1 pre dosing assessment (prior to the day 1 dose of 
both ITZ and GSK39315393) will be the baseline. However, if this assessment is 
missing, data collected from days -1 to day -3 will be considered.  The closest assessment 
prior to day 1 pre dose will be set as the baseline. If there are no valid assessments, the 
baseline will be set to missing.   
4.2. 
Safety Analyses 
The primary objective of this study is to evaluate the safety and tolerability of 
GSK3915393. Safety data will be summarized by dose regimen over time for the safety 
population set. 
4.2.1. 
Adverse Events Analyses 
Adverse events analyses including summaries AEs, SAEs, treatment related AEs and 
other significant AEs will be based on GSK Core Data Standards.  


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COVID-19 events will be summarized and listed based on GSK Core Data Standards.  
Further details will be provided in the Output Programming Specifications (OPS). 
4.2.2. 
Clinical Laboratory Analyses 
Laboratory evaluations including summaries of Chemistry laboratory tests, Haematology 
laboratory tests, Urinalysis, and Liver function tests will be based on GSK Core Data 
Standards.  
Further details and the potentially clinical important values will be provided in the OPS. 
4.2.3. 
Other Safety Analyses 
The summaries of non-laboratory safety test results including vital signs, 12 lead ECG, 
telemetry, Physical Examination and Pregnancy will be based on GSK Core Data 
Standards, unless otherwise specified. Further details and the potentially clinical 
important values will be provided in the OPS. 
4.3. 
Pharmacokinetic Analyses 
Part A and B PK analyses planned for the study are a part of the secondary objectives and 
Part C PK analyses planned for the study is a part of the primary objectives and will be 
based on the PK set. Data displays will be based on GSK Data Standards and statistical 
principles. Full details of the planned displays are provided in the OPS. 
4.3.1. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters defined in Table 3 will be determined from the 
GSK3915393 plasma concentration-time data, as data permits.  Pharmacokinetic 
parameters will be calculated using standard non-compartmental analysis and using 
WinNonlin version 8.0 (or higher).  
All calculations of non-compartmental parameters will be based on actual sampling 
times. For dose escalation meetings nominal sampling times will be used.  
Additionally, Itraconazole plasma concentration data collected during Period 2 and 5 in 
Part C would be summarized separately. 


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Table 3 
Pharmacokinetic Parameters 
Parameter 
Parameter Description 
Part A 
AUC (0-∞) 
Area under the concentration-time curve extrapolated to infinity 
will be calculated as: 
𝐴𝑈𝐶(0 −∞) = 𝐴𝑈𝐶(0 −𝑡) + 𝐶(𝑡)
λ𝑧
 
(NOTE: λ𝑧 is the terminal phase rate constant and C(t) is the last 
quantifiable concentration. % of the extrapolated area should not 
exceed 20%. Any value of AUC (0-∞) derived with more than 20% 
extrapolation should be flagged and excluded from summary 
statistics if >30%). 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration (C(t)) will be calculated using 
the linear trapezoidal rule for each incremental trapezoid and the 
loge trapezoidal rule for each decremental trapezoid. 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-
time data. 
t1/2 
Apparent terminal half-life will be calculated as: 
𝑡1/2 = 𝑙𝑛 2
λ𝑧
  
CL 
The clearance will be calculated as Dose/AUC (0-∞). Calculated 
only for IV dose regimen. 
Vd 
Volume of distribution for IV dose regimen. 
F 
Absolute bioavailability calculated as [AUC(0-∞)po/dosepo] /  
[AUC (0-∞)iv /doseiv] 
FH 
Fraction of drug escaping hepatic metabolism (FH) is calculated as  
FH = (1-EH) (EH = Hepatic extraction ratio) 
• Where, EH = CLH,b ÷ QH,b    
• CLH,b= hepatic blood clearance; QH,b  = hepatic blood flow  
(1.26 L/h/kg) 
• CLH,b (Dose IV ÷ Plasma AUC(0-inf)) IV  ÷ 0.64 (Blood : 
Plasma) 
FA*FG 
Fraction of drug absorbed intact * Fraction of drug escaping gut 
metabolism (FA*FG) is calculated as (FA*FG) = F÷FH 
 


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Parameter 
Parameter Description 
Part B 
AUC (0-10)  
Area under the concentration-time dosing interval curve following 
1st dose from time zero to 10 hours post-dose  
AUC (10-24)  
Area under the concentration-time dosing interval curve following 
2nd dose from 10 hours to 24 hours post-dose. 
AUC (0-24) 
Area under the concentration-time curve from time zero to 24 
hours post-dose. 
Cmax 1st dose 
Maximum observed concentration following 1st dose (0-10h), 
determined directly from the concentration-time data. 
Cmax 2nd dose 
Maximum observed concentration following 2nd dose (10-24h), 
determined directly from the concentration-time data. 
tmax 1st dose 
Time to reach Cmax following 1st dose (0-10h), determined 
directly from the concentration-time data. 
tmax 2nd dose  
Time to reach Cmax following 2nd dose (10-24h), determined 
directly from the concentration-time data. 
Ctrough  
Pre-dose concentrations on days 1-14 (days 2 3,5,7 and 14 in 
cohort 1*) 
 
t1/2 
Apparent terminal half-life will be calculated as: 
𝑡1/2 = 𝑙𝑛 2
λ𝑧
 
Cmax 
accumulation 
Cmax accumulation will be calculated as Cmax 1st DoseD7/Cmax 
1st DoseD1  
Ro 
Observed accumulations ratio will be calculated as AUC (0-10)D7 / 
AUC(0-10)D1 
Part C (CYP3A4 victim assessment) 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-
time data. 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration (C(t)) will be calculated using 
the linear trapezoidal rule for each incremental trapezoid and the 
loge trapezoidal rule for each decremental trapezoid. 
AUC (0-∞) 
Area under the concentration-time curve extrapolated to infinity 
will be calculated as: 
𝐴𝑈𝐶(0 −∞) = 𝐴𝑈𝐶(0 −𝑡) + 𝐶(𝑡)
λ𝑧
 
t1/2 
Apparent terminal half-life will be calculated as: 


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Parameter 
Parameter Description 
𝑡1/2 = 𝑙𝑛 2
λ𝑧
 
FG1 
FG = AUCH2O ÷ AUCGFJ (oral administration of GSK3915393) 
 
F 
Absolute bioavailability calculated as [AUC(0-∞)po/dosepo] /  
[AUC (0-∞)iv /doseiv] 
FH 
Fraction of drug escaping hepatic metabolism (FH) is calculated as  
FH = (1-EH) (EH = Hepatic extraction ratio) 
• Where, EH = CLH,b ÷ QH,b    
• CLH,b= hepatic blood clearance; QH,b  = hepatic blood flow  
(1.26 L/h/kg) 
CLH,b (Dose IV ÷ Plasma AUC(0-inf)) IV  ÷ 0.64 (Blood : Plasma) 
FA 
FA = F÷(FH*FG) 
CL 
The clearance will be calculated as Dose/AUC (0-∞). Calculated 
only for IV dose regimen.  
1 Calculation of FG assumes that metabolism of GSK3915393 in gut is solely mediated by 
CYP3A4 and that GFJ inhibits gut but not hepatic CYP3A4.  Calculation uses AUC (0-
∞)  
[or AUC (0-t) or AUC (0-τ) where AUC (0-∞) cannot be derived]. 
4.3.2. 
Single Dose Pharmacokinetics (part A) 
4.3.2.1. 
Endpoints/Variables 
AUC (0-∞), AUC (0-t), Cmax, tmax, t1/2, F following single oral doses of GSK3915393.  
AUC (0-∞), AUC (0-t), Cmax, tmax, t1/2, CL, Vd following IV dose of GSK3915393. 
4.3.2.2. 
Main Analytical Approach  
All pharmacokinetic parameters will be summarised.  Full details will be provided in the 
OPS. Dose normalised AUC (0-∞) [or AUC(0-t) if AUC (0-∞) cannot be derived] and 
Cmax will be displayed graphically versus dose to provide a visual assessment of dose 
linearity. 
4.3.3. 
Repeat Dose Pharmacokinetics (part B) 
4.3.3.1. 
Endpoints/Variables 
Assessment of the pharmacokinetics upon repeat dosing will be based on AUC(0-т), 
Cmax and tmax following 1st and 2nd dose, trough concentrations, t1/2 (day 1 only, if data 
permit), Cmax accumulation ratio and Ro.  


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In addition to the PK sampling schedule outlined in the protocol a pre dose sample would 
be collected pre dose on days 4, 6, 8, 9, 10, 11, 12 and 13 in cohorts 2 and 3 of part B. 
4.3.3.2. 
Main Analytical Approach  
a. All pharmacokinetic parameters will be summarised by time and dose. Full details 
will be provided in the OPS. 
b. Dose normalised AUC(0-τ) and Cmax after 1st and 2nd doses will be assessed 
descriptively.  
c. Loge transformed AUC (0- τ) for the first dose on Days 1 and 7 will be analysed by a 
mixed effect model with dose, day (Day 1 and 7) and dose-by-day interaction fitted 
as fixed effects and participant as a random effect. The Kenward & Roger (KR) 
degrees of freedom approach will be used. The difference between the least square 
means for day 7 and day 1 at each dose and associated 90% CI will be exponentially 
back transformed to obtain point and 90% CI estimates for Ro for each active dose. 
Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values.  
d. Loge transformed Cmax for the first dose on Days 1 and 7 will be analysed by a 
mixed effect model with dose, day (Day 1 and 7) and dose-by-day interaction fitted 
as fixed effects and participant as a random effect. The Kenward & Roger (KR) 
degrees of freedom approach will be used. The difference between the least square 
means for the day 7 and day 1 at each dose and associated 90% CI will be 
exponentially back transformed to obtain point and 90% CI estimates for Cmax 
accumulation ratio for each active dose. Distributional assumptions underlying the 
model used for analysis will be examined by obtaining a normal probability plot of 
the residuals and a plot of the residuals versus the fitted values.  
e. A preliminary assessment of time to achieve steady state will be made based on 
visual inspection, of pre dose concentrations plotted by day for each dose in order to 
determine the time points (days) to be included in the statistical analysis described in 
f. 
f. A mixed effects model will be fitted to loge transformed pre dose concentrations with 
day (continuous variable) as fixed effects and participant as a random effect for each 
dose separately. The KR degrees of freedom approach will be used. The coefficient 
for the slope of the day effect on the loge-scale will be used to evaluate steady state 
for each dose.  The 90% CIs for the slope for each dose will be calculated. Estimates 
should be exponentially back transformed to be presented. A slope of 1 indicates 
steady state. If individual dose levels are inconclusive on steady state, combined dose 
analysis would be considered.  Distributional assumptions underlying the model used 


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for analysis will be examined by obtaining a normal probability plot of the residuals 
and a plot of the residuals versus the fitted values. 
4.3.4. 
Assessment of Food Effect (Part B) 
4.3.4.1. 
Endpoints/Variables 
Food effect assessments will be based on AUC (0-τ), Cmax and tmax after 1st dose. 
4.3.4.2. 
Main Analytical Approach  
For each dose level separately, Loge-transformed AUC(0-τ) and Cmax after 1st dose (on 
days 3, 5 and 7) will be statistically analysed using a Mixed effects model with:  
• Prandial state ~ (high fat (day 5 data), standard meal (day 7 data) or fasted (day 3 
data)) 
• participant as random effect 
 
The Kenward and Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will be 
used. An unstructured type of the covariance matrices R (accounting for the within 
participant variability) and G (accounting for the between participant variability) will be 
used. 
The estimated geometric mean ratios and 90% CI for (high fat meal: fasted) and (standard 
meal: fasted) will be derived for each dose (i.e., Low dose, Medium dose and High dose). 
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable. If 
there are any departures from the distributional assumptions, alternative transformations, 
such as data squared or square root of data, will be explored. Non-parametric analyses 
will be conducted if the normality assumption does not hold for any of the alternative 
transformations. If this model fails to converge, alternative covariance structures may be 
considered in the following order (1) Compound Symmetry (CS) and (2) Variance 
Components (VC).  
tmax after 1st dose on day 3 and day 5 will be analysed non parametrically applying a 
Wilcoxon signed rank test and a point estimate and distribution free 90% CI for the 
median difference in tmax for (high fat meal  vs fasted) will be derived by specifying the 
CIQUANTDF option in SAS Proc Univariate. The analysis will be repeated for tmax 
after 1st dose on days 3 and day 7 to derive point estimate and distribution free 90% CI 
for the median difference of (standard meal vs fasted).  


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4.3.5. 
CYP3A4 victim assessment – Impact of Grapefruit Juice (Part C) 
4.3.5.1. 
Endpoints/Variables 
AUC (0-∞) [or AUC (0-t) or AUC (0-τ)], Cmax following single oral doses of 
GSK3915393 with water or with GFJ.  
4.3.5.2. 
Main Analytical Approach 
Log transformed AUC (0-∞) [or if not available AUC(0-t) or AUC (0-τ)] for periods 3 
and 4 will be analysed utilising a mixed model with fixed regimen and period effects and 
random subject effect. Between regimen differences will be computed and back 
transformed to provide point estimate and 90% CI for the ratio of AUC for GSK3915393 
PO with GFJ: GSK3915393 PO + water, and an estimate of FG defined as the ratio of 
AUC GSK3915393 PO with water: GSK3915393 PO + GFJ. Distributional assumptions 
underlying the model used for analysis will be examined by obtaining a normal 
probability plot of the residuals and a plot of the residuals versus the fitted values. 
Similar analysis will be conducted for log transformed Cmax to provide an estimate of 
the ratio of Cmax for GSK3915393 PO with GFJ: GSK3915393 PO + water.   
In addition, descriptive summaries of AUC and Cmax will be produced for each regimen. 
4.3.6. 
CYP3A4 victim assessment – impact of itraconazole (part C) 
4.3.6.1. 
Endpoints/Variables 
AUC (0-∞) [or AUC (0-t) or AUC (0-τ)], Cmax following single IV / oral doses of 
GSK3915393 alone/with water or with ITZ. 
4.3.6.2. 
Main Analytical Approach 
Log transformed AUC (0-∞) [or if not available AUC(0-t) or AUC (0-τ)] will be analysed 
for periods 1 and 2 utilising a mixed model with regimen fixed effect and subject random 
effect.  Between regimen differences will be computed and back transformed to provide 
point estimates and 90% CI for the ratios of AUC for GSK3915393 IV + ITZ:  
GSK3915393 IV. Distributional assumptions underlying the model used for analysis will 
be examined by obtaining a normal probability plot of the residuals and a plot of the 
residuals versus the fitted values. 
A similar mixed model analysis utilizing period 3-5 data will be conducted to provide 
point estimates and 90% CI for ratio of AUC for GSK3915393 PO + ITZ:  GSK3915393 
PO + water.   These analyses will also be conducted for log transformed Cmax to derive 
point estimates and 90% CI for the Cmax ratios of interest.    
In addition, descriptive summaries of AUC and Cmax will be produced for each regimen. 


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4.3.7. 
Additional Part C Assessments 
4.3.7.1. 
Endpoints/Variables 
F, FA, FG and FH, CL, tmax and t1/2 following single IV / oral doses of GSK3915393 
alone/with water or with ITZ/GFJ 
4.3.7.2. 
Summary Measure 
F, FA, FG, FH and CL would be summarized. tmax and t1/2 would be summarized by 
regimen. . 
4.3.8. 
Other Endpoints 
4.3.8.1. 
Endpoints/Variables 
Plasma concentration of 4β-hydroxycholesterol and cholesterol, assessed in part B, are 
considered as a potential in vivo marker of CYP3A4 enzyme activity.  
4.3.8.2. 
Summary Measure 
The ratio of plasma concentration of 4β-hydroxycholesterol to total cholesterol will be 
summarised by day and dose (placebo arm will be included). Ratio obtained on day 14 
would be divided by the ratio obtained on day 1 to assess the CYP3A4 enzyme activity 
induction, if 1 indicates no induction.   
4.4. 
Interim Analyses 
Details of dose escalation reviews are covered in the dose escalation plan. 
4.5. 
Changes to Protocol Defined Analyses 
N/A 
5. 
SAMPLE SIZE DETERMINATION 
Twelve, 36 and 12 participants would be randomised to study intervention in parts A, B 
and C respectively.  A further 12 healthy volunteers would be randomised in parts A and 
B if additional dose levels are required to be studied.  
 
The samples size for part A and B were selected to support the planned assessments of 
safety and tolerability, the primary objective of parts A and B of the study. 
In parts A and B, 9 participants will receive each active oral dose.  If 0/9 participants 
experience a particular adverse event, the upper limit of the exact 95% CI indicates that a 
true incidence rate of 33.6% could not be ruled out.  Whereas if 1/9 participants 


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experienced an event, the upper limit of the exact 95% CI indicates that a true incidence 
rate of 48.2% could not be ruled out. 
The sample size for part C was selected taking into consideration the precision of 
estimation of the ratios of AUC and Cmax for the following comparisons of interest.   
• 
GSK3915393 PO + GFJ v GSK3931353 PO + water    
• 
GSK3915393 IV + ITZ v GSK3915393 IV  
• 
GSK3915393 PO + ITZ v GSK3915393 PO + water 
 
Assuming a within subject coefficient of variation of 35%, with 12 subjects the upper and 
lower limits of the 90% CI for the AUC and Cmax ratios will be 0.78 and 1.28 times the 
point estimate respectively. Increases in AUC and Cmax are expected to be observed 
when GSK3915393 is dosed in combination with GFJ or ITZ and it is expected that FG 
(ratio of AUC for GSK3915393 PO + water: GSK3915393 PO + GFJ) will be less than 1. 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
API 
Active Pharmaceutical Ingredient 
AUC 
Area under the concentration time curve 
BID 
Twice Daily 
Cτ 
Trough Concentration 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CSH  
Heterogeneous Compound Symmetry 
CS 
Compound Symmetry 
CV 
Co-efficient of variation 
CYP3A4 
Cytochrome P450 3A4 
DEC 
Dose Escalation Committee 
ECG 
Electrocardiogram 
F 
Absolute bioavailability 
FA 
Product of fraction of drug absorbed 
FG 
Fraction of drug escaping gut metabolism 
FH 
Fraction of drug escaping hepatic metabolism  
FTIH 
First time in humans 
GSK 
GlaxoSmithKline 
GFJ 
Grapefruit Juice 
HV 
Healthy Volunteer 
IV 
Intravenous 
ITZ 
Itraconazole 
NQ 
Non-quantifiable 
OPS 
Output and Programming Specification 
PBO 
Placebo 
PK 
Pharmacokinetics 
QTc 
Electrocardiogram QT interval corrected from Heart Rate 
RD 
Repeat Dose 
Ro 
Observed Accumulation ratio 
Rs 
Steady state accumulation ratio 


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Abbreviation 
Description 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Single Dose 
STD 
Standard Deviation 
t1/2 
Apparent terminal half-life 
Tmax 
Time to maximum observed concentration 
VC 
Variance Components 
Vd 
Volume of distribution 
β 
Beta 
 
6.1.2. 
Trademarks 
Trademarks of the 
GlaxoSmithKline Group of 
Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies 
None 
 
SAS 
 
 
WinNonlin 
 


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7. 
REFERENCES 
European Medicines Agency, EMEA/CHMP/SWP/28367/07 Rev. 1, 20 July 2017, 
Committee for Medicinal Products for Human Use (CHMP). 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-strategies-
identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf 
GlaxoSmithKline Document number 2020N445405_00 Dose Justification for 
GK3915393 First Time in Human Study (213585) based on predicted human 
pharmacokinetic profile and TG2 inhibition 
GlaxoSmithKline Document number TMF-11859187 Protocol A Randomized, Placebo 
Controlled, Double Blind, Single and Repeat Dose Escalation Phase 1 Study to Evaluate 
Safety, Tolerability, and Pharmacokinetics of GSK3915393 in Healthy Participants and 
open label assessment of coadministration of GSK3915393 with grapefruit juice and 
itraconazole on the pharmacokinetics of GSK3915393. 
TMF-11886262: 213585 File Note - Changes to feeding regimen and add additional pre 
dose PK samples in Part B Cohort 2 


Si g nat ure Pa ge f or  2 1 3 5 8 5 T M F- 1 1 9 4 7 3 0 7 v 1. 0
Si g nat ure Pa ge f or T M F- 1 1 9 4 7 3 0 7 v 1. 0
P P D