Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Single ascending dose Repeat dose Phosphatidylinositol 4-kinase beta (PI4KB) inhibitor Chronic Obstructive Pulmonary Disease (COPD)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: no

Brief summary:
This is a two parts study, a single ascending dose followed by 14-days repeat dosing. The single ascending dose part will assess two dose levels of GSK3923868 or placebo across two treatment periods 1 and 2 in a single cohort of participants with a washout period of a minimum of 5 days after each treatment periods. The repeat dose part will assess repeated one dose level of GSK3923868 or placebo in treatment period 3 with up to 14 days of follow up in the same cohort of participants. The duration of study participation for treatment period 1, 2 and 3 will be 6, 6 and up to 29 days (including follow up), respectively.

Detailed description:

Arms:
arm 1: Eligible participants will receive a single dose (SD) of GSK3923868 500 microgram (mcg) in Treatment Period 1 followed by a single dose of placebo matching GSK3923868 in Treatment Period 2. Participants will also receive a repeat dose (RD) of GSK3923868 1500 mcg in Treatment Period 3. There will be a washout period between each treatment period. Participants will have a follow-up of 14 days after the last dose of GSK3923868. arm 2: Eligible participants will receive a single dose of GSK3923868 500 mcg in Treatment Period 1 followed by a single dose of GSK3923868 1000 mcg in Treatment Period 2. Participants will also receive a repeat dose of placebo matching GSK3923868 in Treatment Period 3. There will be a washout period between each treatment period. Participants will have a follow-up of 14 days after the last dose of GSK3923868. arm 3: Eligible participants will receive a single dose of GSK3923868 500 mcg in Treatment Period 1 followed by a single dose of GSK3923868 1000 mcg in Treatment Period 2. Participants will also receive repeat dose of GSK3923868 1500 mcg in Treatment Period 3. There will be a washout period between each treatment period. Participants will have a follow-up of 14 days after the last dose of GSK3923868. arm 4: Eligible participants will receive a single dose of placebo matching GSK3923868 in Treatment Period 1 followed by a single dose of GSK3923868 1000 mcg in Treatment Period 2. Participants will also receive a repeat dose of GSK3923868 1500 mcg in Treatment Period 3. There will be a washout period between each treatment period. Participants will have a follow-up of 14 days after the last dose of GSK3923868.

Interventions: intervention 1: GSK3923868 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3923868 will be administered intervention 2: Placebo will be administered

Protocol document:
Prot_000.pdf: 
Protocol Amendment 02
Study ID:  214075
Official Title of Study: A randomized, double-blind, placebo 
controlled, single and repeat dose study to assess the safety, tolerability, 
and pharmacokinetics of inhaled GSK3923868 in participants with 
Chronic Obstructive Pulmonary Disease (COPD)
Date of Document: 28 Nov 2022


TMF-15098001 
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GSK group of companies 
 
214075 
 
 
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1 
Clinical Study Protocol template V17 dated 24 January 2022 
TITLE PAGE 
Protocol Title: 
A randomized, double-blind, placebo controlled, single and repeat dose study to assess 
the safety, tolerability, and pharmacokinetics of inhaled GSK3923868 in participants with 
Chronic Obstructive Pulmonary Disease (COPD)  
Protocol Number: 214075/Amendment 02 
Compound 
Number:  
GSK3923868 
 
Brief Title:  
 
A study to investigate safety, tolerability, and PK of GSK3923868 inhalation powder in 
COPD 
Study Phase: Phase 1 
Eudra CT Number: 2022-002337-34 
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 
Sponsor Signatory: 
Nicolas Wisniacki,  
VP, Discovery Medicine 
Clinical Pharmacology and Experimental Medicine  
Approval Date: 28 Nov 2022 
  
©2022 GSK group of companies or its licensor. All rights reserved.  Unauthorized 
copying or use of this information is prohibited. 
 


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PROTOCOL AMENDME’NT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 02 
28 Nov 2022 
TMF-15098001 
Amendment 01 
27 October 2022 
TMF-15074949 
Original Protocol 00 
08 July 2022 
TMF-14593236 
 
Amendment 02: 28 Nov 2022 
 
 
Overall Rationale for the Amendment: This amendment has been made in response to 
 
 and to update study procedures.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1: Synopsis and 
subsequent sections 
 
The top dose was changed 
from 3000 mcg to 1500 
mcg. 
  
 
 
 
 
 
. 
Section 1.1: Synopsis and 
subsequent sections 
GSK3923868 was changed 
to GSK3923868 inhalation 
powder when it is referred 
as a product.  
“dry powder” was replaced 
by “inhalation powder” 
These edits were made to 
standardize the 
terminology used to 
describe GSK3923868 
product. 
Section 1.1: Synopsis and 
subsequent sections 
Minor editorial changes 
were made, e.g., changing 
“a” to “an” in the first 
sentence of Single Dose of 
Section 1.1 Synopsis. 
These changes were made 
to improve text flow. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3.3: Repeat Dose 
(Treatment Period 3) 
Section 4.1: Overall 
Design 
 
Section 1.3.3 (update in 
bold):  
Footnote #6: “Dosing on 
Days 6 and 13 can be 
either at home or at the 
site” was added; and 
“home” was removed from 
“home-dosing” 
Patient diary card dispense 
was added to Day 14. 
Footnote #7 was expended 
by adding patient diary 
card dispense on Day 14 as 
follows “and dispense 
Day 14 (for evening 
entry) and Day 15 
(morning entry) patient 
diary card before 
discharge on Day 14.  The 
last diary card (dispensed 
on Day14) will be 
reviewed by the site via 
the phone call on Day 15, 
and returned to the site 
within 2 weeks from Day 
15” 
Section 4.1 (update in 
bold): 
“after home dosing that 
day” was removed from 
the sentence “Participants 
will then return to the unit 
on Day 6 after home 
dosing that day to receive a 
dose in the unit on Day 7 
before being discharged on 
Day 7 to continue home 
dosing from Days 8 to 12”. 
 
The edits were made to: 1) 
provide options for 
participants to receive a 
dose either at home or at 
the unit upon arrival on 
Day 6 and Day 13; and 2) 
add one more patient diary 
card dispense on Day 14. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.2: Background 
The last sentence of last 
paragraph (study 213499) 
has been updated as 
follows (update in bold): 
“At the time of publishing 
this protocol amendment, 
13 participants have been 
dosed.  No SAEs or 
notable AEs have been 
observed so far”. 
This edit was made to 
update an ongoing study 
referred in the protocol. 
Section 2.3.1: Risk 
Assessment 
Respiratory tract irritancy 
mitigation strategy (update 
in bold): 
Safety margins were 
modified to “maximum 
observed clinical exposure 
following 14-day repeat 
doses of 1500 mcg is 
expected to be below the 
rat mean gender-averaged 
NOAEL systemic exposure 
margins (AUC: 6-14 fold; 
Cmax: 26-64 fold; lung 
deposition cover at the rat 
NOAEL for lung 
pathology: 10 fold)” 
These edits were made to 
update safety margins 
based on the new top dose 
of 1500 mcg. 


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Section 4.1: Overall 
Design 
Section 4.2: Justification 
for Dose 
Section 4.1 (update in 
bold): 
Single Dose Treatments - 
“half of” was added to the 
second last paragraph as 
follows “The planned 
doses may be modified 
based on emerging safety 
and tolerability data but 
will not exceed half of the 
maximum single and repeat 
dose level administered in 
the FTIH Study of 3000 
mcg once daily”. 
Repeat Dose Treatment – 
“half of” was added to the 
third paragraph as follows 
“This planned dose may be 
modified based on 
emerging data but will not 
exceed half of 3000 mcg, 
the maximum repeat dose 
level administered in the 
FTIH Study”. 
Section 4.2.1: Starting 
Dose and Dose Escalation 
(update in bold): 
The sentence “This dose 
was also the highest dose 
administered and was well 
tolerated in the FTIH 
Study” was edited to “This 
dose was half of the 
highest dose (3000 mcg) 
administered that was well 
tolerated in the FTIH 
Study”. 
Section 4.2.2: Safety 
Margins: 
Safety margins for 1500 
mcg have been updated in 
These edits were made to 
justify 1500 mcg selection. 


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the following paragraph 
(update in bold). 
“Based on the PK data 
generated from FTIH 
Study 213497, the systemic 
exposure of participants 
following 1500 mcg 
GSK3923868 once daily 
for 14 days using the 
 device would 
be within the systemic 
exposure safety margins 
provided by the Rat IV 
study NOAEL (providing 
26 to 64 fold cover for 
Cmax and 6 to 14 fold 
cover for AUC(0-24) based 
on the individual 
participant exposures on 
Day 14 with 3000 mcg 
once daily in the FTIH 
Study” . 
Section 4.2.3: Predicted 
Target Engagement at 
Steady State: 
Target engagement at 1500 
mcg has been updated in 
the following paragraph 
and “In addition” was 
removed (update in bold). 
“Modelling and 
simulation was conducted 
utilising the PBPK model 
and the PKPD model 
(incorporated the PI4KB 
enzyme kinetics data which 
accounted for competitive 
binding with ATP) 
prediction shows at steady 
state trough in lungs, the 
median TE of 
GSK3923868 following a 
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Section # and Name 
Description of Change 
Brief Rationale 
1500 mcg once daily dose 
was 
 
 
 
 as 
illustrated in  Figure 1 
below”. 
The following sentence 
was deleted. 
“Additionally, for a 1000 
mcg dose given using the 
 device (with the 
assumption of dose 
proportionality in PK), the 
model predicted about 
 
 
 
 
Original Figure 1 was 
replaced with 1500 mcg 
target engagement 
prediction and the figure 
title was updated as 
follows (update in bold). 
“Predicted Distribution of 
Percent Target 
Engagement (TE) at 
Steady State Trough (1500 
mcg OD)” 
Section 6.1: Study 
Intervention(s) 
Administered 
Table 3/Repeat Dose 
(Period 3):  
Unit dose strength was 
changed from 
 
. 
Dose level was changed 
from 
 
 
These edits were made to 
clarify that 
 
 will be 
used for treatment period 3. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2: Preparation, 
Handling, Storage and 
Accountability 
The bullet “
 
should be kept in their 
primary packaging until 
dispensing into participant 
dosing bottles” was 
removed. 
This edit was made to 
update the change in 
dispensing study 
intervention strategy, i.e., 
no sub-dispensing will be 
conducted. 
Section 6.5.1.2: Study 
specific dose escalation 
stopping criteria 
“severe non-serious” and 
“and at least possibly 
related to the study drug” 
was added to the bullet 
“Two participants 
experience any severe 
non-serious adverse event 
considered clinically 
important by the 
Investigator and at least 
possibly related to the 
study drug” 
This edit was made to 
further clarify this stopping 
criterium. 
Section 8.2.4.2: Peak 
Expiratory Flow 
“and recorded in the 
eCRF” was removed from 
“PEF will be performed at 
time points outlined in the 
SoA and recorded in the 
eCRF” 
This edit was made to 
clarify that PEF data will 
be collected for 
participants to monitor 
their lung functions only. 
Section 9: Statistical 
Considerations 
“and in the OPS, 
respectively” was added to 
the end of the second 
paragraph. 
This edit was made to 
clarify study reporting 
details.  
Section 9.4.2.2: Laboratory 
values, vital signs, 12-lead 
electrocardiogram and 
Spirometry 
“FVC” was removed from 
the last bullet. 
FVC data will be collected 
at screening only and not 
for analyses. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.10: Appendix 
10: Protocol Amendment 
History 
Section 10.11: Appendix 
11: Abbreviations and 
Definitions and 
Trademarks 
New Section 10.10 and 
Appendix 10 were inserted 
for Protocol Amendment 
History.  Consequently, 
original Section 10.10 and 
Appendix 10 were updated 
to Section 10.11 and 
Appendix 11. 
This edit was made to 
include protocol 
amendment history. 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 13 
1.1. 
Synopsis ..................................................................................................... 13 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) ........................................................................ 16 
1.3.1. 
Screen and Follow Up.................................................................. 16 
1.3.2. 
Single Ascending Dose (Treatment Periods 1 and 2) ................... 18 
1.3.3. 
Repeat Dose (Treatment Period 3) .............................................. 20 
2. 
INTRODUCTION .................................................................................................... 24 
2.1. 
Study Rationale .......................................................................................... 24 
2.2. 
Background ................................................................................................ 24 
2.3. 
Benefit/Risk Assessment ............................................................................ 25 
2.3.1. 
Risk Assessment ......................................................................... 26 
2.3.2. 
Benefit Assessment ..................................................................... 28 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 28 
3. 
OBJECTIVES AND ENDPOINTS AND/OR ESTIMANDS ....................................... 28 
4. 
STUDY DESIGN .................................................................................................... 29 
4.1. 
Overall Design ............................................................................................ 29 
4.1.1. 
Participant Input into Design ........................................................ 31 
4.2. 
Justification for Dose .................................................................................. 31 
4.2.1. 
Starting Dose and Dose Escalation.............................................. 32 
4.2.2. 
Safety Margins ............................................................................. 32 
4.2.3. 
Predicted Target Engagement at Steady State ............................ 32 
4.3. 
End of Study Definition ............................................................................... 33 
5. 
STUDY POPULATION ........................................................................................... 33 
5.1. 
Inclusion Criteria ......................................................................................... 33 
5.2. 
Exclusion Criteria ........................................................................................ 36 
5.3. 
Lifestyle Considerations .............................................................................. 37 
5.3.1. 
Meals and Dietary Restrictions .................................................... 37 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 38 
5.3.3. 
Activity ......................................................................................... 38 
5.4. 
Screen Failures........................................................................................... 38 
5.5. 
Criteria for Temporarily Delaying ................................................................ 38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 39 
6.1. 
Study Intervention(s) Administered ............................................................. 39 
6.1.1. 
Medical Devices ........................................................................... 39 
6.2. 
Preparation, Handling, Storage and Accountability ..................................... 40 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 40 
6.4. 
Study Intervention Compliance ................................................................... 41 
6.5. 
Dose Modification ....................................................................................... 41 
6.5.1. 
Dose Escalation Stopping Criteria ............................................... 42 
6.5.2. 
Pharmacokinetic Criteria for Dose Modification ............................ 42 
6.5.3. 
Retreatment Criteria .................................................................... 42 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 43 
6.7. 
Treatment of Overdose ............................................................................... 43 


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6.8. 
Concomitant Therapy.................................................................................. 43 
6.8.1. 
Rescue Medicine ......................................................................... 44 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 44 
7.1. 
Discontinuation of Study Intervention .......................................................... 44 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 45 
7.1.2. 
QTc Stopping Criteria .................................................................. 45 
7.1.3. 
Spirometry Stopping Criteria ........................................................ 46 
7.1.4. 
COPD Exacerbation Stopping Criteria ......................................... 46 
7.1.5. 
Pharmacokinetic Stopping Criteria ............................................... 46 
7.1.6. 
Temporary Discontinuation .......................................................... 46 
7.1.7. 
Rechallenge ................................................................................. 46 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 46 
7.3. 
Lost to Follow Up ........................................................................................ 47 
7.4. 
Management of Participants who Develop COVID-19 Symptoms 
During the Study ......................................................................................... 47 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 48 
8.1. 
Efficacy Assessments ................................................................................. 48 
8.2. 
Safety Assessments ................................................................................... 48 
8.2.1. 
Physical Examinations ................................................................. 49 
8.2.2. 
Vital Signs .................................................................................... 49 
8.2.3. 
Electrocardiograms ...................................................................... 49 
8.2.4. 
Lung function Measurements ....................................................... 49 
8.2.5. 
Clinical Safety Laboratory Tests .................................................. 50 
8.2.6. 
Pregnancy Testing ....................................................................... 50 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 51 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 51 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 51 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 52 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 53 
8.3.5. 
Pregnancy ................................................................................... 53 
8.3.6. 
Cardiovascular and Death Events ................................................ 54 
8.3.7. 
Medical Device Deficiencies ........................................................ 54 
8.4. 
Pharmacokinetics ....................................................................................... 55 
8.5. 
Genetics ..................................................................................................... 56 
8.6. 
Biomarkers ................................................................................................. 56 
8.7. 
Immunogenicity Assessments ..................................................................... 56 
8.8. 
Health Economics ....................................................................................... 56 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 56 
9.1. 
Statistical Hypotheses................................................................................. 56 
9.2. 
Sample Size Considerations ....................................................................... 57 
9.3. 
Analysis Sets .............................................................................................. 57 
9.4. 
Statistical Analyses ..................................................................................... 57 
9.4.1. 
General Considerations ............................................................... 58 
9.4.2. 
Primary Endpoints Analysis ......................................................... 58 
9.4.3. 
Secondary Endpoint Analysis ...................................................... 58 
9.5. 
Interim Analysis .......................................................................................... 59 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 60 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 60 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 60 
10.1.2. 
Financial Disclosure ..................................................................... 60 
10.1.3. 
Informed Consent Process .......................................................... 61 
10.1.4. 
Data Protection ............................................................................ 61 
10.1.5. 
Committees Structure .................................................................. 62 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 62 
10.1.7. 
Data Quality Assurance ............................................................... 63 
10.1.8. 
Source Documents ...................................................................... 63 
10.1.9. 
Study and Site Start and Closure ................................................. 64 
10.1.10. Publication Policy ......................................................................... 65 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 66 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 68 
10.3.1. 
Definition of AE ............................................................................ 68 
10.3.2. 
Definition of SAE .......................................................................... 69 
10.3.3. 
Definition of Cardiovascular Events ............................................. 70 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 71 
10.3.5. 
Reporting of SAE to GSK ............................................................. 72 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ....................................... 74 
10.4.1. 
Definitions: ................................................................................... 74 
10.4.2. 
Contraception Guidance: ............................................................. 75 
10.4.3. 
Collection of Pregnancy Information ............................................ 76 
10.5. 
Appendix 5: Genetics .................................................................................. 78 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 79 
10.7. 
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies .................................. 81 
10.7.1. 
Definition of Medical Device AE and ADE .................................... 82 
10.7.2. 
Definition of Medical Device SAE, SADE and USADE ................. 82 
10.7.3. 
Definition of Device Deficiency ..................................................... 83 
10.7.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies ................................................................................. 83 
10.7.5. 
Reporting of SAEs ....................................................................... 85 
10.7.6. 
Reporting of SADEs ..................................................................... 86 
10.8. 
Appendix 8: Country-specific Requirements ............................................... 87 
10.9. 
Appendix 9: COVID-19 ............................................................................... 88 
10.9.1. 
Overall Rationale for this Appendix .............................................. 88 
10.9.2. 
Study Procedures During COVID-19 Pandemic ........................... 88 
10.9.3. 
Data Management/Monitoring ...................................................... 88 
10.10. Appendix 10: Protocol Amendment History ................................................. 90 
10.11. Appendix 11: Abbreviations and Definitions and Trademarks ..................... 91 
11. REFERENCES ....................................................................................................... 94 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomized, double-blind, placebo controlled, single and repeat dose 
study to assess the safety, tolerability and pharmacokinetics of inhaled GSK3923868 in 
participants with Chronic Obstructive Pulmonary Disease (COPD) 
Brief Title: A study to investigate safety, tolerability, and PK of GSK3923868 inhalation 
powder in COPD 
Rationale: 
GSK3923868 is a selective and potent inhibitor of phosphatidylinositol 4-kinase beta 
(PI4KB) being developed for respiratory disease and specifically the treatment of 
rhinovirus associated exacerbations of chronic obstructive pulmonary disease (COPD) 
and asthma.  
Data from this Phase 1 study will provide an assessment of the safety, tolerability, and 
pharmacokinetics of GSK3923868 inhalation powder in participants with stable COPD to 
support future studies in which COPD patients will be treated at the onset of cold-like 
symptoms and possibly at the beginning of an infective exacerbation. GSK3923868 is not 
an immunomodulatory drug. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and tolerability of 
GSK3923868 following single and 
repeat inhaled administration in 
participants with COPD 
• Occurrence of adverse events (AEs) and 
serious adverse events (SAEs). 
• Clinically significant changes in laboratory 
values, vital signs,12-lead 
electrocardiogram (ECG) and spirometry 
measurements up to Follow Up. 


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Objectives 
Endpoints 
Secondary 
• 
To evaluate the plasma 
pharmacokinetics of GSK3923868 
following single and repeat inhaled 
administration in participants with COPD 
Derived pharmacokinetic parameters as data 
permit, including (but not limited to): 
• 
Area under the plasma-concentration time 
curve (AUC): area under the concentration-
time curve from time 0 (predose) to 24 
hours post dose administration following 
the first dose (AUC[0-24]) or area under the 
concentration-time curve from time 0 to the 
time of the last quantifiable concentration 
(AUC[0-t]) for single dose and area under 
the concentration-time curve from time 0 
(predose) to 6 hours post dose 
administration following the first dose 
(AUC[0-6]) for repeat dose 
• 
Maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration 
(Tmax)  
 
Overall Design: 
This is a single cohort, randomized, double-blind, placebo controlled single and repeat 
dose study designed to assess the safety, tolerability and plasma PK of GSK3923868 
administered as an inhalation powder blend (GSK3923868 
) using 
the 
 inhaler in participants with stable COPD.  This study contains two 
parts, a single ascending dose followed by 14-days repeat dosing. 
The single ascending dose part will assess two dose levels of GSK3923868 inhalation 
powder or placebo across two treatment periods in a single crossover cohort of 
participants. 
The repeat dose part will assess one dose level of GSK3923868 inhalation powder or 
placebo in one treatment period in the same cohort of participants. 
Brief Summary: 
The purpose of this study is to measure safety, tolerability and pharmacokinetics of single 
or repeat inhaled doses of GSK3923868 in participants with stable COPD.  The study 
treatment will be one day for the single dose assessments and 14 days for the repeat dose 
assessment.  The study duration will be from 64 to 71 days.  The visit frequency is 
detailed in the Schedule of Activities (SoA) in Section 1.3 
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Number of Participants: 
A total of approximately 12 participants with COPD will be enrolled in this study.  
Sufficient patients will be screened and those who meet the study entry criteria will be 
randomized to receive GSK3923868 inhalation powder or placebo in a 3:1 ratio with the 
intention of a minimum of 8 and a maximum of 12 participants to complete the study. 
Note: Enrolled means a participant agrees to participate in a clinical study following 
completion of the informed consent process and screening. Potential participants who are 
screened for the purpose of determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise specified by the protocol. A 
participant will be considered enrolled if the informed consent is not withdrawn prior to 
participating in any study activity after screening. 
Intervention Groups and Duration: 
This single cohort, randomized, double-blind, placebo-controlled study contains two 
single and one repeat dose treatments. 
Single Dose 
The single dose treatments will assess two ascending single doses of GSK3923868 as an 
inhalation powder using the 
 inhaler in one cross-over cohort of participants 
with COPD.  Participants will receive single ascending doses of GSK3923868 inhalation 
powder or matching placebo (3:1 ratio) in two treatment periods. The proposed starting 
dose is 500 mcg.  Progression to the next single dose level of 1000 mcg will occur on an 
individual participant basis and only if, in the judgement of the Investigator, it is 
supported by the safety and tolerability profile in that patient taking 500 mcg. 
Participants will be enrolled for approximately 42 days for the single dose assessments 
(up to 30 days screening, 2 assessment/washout periods up to 6 days each). 
Repeat Dose 
The repeat dose treatment will assess 1500 mcg of GSK3923868 in the same cohort of 
participants that has completed single dose assessments.  Participants will receive either 
GSK3923868 or placebo as an inhalation powder via 
 inhaler (3:1 ratio) once 
daily for 14 days. Progression to repeat dosing will occur on an individual participant 
basis and only if the Investigator agrees it is supported by the safety and tolerability 
profile of single doses. 
Participants will be enrolled for approximately 15 days for the repeat dose period and 
follow-up period from 7 to 14 days. 
In total, participants will be enrolled for approximately 64 to 71 days in the study (42 
days for two single dose periods including screen and washouts, and 15 days for one 
repeat dose period including a 7 to 14-day follow-up). 
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Data Monitoring/ Other Committee: No 
Regular (i.e., every 4 weeks) meetings between the Investigator and Sponsor study teams 
will review all available safety data across all participants in the study. 
1.2. 
Schema 
 
1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Screen and Follow Up 
Procedure 
Screening1 
(up to -30 days  
before Day 1) 
Early 
Discontinuation/Withdrawal 
Visit (7  2 days post last 
dose) 
Follow Up 
Phone Call 
(7 to 14 days  
post last dose) 
Phone Call 
 
 
X 
Informed Consent 
X 
 
 
Review Inclusion and Exclusion 
Criteria 
X 
 
 
Demography 
X 
 
 
Medical & Disease History 
X 
 
 
Full Physical Examination  
(includes height, weight and BMI) 
X 
 
 
Brief Physical Examination 
 
X 
 
Alcohol Urine Test 
X 
X 
 
Urine Drug Screen 
X 
X 
 
COVID-19 Screening2 
X 
X 
 
AE Review 
 
X 
X 
SAE Review 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
Inhaler Training 
X 
 
 
Spirometry (FEV1 & FVC)3 
X 
X 
 
Vital Signs4 
X 
X 
 
12-Lead Safety ECG5  
X 
X 
 
Safety Laboratory Assessment6 
X 
X 
 
Urinalysis 
X 
X 
 
Serum FSH and Estradiol7 
X 
 
 
Urine Pregnancy Test 
X 
X 
 
HIV, Hepatitis B and C Screening 
X 
 
 


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Procedure 
Screening1 
(up to -30 days  
before Day 1) 
Early 
Discontinuation/Withdrawal 
Visit (7  2 days post last 
dose) 
Follow Up 
Phone Call 
(7 to 14 days  
post last dose) 
PK Blood Sample 
 
X 
 
 
1. 
 
Screening may be performed across multiple visits if necessary. 
2.  To be performed according to local site policy. 
3.   Pre- and post-bronchodilator FEV1, predicted FEV1 and FVC are needed at 
screen only.  
4.   Includes systolic and diastolic blood pressure, heart rate, respiration rate 
and tympanic temperature 
5. Triplicate ECGs will be obtained at screening and single ECGs at all other 
occasions. 
6. Clinical chemistry, hematology. 
7. As needed in women of nonchildbearing potential only  
 
 


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Clinical Study Protocol template V17 dated 24 January 2022 
1.3.2. 
Single Ascending Dose (Treatment Periods 1 and 2) 
Procedure 
Treatment Periods 1 and 2 
 
D-1 
D1 
D2 
D3 
 
 
Pre-
dose 
0h 
5m 
15m 
30m 
45m 
1h 
2h 
4h 
6h 
Site Visit 
X 
X 
 
 
Site Overnight Stay1 
X 
X 
 
 
Discharge from Site 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Review Inclusion and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Urine Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Testing2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaler Training (refresher)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation (Period 1 only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment Administration4 
 
 
X 
 
 
 
 
 
 
 
 
 
 
AE Review (include washout) 
 
 
SAE Review (include washout) 
 
Conmed Review 
 
 
Spirometry (FEV1) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Vital Signs5 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
12-Lead Safety ECG (single) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Laboratory Safety Assessment6 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Genetic sample7 (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Study Protocol template V17 dated 24 January 2022 
1.  Day -1 site admission would be optional. 
2. To be performed according to local site policy on Day -1. 
3. To be provided before first dose administration. If necessary, another inhaler refresher training may be provided in treatment period 
4. Participants should fast for at least 6 hours before dosing until 1 hour post-dose.  No water from 1 hour before dosing until 1 hour post-dose.  See Section 
5.3 for details. 
5. Includes systolic and diastolic blood pressure, heart rate, respiration rate and tympanic temperature. Tympanic temperature will be measured once per day in 
the morning only. 
6. Clinical chemistry and hematology only. 
7. Genetic sampling can be conducted at any onsite visit during the study. 
 
 
 


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1.3.3. 
Repeat Dose (Treatment Period 3) 
Procedure 
D
-1 
D1 
D
2 
to 
5 
D6 
D7 
D
8 
to 
12 
D 13 
D14 
D1
5 
Pre-
dos
e 
0
h 
5
m 
15
m 
30
m 
45
m 
1
h 
2
h 
4
h 
6
h 
Pre-
dos
e 
0
h 
1
h 
Pre-
dos
e 
0
h 
5
m 
15
m 
30
m  
45
m 
1
h 
2
h 
6
h 
Site Visit 
X 
X 
 
X 
X 
 
X 
X 
 
Site Overnight 
Stay1 
X 
 
 
X 
 
 
X 
 
 
Discharge 
from Site 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Phone Call2 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Review 
Inclusion and 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Urine 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
COVID-19 
Testing3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Brief Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Inhaler 
Training 
(refresher)4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site 
Treatment 
Administratio
n5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
Home Dosing6 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
X6 
 
 
 
 
 
 
 
 
 
 
Dispense 
Patient Diary7 
 
X 
 
 
X 
 
 
X 
 


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Clinical Study Protocol template V17 dated 24 January 2022 
Procedure 
D
-1 
D1 
D
2 
to 
5 
D6 
D7 
D
8 
to 
12 
D 13 
D14 
D1
5 
Pre-
dos
e 
0
h 
5
m 
15
m 
30
m 
45
m 
1
h 
2
h 
4
h 
6
h 
Pre-
dos
e 
0
h 
1
h 
Pre-
dos
e 
0
h 
5
m 
15
m 
30
m  
45
m 
1
h 
2
h 
6
h 
Site Visit 
X 
X 
 
X 
X 
 
X 
X 
 
Review 
Patient Diary 
and Treatment 
Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
  
 
AE Review 
(continuous 
from 
treatment 
period 2) 
SAE Review 
(continuous 
from 
treatment 
period 2) 
 
Conmed 
Review 
 
Spirometry 
(FEV1) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
PEF8 
 
Vital Signs9 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
12-Lead 
Safety ECG 
(single) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
Laboratory 
Safety 
Assessment10 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Urine 
Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PK Blood 
Sample 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 


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1. Day -1, Day 6 and Day 13 site admissions would be optional. 
2. Telephone call on Days 2, 4, 8, 10, 12 and 15. 
3. To be performed according to local site policy.  
4. If necessary, inhaler refresher training may be provided. 
5. Participants should fast for at least 6 hours before dosing until 1 hour post dose.  No water from 1 hour before dosing until 1 hour post-dose.  See 
Section 5.3 for details. 
6. Dosing on Days 6 and 13 can be either at home or at the site.  Day 14 dosing will be timed according to the Day 13 dosing time so that Day 14 pre-
dose PK sample can be used as 24h post-dose in PK parameter calculations. 
7. Patient diary card will be used to capture study intervention information, PEF measurements, AE/SAE and concomitant medication use.  Dispense 
Day 1 (for evening entry), Day 2 to 5 (full day entry), and Day 6 (for morning entry) patient diary card before discharge on Day 1, and dispense Day 7 
(for evening entry), Day 8 to 12 (full day entry), and Day 13 (for morning entry) patient diary card before discharge on Day 7, and dispense Day 14 (for 
evening entry) and Day 15 (morning entry) patient diary card before discharge on Day 14.  The last diary card (dispensed on Day14) will be reviewed 
by the site via the phone call on Day 15, and returned to the site within 2 weeks from Day 15. 
8. PEF measurements will be taken in triplicate twice each day (once in morning upon waking and once in the evening before bedtime) from Day 1 
morning until Day 15 morning.  PEF will be reviewed by the Investigator at each site visit or phone call (Day 15). 
9. Includes systolic and diastolic blood pressure, heart rate, respiration rate and tympanic temperature. Tympanic temperature will be measured once 
per day in the morning only. 
10. Clinical chemistry and hematology only.9 


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• The timing of planned study assessments may change during the course of the study based on emerging data/in-stream data review 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
• Any changes in the timing of time points for any planned study assessments as the result of emerging 
pharmacokinetic/pharmacodynamic data from this study must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files but will not constitute a protocol amendment. 
The Competent Authority (CA) and ethics committee (EC) will be informed of any safety issues that constitute a substantial amendment 
and require alteration of the safety monitoring scheme or amendment of the informed consent form (ICF). The changes will be approved 
by the CA and the EC before implementation.


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
GSK3923868 is a selective and potent inhibitor of phosphatidylinositol 4-kinase beta 
(PI4KB) being developed for respiratory disease and specifically the treatment of 
rhinovirus associated exacerbations of COPD and asthma.  
Data from this Phase 1 study will provide an assessment of the safety, tolerability, and 
pharmacokinetics of GSK3923868 inhalation powder in participants with stable COPD to 
support future studies in which COPD patients will be treated at the onset of cold-like 
symptoms and possibly at the beginning of an infective exacerbation. GSK3923868 is not 
an immunomodulatory drug. 
2.2. 
Background 
Human rhinovirus are small, non-enveloped, positive sense RNA viruses that cause the 
common cold.  The symptoms related to HRV infection are generally mild and limited to 
the upper respiratory tract.  However, in patients with chronic respiratory diseases such as 
COPD and asthma, HRV is the predominant viral stimulus leading to disease 
exacerbations [Hershenson 2013].  
PI4KB is a human intracellular lipid kinase and is a host factor required for the 
replication of multiple picornaviruses, including HRV.   
GSK3923868 is a selective inhibitor of PI4KB.  Preclinical data has shown that 
GSK3923868 exhibits potent and slowly reversible inhibition of HRV replication.  
A first time in human study designed to evaluate the safety, tolerability and PK profile of 
single and repeat inhaled doses of GSK3923868 in both healthy participants and 
participants with asthma is ongoing. This study uses the 
 inhaler for drug 
delivery.  
At the time of publishing this protocol, there are currently two on-going studies and no 
completed studies. 
The study 213497 [GSK Document Number 2020N430088_03] is a FTIH study that has 
completed single ascending and repeat dosing in healthy participants.  These healthy 
participants received inhaled GSK3923868 at doses up to 3000 mcg once daily for 14 
days (the predefined maximum) dose which was found to be well tolerated. 
The repeat dose in asthmatics has completed recruitment, with 7 moderate and 4 mild 
asthmatics completing the study to date.  Transient increases in ALT and AST were noted 
in two participants (one active and one placebo) with asthma, which normalized after 
dosing was stopped.  Both participants were asymptomatic.  There have been no other 
clinically significant findings or episodes of bronchospasm reported and the drug has 
been otherwise well tolerated.  The plasma PK in asthmatics was also comparable to that 
observed in healthy participants. 
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Study 213499 [GSK Document Number TMF-14737217.  ] is a Phase 1b study that is 
currently on-going and recruiting mild asthma patients to undergo experimental HRV 
infection and will receive doses of 3000 mcg GSK3923868 inhalation powder or placebo 
for up to 14 days.  At the time of publishing this protocol amendment, 13 participants 
have been dosed.  No SAEs or notable AEs have been observed so far. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3923868 may be found in the Investigator’s 
Brochure [GSK Document Number: RPS-CLIN-024977]. 
 


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention [GSK3923868] 
Bronchospasm 
Can potentially occur with any inhaled 
treatment. 
 
The FTIH study 213497 assessed single 
ascending (50 to 3000 mcg) and 3000 mcg 
repeat doses of GSK3923868 inhalation powder 
for 14 days in healthy participants and 7 days in 
asthmatics.  There was no evidence of 
bronchospasm in adverse events or with daily 
pre- and post-dose FEV1 assessments. 
 
The risk of bronchospasm in participants with 
COPD is therefore considered to be very low. 
 
Inclusion/Exclusion criteria: only participants 
with stable COPD with a post-bronchodilator 
FEV1  40% of predicted normal value will be 
recruited.  
 
Monitoring: initial doses of study treatment will 
be administered in a clinical unit in the presence 
of clinical staff. Spirometry will be conducted pre 
and post dose to monitor participants.  
 
Management: treatment with a short-acting 
inhaled bronchodilator will be available. If 
bronchospasm occurs, GSK3923868 will be 
discontinued immediately. The participant will 
be assessed and, if necessary, further therapy 
will be given as deemed appropriate by the 
Investigator or the attending physician. 
Participants will be withdrawn from the study if 
bronchospasm occurs. 
Respiratory tract irritancy 
In rats dosed for 4 weeks by inhaled 
administration, microscopic findings were noted 
in the lungs and bronchi, with minimal 
degeneration/regeneration of the epithelium at 
the bronchioloalveolar junction at 2060 
µg/kg/day. In addition, an increased incidence 
Appropriate safety margin: maximum observed 
clinical exposure following 14-day repeat doses 
of 1500 mcg is expected to be below the rat 
mean gender-averaged NOAEL systemic 
exposure margins (AUC: 6-14 fold; Cmax: 26-64 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention [GSK3923868] 
of inflammatory cell infiltrate (minimal or slight 
severity), composed predominantly of 
granulocytes, of the peribronchiolar/perivascular 
interstitium was also seen at 2060 µg/kg/day. 
Minimal or slight inflammatory cell infiltrate was 
seen at a higher than control incidence in 
females given 2060 µg/kg/day only. However, 
no microscopic findings in dog IH and rat IV 
studies. 
fold; lung deposition cover at the rat NOAEL for 
lung pathology: 10-fold).  
 
Monitoring: respiratory AEs will be monitored 
and spirometry will be conducted pre- and post-
dose in all three initial single doses. In addition, 
PEF monitoring will be implemented. Single 
dose escalation will proceed in an individual 
participant basis and only proceed after a 
blinded review of safety, tolerability.  
Study Procedures 
Spirometry assessments 
Shortness of breath, coughing, light 
headedness or fainting, and/or chest tightness 
during the spirometry assessments 
As specified in the informed consent form for 
this study, if any of these symptoms should 
occur, the participant will receive appropriate 
medical treatment. 
 


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2.3.2. 
Benefit Assessment 
No clinical benefit is expected for the COPD participants enrolled in this study, as 
evidence for the potential of clinical benefits of GSK3923868 is yet to be determined. 
Furthermore, clinical benefit would not be expected in participants not experiencing a 
HRV infection.  
Participants may benefit from the thorough medical assessments they receive during the 
course of the study. 
2.3.3. 
Overall Benefit: Risk Conclusion 
The potential risks associated with GSK3923868 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. Enrolment of participants with 
stable COPD is considered justified by the anticipated benefits that may be afforded to 
participants with COPD and asthma in the future. 
3. 
OBJECTIVES AND ENDPOINTS AND/OR ESTIMANDS 
Objectives 
Endpoints 
Primary 
 
• To assess the safety and tolerability of 
GSK3923868 following single and repeat 
inhaled administration in participants with 
COPD 
• Occurrence of AEs and SAEs 
• Clinically significant changes in laboratory 
values, vital signs,12-lead ECG and 
spirometry measurements up to Follow Up 
Secondary 
 
• To evaluate the plasma pharmacokinetics 
of GSK3923868 following single and 
repeat inhaled administration in 
participants with COPD 
Derived pharmacokinetic parameters as data 
permit, including (but not limited to): 
• Area under the plasma-concentration time 
curve (AUC): AUC(0-24) or AUC(0-t) for 
single dose and AUC(0-6) for repeat dose 
• Cmax, Tmax  


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This randomized, double-blind, placebo controlled, single and repeat dose study will 
assess the safety, tolerability and plasma PK of GSK3923868 administered as an 
inhalation powder blend (GSK3923868 
for inhalation) using the 
 
 inhaler in three cross-over treatments to one cohort of participants with stable 
COPD.  The study design schematic is presented in Section 1.2. Study treatment and 
post-treatment follow-up Schedule of Activities (SoA) Tables are provided in Section 
1.3. Treatment sequence and randomization is shown in Table 1. 
Table 1 
Study treatment sequence and randomization  
Treatment  
Period 
Planned  
Dose 
Cohort 1 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
1 (Single Dose) 
500 mcg GSK3923868 
A 
A 
A 
P 
2 (Single Dose) 
1000 mcg GSK3923868 
P 
A 
A 
A 
3 (14-Day Repeat Dose) 
1500 mcg GSK3923868 
A 
P 
A 
A 
A = Active Treatment; P = Placebo Treatment 
The total duration of study participation is shown in Table 2. 
Table 2 
Study duration by treatment 
Screen 
Treatment Period 
1 
(500 mcg single 
dose) plus 
washout 
Treatment Period 
2 
(1000 mcg single 
dose) plus 
washout 
Treatment 
Period 3 
(1500 mcg 
repeat dose) 
Follow-up 
Period 
Total Duration 
Up to 30 days 
before first dose 
6 days (2 days 
inpatient + 4 days 
outpatient) 
6 days (2 days 
inpatient + 4 days 
outpatient) 
15 days (3 
days inpatient 
+ 12 days 
outpatient) 
7- 14 days 
post-dose 
64 - 71 days 
 
Participants who meet the study entry criteria will be randomized to receive 
GSK3923868 inhalation powder or placebo before study intervention administration on 
Day 1 of Treatment Period 1. 
If a participant withdraws prematurely from the study or discontinues treatment early, 
additional participants may be recruited to start from 500 mcg single dose treatment 
sequence at the discretion of the Sponsor in consultation with the Investigator. 
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Single Dose Treatments 
Sufficient participants will be screened and those who meet the study entry criteria will 
be randomized to receive GSK3923868 or placebo using a 
 inhaler in a 3:1 
ratio with the intention of a minimum of 8 and a maximum of 12 participants to complete 
the study. 
The proposed starting dose for the first treatment period is 500 mcg (refer to Section 4.2 
for Dose Justification).  Participants will be admitted to the unit on Day -1 and receive a 
single dose of 500 mcg in the unit on Day 1.  Participants will then be discharged on Day 
2 after completion of all SoA-specified procedures/activities, and followed up by a 
telephone call on Day 3.  
Escalation to treatment period 2 (1000 mcg) will occur on an individual participant 
basis.  A review of safety and tolerability will be conducted prior to administration of the 
next dose level. This review will occur after at least 3 days of data collection from the 
participant.   
Participants will return for their next scheduled dosing period once all information for 
dose escalation has been received and reviewed, which is anticipated to be at least 5 days 
after administration of the study drug from the prior dosing period. 
The planned doses may be modified based on emerging safety and tolerability data but 
will not exceed half of the maximum single and repeat dose level administered in the 
FTIH Study of 3000 mcg once daily [GSK Document Number 2020N430088_03]. 
Participants will be enrolled for approximately 42 days for the single dose assessments 
(up to 30 days screening, 2 assessment/washout periods up to 6 days each) (Table 2). 
Repeat Dose Treatment 
Escalation to treatment period 3 (1500 mcg) will also occur on an individual participant 
basis.  Once participants completed the single dose treatment and all information for dose 
adjustment/ escalation has been reviewed, the participants may start a 14-day repeat dose 
treatment (period 3) following at least a 6-day washout after administration of last single 
dose.  Participants will receive either GSK3923868 in inhalation powder or placebo 
administered using a 
 inhaler as described in Table 1   
The proposed dose for the repeat dose is 1500 mcg.  The repeat dose period requires three 
single-night unit stays (Days -1, 6 and 13).  Participants will be admitted on Day -1 to 
receive their first dose of 1500 mcg in the unit on Day 1. Participants will be discharged 
on Day 1 after completion of all procedures/activities to continue repeat dosing at home 
from Days 2 to 6. Participants will then return to the unit on Day 6 to receive a dose in 
the unit on Day 7 before being discharged on Day 7 to continue home dosing from Days 
8 to 12.  Participants will be admitted once more on Day 13 to receive their last dose of 
the period in the unit on Day 14.  Participants will be discharged on Day 14 and followed 
up by telephone call on Day 15 with final telephone follow up approximately 7 to 14 days 
after their final dose. 
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This planned dose may be modified based on emerging data but will not exceed half of 
3000 mcg, the maximum repeat dose level administered in the FTIH Study [GSK 
Document Number 2020N430088_03]. 
Participants will be enrolled for approximately 29 days for the repeat dose assessment 
(one treatment assessment up to 15 days and follow-up period from 7 to 14 day) (Table 2 
Scientific Rationale for Study Design). 
This study will be the first administration of GSK3923868 inhalation powder to 
participants with stable COPD and the first outpatient-based study with GSK3923868 
inhalation powder.  GSK3923868 inhalation powder is being studied in healthy 
participants and participants with mild to moderate asthma and has been found to be well 
tolerated in both populations. 
As this study represents a change in population a cautious approach is being adopted. 
Two single dose treatment periods of 500 mcg and 1000 mcg, respectively, have been 
incorporated to allow for review of safety and tolerability and ensure the safety of 
participants before progression to repeat 1500 mcg once daily treatment for 14-days. 
The randomized, placebo-controlled study design is a well-established methodology in 
experimental studies to allow for the valid evaluation of effects attributable to treatment 
versus those independent of treatment.  The double-blind design is a standard 
methodology for randomized controlled trials to avoid potential bias.  The crossover 
randomisation approach will reduce the potential impact of inter-individual variability on 
the study outputs. 
A minimum washout period of 5 days between single doses and before repeat dosing is 
based on observed PK data from the FTIH Study [GSK Document Number 
2020N430088_03].  The time points for monitoring safety and tolerability endpoints are 
based on the experience with administration of GSK3923868 inhalation powder as both 
single and repeat doses to healthy participants and mild to moderate asthmatics. 
4.1.1. 
Participant Input into Design 
There was no specific elicitation of participant input into the design of this study. 
4.2. 
Justification for Dose 
For this 
 device, the term “dose” refers to the nominal content of active 
pharmaceutical ingredient contained within the GSK3923868 
 for inhalation, 
administered using the 
 inhaler. 
Dose selection was based on the emerging safety, tolerability and plasma PK data of 
single and repeat dose treatment of GSK3923868 inhalation powder using the 
 
inhaler in healthy participants and participants with mild to moderate asthma. 
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4.2.1. 
Starting Dose and Dose Escalation 
The first dose to be administered in this study will be a single dose of 500 mcg 
GSK3923868 inhalation powder in treatment period 1 followed by a single dose 
escalation to 1000 mcg GSK3923868 inhalation powder in treatment period 2. 
The 1500 mcg GSK3923868 inhalation powder once daily dose given for 14-days in 
treatment period 3 will be the highest dose level to be evaluated in this study.  This dose 
was half of the highest dose administered (3000 mcg) that was well tolerated in the FTIH 
Study [GSK Document Number 2020N430088_03], including administration for 7 days 
to participants with asthma.  
4.2.2. 
Safety Margins  
Based on the PK data generated from FTIH Study 213497, the systemic exposure of 
participants following 1500 mcg GSK3923868 inhalation powder once daily for 14 days 
using the 
 device would be within the systemic exposure safety margins 
provided by the Rat IV study NOAEL (providing 26 to 64 fold cover for Cmax and 6 to 
14 fold cover for AUC(0-24) based on the individual participant exposures on Day 14 
with 3000 mcg once daily in the FTIH Study [GSK Document Number 
2020N430088_03]. 
4.2.3. 
Predicted Target Engagement at Steady State 
Modelling and simulation was conducted utilising the PBPK model and the PKPD model 
(incorporated the PI4KB enzyme kinetics data which accounted for competitive binding 
with ATP) prediction shows at steady state trough in lungs, the median TE of 
GSK3923868 following a 1500 mcg once daily dose was 
 and there is a 
 
probability that steady state trough TE would be above 
as illustrated in  Figure 1 
below.  
 
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Figure 1 
Predicted Distribution of Percent Target Engagement (TE) at Steady 
State Trough (1500 mcg OD) 
This level of target engagement is expected to be relevant for the assessment of efficacy 
in future studies in COPD patients. 
4.3. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the last scheduled procedure shown in the SoA. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
AGE 
1.  Between 40 and 70 years of age inclusive, at the time of signing the informed consent. 
• Note: Participants must show evidence of complete COVID-19 vaccination before 
being eligible to participate.  A complete COVID-19 vaccination is currently 
defined as having taken either two basic vaccinations plus one booster three 
months afterwards or two vaccinations plus a confirmed COVID-19 infection 
before vaccinations.  
 
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TYPE OF PARTICIPANT 
2. The participant has a confirmed diagnosis of COPD for > 6 months, as defined by the 
GOLD guidelines. 
3. The participant has a post-bronchodilator FEV1/FVC ratio < 0.7 within 30 min after 
administration of 400 μg salbutamol or equivalent and post-bronchodilator FEV1 ≥ 40% to 
< 80% of predicted value. 
• Note: Predicted values based on ERS guidelines, [Quanjer 2012] . 
4. Participant is a smoker or an ex-smoker with a smoking history of at least 10 pack years. 
• Notes:  
The following equation should be used to calculate pack years.  
𝑝𝑎𝑐𝑘 𝑦𝑒𝑎𝑟𝑠= (𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑠 𝑠𝑚𝑜𝑘𝑒𝑑 𝑝𝑒𝑟 𝑑𝑎𝑦
20
) × 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑦𝑒𝑎𝑟𝑠 𝑠𝑚𝑜𝑘𝑒𝑑 
 
WEIGHT 
5. Body weight at least 45 kg and BMI within the range 18.0 to 32 kg/m2 (inclusive). 
 
SEX 
6. Males and female participants, as follows: 
Male Participants: No additional requirements. 
Female Participants: A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
• Is a WONCBP. 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described in 
Appendix 4 during the intervention period for at least 10 days after the last dose 
of study intervention.   
A WOCBP must have both: 
o A confirmed menstrual period before the first dose of study intervention. 
AND 
o A negative highly sensitive (see Appendix 4) pregnancy test (urine or 
serum as required by local regulations) within 30 days before the first 
dose of study intervention. 
▪ Note: If a urine test cannot be confirmed as negative (e.g. an 
ambiguous result), a serum pregnancy test is required.  In such 
cases, the participant will be excluded from participation if the 
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SEX 
Note: Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.  Additional 
requirements for pregnancy testing during and after study intervention are located in 
Appendix 4. 
 
INFORMED CONSENT 
7. Capable of giving signed informed consent as described in Section 10.1 which includes 
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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. 
Participant has poorly controlled or unstable COPD, defined as the occurrence of any of 
the following: 
• Acute worsening of COPD (an exacerbation) that is managed with oral 
corticosteroids and/or antibiotics within 4 weeks of screening. 
OR 
• More than two exacerbations in the previous 3 months before screening that 
required a course of oral corticosteroids and/or antibiotics, or for which the 
participant was hospitalised. 
2. 
Participant has a past or current medical condition(s) or disease(s) that is/are not well 
controlled and, which in the judgement of the Investigator, may affect participant safety or 
affect study endpoints. 
• Note: Participants with adequately treated and well controlled concurrent medical 
conditions (e.g., hypertension) ARE permitted to be entered into this study. 
3. 
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with 
the exception of Gilbert’s Syndrome, and asymptomatic gallstones). 
4. 
Evidence of concurrent significant pulmonary diseases, other than COPD, including (but 
not limited to): active tuberculosis, lung cancer, clinically symptomatic bronchiectasis, 
pulmonary fibrosis, asthma or any other respiratory condition that, in the opinion of the 
Investigator, may compromise the safety of the participants or affect the interpretation of 
results. 
 
PRIOR/CONCOMITANT THERAPY 
5. Participant has had a respiratory tract infection treated with antibiotics within 4 weeks prior 
to screening. 
6. Participant requires regular treatment with oral corticosteroids or has received a course of 
oral or parenteral corticosteroids within 4 weeks prior to screening. 
7. Participant requires long-term oxygen therapy. 
8. Participant requires treatment with medications considered as strong inhibitors of CYP3A4 
(e.g., macrolide antibiotics) up to 14 days before first dose.  
 
PRIOR/CONCOMITANT CLINICAL STUDY EXPERIENCE 
9. Participation in this study would result in loss of blood or blood products in excess of 500 
mL within a 56-day period. 
10. Exposure to more than 4 new chemical entities within 12 months before the first dosing 
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PRIOR/CONCOMITANT CLINICAL STUDY EXPERIENCE 
11. Current enrolment or past participation in a clinical trial and has received an 
investigational product within the following period before the first dosing day in this study: 
30 days, 5 half-lives or twice the duration of the biological effect of the investigational 
product (whichever is longer). 
 
DIAGNOSTIC ASSESSMENTS 
12. Positive human immunodeficiency virus (HIV) antibody test. 
13. Positive pre-study drug (except for as results of opioids prescribed for medical reasons 
and/or inadvertent consumption of poppy seeds, see Section 6.8) /alcohol screening 
result. 
14. Presence of HBsAg/anti-hepatitis B core antibodies (IgM) at screening or within 3 months 
prior to first dose of study intervention. 
15. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose 
of study intervention. 
16. QTcF > 450 msec at screening visit based on the average of triplicate ECGs. 
17. A positive laboratory confirmation of COVID-19 infection, or high clinical index of 
suspicion for COVID-19 
 
OTHER EXCLUSIONS 
18. History of regular alcohol consumption within 6 months prior to the study defined in 
Germany as: 
• An average daily intake of pure alcohol of > 24 g per day for males and >12 g per 
day for females.  
19. Sensitivity to the study intervention or components thereof (including 
 
), or drug or other allergy that, in the opinion of the Investigator or 
medical monitor, or vulnerable participants (e.g., participants in detention, protected adults 
under guardianship, trusteeship, or committed to an institution by government or juridical 
order) contraindicate participation in the study.   
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• Standardized meals will be provided while the participant is confined to the 
clinical unit. At all mealtimes, food will be served only after the completion of 
protocol specific procedures.  
• Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, from 7 days before the start of study intervention until after the final dose. 
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• No water is allowed 1 hour before and after dosing, water is allowed ad libitum at 
all other times 
• Participants should fast for at least 6 hours until 1 hour after each dose. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• Inpatient 
a. During PK sampling days, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 
12 hours before the start of dosing until after collection of the final PK 
sample. 
b. Use of tobacco products will be allowed, but not between 1 hour before and 
after drug inhalation (see Section 5.1). 
c. Alcohol consumption is not permitted in the clinical unit or for at least 12 
hours prior to clinical visits. 
• Outpatient 
a. Use of tobacco products will be allowed, but not between 1 hour before and 
after drug inhalation (see Section 5.1). 
5.3.3. 
Activity 
• Participants will abstain from strenuous exercise for 72 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during the study (e.g., watching television, reading). 
5.4. Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical 
study is not subsequently randomized/entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, information 
from any previous trials with the same IP, any protocol deviations and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once, especially for COVID-19-related screen failures.  Participants 
recovered from COVID-19 infections may be rescreened. Rescreened participants should 
be assigned a new participant number for every screening/rescreening event.  Unused 
reserve participants that meet eligibility criteria are not considered screen failures. 
5.5. 
Criteria for Temporarily Delaying  
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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 
Table 3 
Study Intervention(s) Administered 
Study Intervention 
Treatment: 
Single Dose  
Period 1 
Single Dose  
Period 2 
Repeat Dose 
(Period 3) 
All Treatment 
Periods 
Intervention name: 
GSK3923868 
 for inhalation. 
Placebo to 
match 
GSK3923868 
 for 
inhalation. 
Type: 
Drug 
Placebo 
Dose Formulation: 
 containing inhalation powder blend. 
Delivered via 
 device. 
Unit Dose Strength: 
500 mcg 
1000 mcg 
500 mcg 
N/A 
Dosage Level(s)1: 
 
 
 
 
  
 
 
 
Number  
 to 
match active 
treatment. 
Route of 
Administration: 
Inhalation 
Use: 
Experimental 
Placebo 
IMP and NIMP: 
IMP 
Sourcing: 
Provided centrally by the Sponsor 
Packaging and 
Labelling: 
Study Intervention will be provided in a 
. 
 and one 8 g 20% RH maintaining desiccant sachet. 
Each 
will be labelled as required per country requirement. 
Current Name: 
N/A 
N/A 
NA 
N/A 
1 
. 
6.1.1. 
Medical Devices 
• The GSK manufactured medical devices (or devices manufactured for GSK by a third 
party) provided for use in this study are 
 
 
• Instructions for medical device use are provided in the SRM. 
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• All device deficiencies, (including malfunction, use error and inadequate labelling) 
shall be documented, and reported by the investigator throughout the clinical 
investigation (see Section 8.3.7 and Section 10.7) and appropriately managed by the 
sponsor. 
6.2. 
Preparation, Handling, Storage and Accountability 
• 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. 
• 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. 
• 
 devices will be supplied in bulk.  After use, the devices will be 
placed in a plastic bag, and the bag will be labelled with the participant number, day 
of dosing, and date.  Devices will be disposed of at site after reconciliation is verified 
by Study Monitor. 
• 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). 
• Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  
• 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 contact with the study intervention. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact. 
• A 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 
All participants will be randomized, according to the randomization schedule generated 
prior to the study by the Biostatistics Department at GSK.  Each participant will be 
dispensed blinded study intervention, labelled with his/her unique randomisation number, 
throughout the study.  Each participant scheduled to receive study drug will receive a 
treatment allocation number when randomized.  Participants will be randomized in a 3:1 
ratio to receive study treatment (active drug: placebo) in this study. 
 
This will be a double-blind study with participants and the site staff blinded. The site 
pharmacy will be unblinded.  
 
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The blind may be broken if, in the opinion of the Investigator, it is in the participant’s 
best interest for the investigator to know the study treatment assignment.  The Sponsor 
study team must be notified before the blind is broken unless identification of the study 
treatment is required for a medical emergency in which the knowledge of the specific 
blinded study treatment will affect the immediate management of the participant’s 
condition.  In this case, the Sponsor study team must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation and eCRF, as applicable. 
 
Unblinded monitors, and in the event of a Quality Assurance audit, the auditor(s), will be 
allowed access to un-blinded study treatment records at the site to verify that 
randomization/dispensing has been done accurately. 
 
A participant will be withdrawn from the study if that participant’s intervention 
assignment is unblinded.  The primary reason for the event or condition which led to the 
unblinding will be recorded in the CRF. 
GSK’s GCSP staff may unblind the intervention assignment for any participant with an 
SAE. If the SAE requires that an expedited regulatory report be sent to one or more 
regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 
6.4. 
Study Intervention Compliance 
• When 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. 
• When participants self-administer study intervention at home (treatment period 3), 
compliance with study intervention will be assessed by direct questioning and 
counting returned 
 during the site visits and documented in the source 
documents and relevant form.  Deviation(s) from the prescribed dosage regimen 
should be recorded. 
• A record of the quantity of GSK3923868 dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded. 
6.5. 
Dose Modification 
This protocol allows alteration from the currently outlined dosing schedule, but the 
maximum daily dose will not exceed 1500 mcg.  Refer to Section 4.3 for dose 
justification. 
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The decision to proceed to the next dose level (either an increase or a decrease) will be 
made by the investigator and the study team on an individual participant basis and 
based on safety and tolerability data obtained in that participants at the prior dose level.  
The Investigator and Sponsor study team will review all available data for dose selection 
and/or modification. See Section 10.1.5 for more information. 
6.5.1. 
Dose Escalation Stopping Criteria 
6.5.1.1. 
Participant specific dose escalation stopping criteria 
Participants who experience an exacerbation during the study will stop dose escalation 
and be withdrawn from the study.  Refer to Section 7.1.4 for COPD exacerbation 
definition and stopping criteria. 
 
In case of excessive use of rescue medication above 3-fold the participant’s normal usage 
and in the absence of a precipitating cause such as Upper or Lower Respiratory Tract 
Infection, the participant will be urgently reviewed by the Investigator with a view to 
being withdrawn. The rescue medication usage will be specifically reviewed at next 
phone call and/or site visits. 
 
6.5.1.2. 
Study specific dose escalation stopping criteria 
Dose escalation and study will be temporarily halted and no further participants will be 
dosed until completion of a full safety review if one or more of the following criteria are 
met: 
• One participant experiences a serious adverse event that is considered at least 
possibly related to the study drug. 
• Two participants experience a severe adverse event or bronchospasm that is 
considered at least possibly related to the study drug. 
• Two participants meet liver chemistry stopping criteria outlined in Section 7.1.1. 
• Two participants meet QTc stopping criteria outlined in Section 7.1.2. 
• Two participants meet spirometry stopping criteria outlined in Section 7.1.3. 
• Two participants experience any severe non-serious adverse event considered 
clinically important by the Investigator and at least possibly related to the study drug.  
Relevant reporting and discussion with the medical monitor, relevant GSK personnel, and 
the IRB/IEC will take place before resumption of dosing. 
6.5.2. 
Pharmacokinetic Criteria for Dose Modification 
There are no PK criteria for dose modification. 
6.5.3. 
Retreatment Criteria 
Retreatment is not permitted in this study. 
 


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6.6. 
Continued Access to Study Intervention after the End of the 
Study 
Participants will not receive any additional treatment with GSK3923868 after completion 
of the study. 
6.7. 
Treatment of Overdose 
For this study, any dose of GSK3923868 inhalation powder greater than the planned 
nominal dose for the treatment period within a 24-hour time period up to minus 2 hour 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. The Investigator (or 
physician in charge of the participant at the time) will use clinical judgement to treat any 
overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities for 24 
hours. 
3. Obtain a plasma sample for PK analysis if requested by the medical monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) or other specific categories of 
interest that the participant is receiving at the time of enrolment or receives during the 
study must be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the 
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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.  
Participants are also permitted to use any medicines (e.g., beta-2 agonists, 
anticholinergics, methylxanthines, inhaled corticosteroids) to control their COPD.   Other 
concomitant medications may be considered on a case-by-case basis by the investigator 
in consultation with the medical monitor if required. 
Concomitant medication for concurrent well controlled medical conditions (e.g., 
hypertension, arthritis) may be continued, including opioids such as codeine. 
Although GSK3923868 is not expected to be a perpetrator or victim of pharmacokinetic 
drug-drug interactions, strong CYP3A4 inhibitors (e.g., macrolides) are not permitted. 
6.8.1. 
Rescue Medicine 
Short-acting beta-2 agonists (e.g., salbutamol) or inhaled anticholinergic (e.g., 
ipratropium bromide) will be permitted to be used as rescue medication.  This will be 
provided by the participant or, if necessary, supplied by the study site. 
The use of rescue medications is allowable and at any time during the study. The date and 
time of rescue medication administration as well as the name and dosage regimen of the 
rescue medication must be recorded. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Study discontinuation specifics are detailed in Appendix 1 
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 then 
be withdrawn from the study.  See the SOA 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. 
If the following criteria are met, the study will be temporarily paused, and all available 
safety data will be reviewed by the Sponsor and Investigator: 
• One SAE occurring in 1 or more participants receiving GSK3923868 that is 
considered at least possibly related to the study drug 
Further participants may be dosed only if, after review, the Sponsor and Investigator 
considers it safe to do so. 


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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 Figure 2 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. 
Figure 2 
 Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm 
 
Refer to Section 10.6 (Appendix 6) for liver safety actions and follow-up assessments.  
The investigator should consider that intensive muscular exercise can also cause 
asymptomatic elevations of liver function tests such as ALT and AST in using this 
algorithm  [Pettersson, 2007]. 
7.1.2. 
QTc Stopping Criteria 
The Fridericia QT correction (QTcF) formula will be used in the study. 
A participant that meets either bulleted criteria based on the average of triplicate ECG 
readings will be considered for withdrawal from the study intervention: 
• QTcF > 500 msec 
• Change from baseline: QTcF > 60 msec 
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If a clinically significant finding is identified after enrolment, the investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as 
an AE. 
Note: Single safety ECG assessments are performed following enrolment in this study. If 
a single ECG should meet the criteria above, obtain two further ECGs over a brief period 
(e.g., 5 to 10 minutes). The averaged QTcF value of the 3 ECGs should be used to 
determine whether the participant should be withdrawn from the study. 
7.1.3. 
Spirometry Stopping Criteria 
Any participant experiencing a reduction in FEV1 at the 1-hour post-dose compared to 
daily pre-dose value of > 20% will be withdrawn from the study. 
7.1.4. 
COPD Exacerbation Stopping Criteria 
Any participant experiencing an exacerbation of COPD must be withdrawn from the 
study. A COPD exacerbation is defined as follows: 
• Episodes characterised by a progressive increase in symptoms of shortness of 
breath, cough, sputum, wheezing or chest tightness and progressive decrease in 
lung function, i.e., they represent a change from the patient’s usual status that is 
sufficient to require a change in treatment [GOLD,2020]. 
7.1.5. 
Pharmacokinetic Stopping Criteria 
There are no PK stopping criteria in this study. 
7.1.6. 
Temporary Discontinuation 
Participant withdrawn from the study treatment will be withdrawn from the study. 
7.1.7. 
Rechallenge 
Study intervention restart or rechallenge after stopping criteria are met by any participant 
in this study is not allowed. 
7.2. 
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.  See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed. 
• The participant will be permanently discontinued from the study intervention and 
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• 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. 
• If participants prematurely discontinue in the study, they may be replaced at the 
discretion of the Medical Monitor in consultation with the Principal Investigator.  
The replacement participant will be assigned to treatment period 1 regardless of 
when/where the last participant prematurely discontinued. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he/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, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of the study as a whole is handled as part of Appendix 1. 
7.4. 
Management of Participants who Develop COVID-19 
Symptoms During the Study 
If a participant develops COVID-19 like symptoms during the course of the study the 
following actions should be taken: 
• During single dose treatment of the study (periods 1 and 2), when in the Unit 
participants who develop a high clinical index of suspicion for COVID-19 disease 
should be isolated and tested for COVID-19 in accordance with site procedures.  
Participants who develop symptoms suspicious of COVID-19 during washout 
periods should inform the site immediately. 
• During repeat dose of the study (period 3), study treatment should be halted for 
any participants who develop a high clinical index of suspicion for COVID-19 
disease; they should be isolated and tested for COVID-19 in accordance with site 
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• In all cases, for participants who are in the Unit, assessments should be continued 
as per the protocol during this period. Participants with a confirmed COVID-19 
test may continue to complete safety monitoring assessments but will receive no 
further doses of the study treatment. In other cases, withdrawal of participants 
from the study will be at the discretion of the Principal Investigator and discussed 
with the GSK Medical Monitor if required. 
• Refer to Appendix 9 for further COVID-19 related study management details. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the timeframe defined in the SoA. 
• Safety/laboratory/analyte results that could unblind the study will not be reported 
to the investigative site or other blinded personnel until the study has been 
unblinded. 
• 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. 
• Additional considerations around Covid-19 can be found in Appendix 9. 
8.1. 
Efficacy Assessments 
There are no planned efficacy assessments in this study. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA. 


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8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems. 
Height (at the screen only) 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. 
• Refer to the SRM for further information. 
8.2.2. 
Vital Signs 
• Vital signs will be measured in semi-supine position after at least 10 minutes rest 
and will include systolic and diastolic blood pressure, heart rate, respiratory rate 
and tympanic temperature.  Temperature will be measured once per day in the 
morning only. 
• Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. 
• Refer to the SRM for further information. 
8.2.3. 
Electrocardiograms 
• 12-lead ECG safety ECGs will be performed in semi-supine position after at least 
10 minutes rest. 
• All safety ECGs must be obtained using an ECG machine that automatically 
calculates the heart rate and measures, PR, QRS, QT and QTcF intervals. 
• Safety ECGs will be interpreted on-site by the Investigator to ensure participant 
safety. At time points where triplicate ECGs are required, the ECGs will be 
obtained at least 2 minutes apart and over a recording period of up to 10 minutes. 
• Baseline QTcF will be based on the predose ECGs collected before the first dose. 
• Refer to Section 7.1.2for QTc specific stopping criteria. 
• Refer to the SRM for further information. 
8.2.4. 
Lung function Measurements 
8.2.4.1. 
Spirometry 
Spirometry will be performed at time points outlined in the SoA.  Spirometry will be 
performed at the site using available equipment.   
For each time point, at least 3 acceptable spirometry manoeuvres (from a maximum of 8 
attempts) should be achieved.  The highest FEV1 will be entered into the eCRF.   


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Participants should withhold use of short-acting bronchodilators for at least 6 hours and 
LABA for at least 12 hours prior to each spirometry measurement.  Further details on 
performing the spirometry assessments are provided in the SRM. 
8.2.4.2. 
Peak Expiratory Flow 
PEF will be performed at time points outlined in the SoA.   
Further information on PEF assessments is outlined in the SRM. 
8.2.5. 
Clinical Safety Laboratory Tests 
• 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. 
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor.  
o If clinically significant values do not return to normal/baseline within a 
period of time judged reasonable by the investigator, the etiology should 
be identified and the sponsor notified. 
• All protocol-required laboratory 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 performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded. 
8.2.6. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted per SoA (Section 1.3). 
• If a pregnancy is reported then the Investigator should inform GSK within 24 
hours of learning of pregnancy and should follow the procedures outlined in 
Section 10.4.3. 
• Additional urine or serum pregnancy tests may be performed, as determined 
necessary by the Investigator or as required by local regulation, to establish the 


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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 AEs or SAEs can be found in Section 10.3. 
The definitions of device-related safety events, ADEs and SADEs, can be found in 
Section 10.7. Device deficiencies are covered in Section 10.7 
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 recording events that meet the definition of an AE or SAE and remain responsible for 
following up.  
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 informed consent form (ICF) until 
the follow-up visit at the timepoints specified in the SoA (Section 1.3).  
• All AEs will be collected from the start of intervention until the follow-up visit at the 
timepoints 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 Section 10.3. 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 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  


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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 7.3). Further information on follow-up procedures is given in Section 
10.3. 


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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, 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 IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• Investigator safety reports must be prepared for SUSARs 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 and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until 10 
days post-intervention (Section 5.1). 
• 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 or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) 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 
as such. 
• The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The investigator will collect follow-up information on the participant 
/pregnant female partner 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/pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 


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8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 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. 
8.3.7. 
Medical Device Deficiencies 
A medical device 
 is being provided for use in this study. To fulfil regulatory 
reporting obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during 
the study with such a device.  
The definition of a medical device deficiency can be found in Section 10.7. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 10.3 of the protocol.  
8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical 
device is used.  
• If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such a device deficiency is considered 
reasonably related to a medical device provided for the study, the investigator will 
promptly notify the sponsor. 
• The method of documenting medical device deficiencies is provided in Section 
10.7. 
8.3.7.2. 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those who discontinue study 
intervention or the study, and associated persons. 
• The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
CCI


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8.3.7.3. 
Prompt Reporting of Medical Device Deficiencies to the Sponsor 
• Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a device 
deficiency. 
• The medical device deficiency report form will be sent to the sponsor by facsimile 
transmission. If facsimile transmission is unavailable, then notification by telephone 
is acceptable for incidents, with a copy of the "Medical Device Incident Report Form" 
sent by overnight mail. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
8.3.7.4. 
Regulatory Reporting Requirements for Device Deficiencies 
• The investigator will promptly report all device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical studies. 
• The investigator, or responsible person according to local requirements (e.g., the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.4. 
Pharmacokinetics 
Plasma samples will be collected for measurement of plasma concentrations of 
GSK3923868 as specified in the SoA (Section 1.3). Details of sample collection will be 
provided in the SRM. 
• A maximum of 3 samples may be collected at additional timepoints during the 
study if warranted and agreed upon between the investigator and the sponsor. The 
timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
• Samples collected for analyses of GSK3923868 plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study. 
• PK Samples will be analyzed using an appropriately validated assay method by or 
under the supervision of the sponsor. 
• Genetic analyses will not be performed on these plasma samples unless consent 
for this was included in the informed consent. Participant confidentiality will be 
maintained. 


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• Intervention concentration information that may unblind the study will not be 
reported to the investigative site or blinded personnel until the study has been 
unblinded. 
8.5. 
Genetics 
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study.  Participation is 
optional.  Participants who do not wish to participate in the genetic research may still 
participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Section 10.5 [Genetics and Pharmacogenomics] for information regarding genetic 
research. Details on processes for collection and shipment and destruction of these 
samples can be found in SRM. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
8.8. 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GlaxoSmithKline. 
Reporting of study data will be performed in accordance with applicable GSK and/or 
CRO standards. Complete details of the planned statistical analyses will be provided in 
the SAP and in the OPS, respectively. 
Any deviations from the planned analyses will be described in the SAP addendum and 
justified in the final integrated clinical study report. 
9.1. 
Statistical Hypotheses 
No formal statistical hypotheses will be tested. The primary objective is to evaluate the 
safety and tolerability of GSK3923868 inhalation powder in participants with COPD. 


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9.2. 
Sample Size Considerations 
No formal statistical techniques were used to calculate the sample size for this study.  
The number of participants included is deemed an adequate number to provide an 
assessment of safety and tolerability and pharmacokinetics measurements.  
Sufficient participants with COPD will be screened and randomized to receive 
GSK3923868 inhalation powder or placebo in a 3:1 ratio with the intention of a minimum 
of 8 and a maximum of 12 participants to complete the study.   
In total, up to 9 participants are planned to receive each dose of active drug in each 
period. If the true adverse outcome rate is 5%, the chance of observing at least one 
adverse event at a given dose is 37%. If the true adverse outcome rate is 20%, the chance 
of observing at least one adverse event at a given dose level is 87%.  For sample size of 6 
participants on active drug in each period, if the true adverse outcome rate is 5%, the 
chance of observing at least one adverse event at a given dose is 27%. If the true adverse 
outcome rate is 20%, the chance of observing at least one adverse event at a given dose 
level is 74%. 
This level of predictivity is deemed adequate within this phase of development. 
9.3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined 
Participant Analysis 
Set 
Description 
Screened 
All participants who were screened for eligibility. 
Enrolled 
All participants who passed screening and entered the study. 
Randomized  
All randomized participants. Participants will be included in the analyses 
according to the intervention they were randomized to. 
Safety 
All participants who received at least 1 dose of study treatment. This population 
will be based on the treatment the participant received. 
Pharmacokinetic (PK) 
All randomized participants in the Safety population who had at least 1 non-
missing PK assessment (NQ values will be considered as non-missing values).  
Participants will be analyzed according to the treatment they received.  
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to FPFV and it will include a more 
technical and detailed description of the statistical analyses described in this section.  


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This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Exploratory analyses will be described in the SAP. 
9.4.1. 
General Considerations 
Unless otherwise specified, baseline will be the last value/assessment before the first dose 
of study treatment (Day 1 pre-dose). If there are multiple assessments collected at the 
same scheduled time, the average of these assessments will be used as the baseline. 
9.4.2. 
Primary Endpoints Analysis 
All safety analyses will be performed on the Safety Population and details will be 
provided in the SAP. 
 
9.4.2.1. 
Adverse Events and Serious Adverse Events 
The proportion of participants reporting AEs will be tabulated by study intervention and 
by dose for participants on GSK3923868. AEs will also be tabulated by severity and 
relationship to study product. AEs will be tabulated using MedDRA preferred terms. 
The number and percentage of participants experiencing each specific AEs (All AEs, 
Grade 2 or higher, and SAEs) will be tabulated by severity and by relationship to study 
product. For the calculations in these tables, each participant’s AEs will be counted once 
under the maximum severity or the strongest relationship to study product. 
 
AEs leading to withdrawal will also be summarized. 
 
9.4.2.2. 
Laboratory values, vital signs, 12-lead electrocardiogram and 
Spirometry 
Whilst all data collected will be summarized, only measurements which are clinically 
significant at any timepoint between randomization and follow up will be reported as part 
of the primary endpoint. Potential clinical interest (PCI) ranges will be defined in the 
SAP. 
 
This data includes:  
• Laboratory results for hematology, clinical chemistry and urinalysis (see 
Appendix 2 for full details).  
• Vital Signs measurements for semi supine systolic and diastolic blood pressure, 
pulse rate, respiratory rate and temperature. 
• 12-lead safety electrocardiogram (ECG) measurements for heart rate, PR, QRS, 
QT and QT interval corrected for heart rate according to Frederica’s formula 
(QTcF) intervals. 
• Spirometry measurements for FEV1. 
 
9.4.3. 
Secondary Endpoint Analysis 
All pharmacokinetic analyses will be performed on the PK Population. 


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Pharmacokinetic analysis will be the responsibility of the CPMS department within 
GlaxoSmithKline. 
Plasma GSK3923868 concentration-time data will be analyzed by non-compartmental 
methods with WinNonlin. Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined if data permitting, for each dose of GSK3923868: 
• Treatment period 1 & 2 (single ascending doses): AUC(0-t), AUC(0-24), Cmax 
and Tmax 
• Treatment period 3 (repeat dose): Cmax, Tmax and AUC(0-6) on Day 1 and Day 
14 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarised descriptively. Analysis of dose proportionality and dose accumulation 
following repeated dosing (period 3 only) will be conducted. A population PK model 
(POP PK) may be developed with all available data from this and historical studies as 
appropriate and will be reported separately. Further details of the analysis plan and 
methods will be defined within the SAP. 
9.5. 
Interim Analysis 
No interim analysis planned. 


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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 (Somerset West, Republic of South Africa, 
October 1996) and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
Applicable ICH E6 (R2) GCP guidelines 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and/or 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: 
o 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 
o Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
o 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, 
including the risk and benefits, 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, privacy and data 
protect 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.  
• If follow-up information from a treating physician or other licensed medical 
practitioner is required for a medical device incident with an AE/SAE involving 
an associated person(s), the Associated Person Safety Reporting Information and 
Authorization Letter must be signed by the associated person to obtain consent.  
• A participant who is rescreened is not required to sign another ICF if the 
rescreening occurs within 30 days from the previous ICF signature date. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK3923868 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have the GSK3923868 approved 
for medical use or approved for payment coverage.  
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 


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the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
There are no formal data review committees to be established for this study.   
• Participant safety will be continuously monitored by the investigator and sponsor 
study team.  
• An initial safety review for this study is planned for the first participant who is 
dosed and has provided safety data for 3 days after administration of 500 mcg. 
• The data may be unblinded should a safety concern arise during the blinded 
review. 
• Dose modification and escalation stopping criteria are outlined in Section 6.5. 
• Further details on the dose escalation process are outlined in the Dose Escalation 
Plan. 
10.1.6. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
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 study 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 study 
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. 
• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• GSK intends to make anonymized patient-level data from this study 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 


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provided by study participants are used to maximum effect in the creation of 
knowledge and understanding 
• A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs 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.  
• Guidance on completion of CRFs will be provided in the eCRF Completion 
Guidelines Document Veeva Vault Location. 
• Quality tolerance limits will be pre-defined in the Veeva Vault system 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 study-specific monitoring plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the 
study Data Management Plan or equivalent CRO document. 
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
• 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 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.  
10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 


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• 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 Acknowledgment. 
• 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.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant screened and will be the study start 
date. 
Study/Site Termination 
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: 
• Discontinuation of further study intervention development due to strategic 
considerations 
• The study has met its stopping criteria defined in Section 6.5 and Section 7 
• Any safety concerns arising from other studies with GSK3923868 (preclinical or 
clinical) that warrant the study discontinuation 
For site termination: 


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• 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 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 4 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 4 
Protocol-required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
AST)/SGOT 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT)/SGPT 
Total protein 
 
Glucose (non-
fasting) 
Calcium 
(corrected) 
Alkaline 
phosphatase2 
Albumin 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes by dipstick 
• Upon a positive urine test from leucocytes, blood, nitrite or protein, the 
Investigator may require further urine analysis such as flow cytometry.  
Results of the additional analyses will be kept in the database.  If the flow 
cytometry examination shows a different result than the urine sticks, the 
urine will be investigated by fully automated digital imaging where 
leukocytes, erythrocytes, and casts in the urine will be analyzed.   
Pregnancy 
testing 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test for women of childbearing potential3 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of 
nonchildbearing potential only) 
• Alcohol urine test 
• Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines; may require urine 
creatinine analyses) 


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Laboratory 
Assessments 
Parameters 
•  Serology (HIV antibody, HBsAg, anti- hepatitis B core antibodies (IgM) 
and hepatitis C virus antibody) 
• COVID-19 testing will be in line with site procedure  
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 10.6 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. 
3. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
 
Investigators must document their review of each laboratory safety report. 


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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. 
 
Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
participant diary and that is communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participants will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant’s concern. Detailed information about 
reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participant and by review 
of available medical records at the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant in their diary.  
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 condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 


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• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
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 that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
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 fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 


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• 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) that 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 
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 


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Cardiovascular Events (CV) Definition: 
• 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. 
• 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 one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self- 
care ADL. Selfcare ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment 
to determine the relationship. 


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• 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. 
• 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 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any postmortem 
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. 


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SAE Reporting to GSK via 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. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to 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. 
• 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 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
• 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. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 


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1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) 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. 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance: 
Male participants have no restrictions as outlined in Section 5.1. 
Female partners of childbearing potential who are not currently pregnant must use an 
additional highly effective contraceptive method with a failure rate of < 1 % per year, as 
outlined in the se below: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
IUD 
IUSc 
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. 


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
Sexual abstinence 
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 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. 
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 for this 
study. Male condom and female condom should not be used together (due to risk of failure from friction) 
10.4.3. 
Collection of Pregnancy Information 
Female participants who become pregnant: 
• Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• The initial information will be recorded on the appropriate form and submitted to 
GSK within 24 hours of learning of a participant's pregnancy.  
• Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which 
will be forwarded to GSK Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  
• Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.  


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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such.  
• Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Section 10.3 (Appendix 3). While the investigator is not 
obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting 
Any female participant who becomes pregnant while participating: 
• will discontinue study intervention or be withdrawn from the study. 


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10.5. 
Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis. 
• DNA samples will be used for research related to GSK3923868. They may also be 
used to develop tests/assays including diagnostic tests) related to GSK3923868. 
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome (as appropriate). 
• Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data.  
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• The samples will be retained while research on GSK3923868 (or study interventions 
of this class) continues but no longer than 15 years after the last participant last visit 
or other period as per local requirements. 


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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase 1 liver chemistry stopping criteria and required follow up assessments.  In applying 
the liver chemistry stopping criteria, the investigator should consider that intensive 
muscular exercise can also cause asymptomatic elevations of liver function tests such as 
ALT and AST [Pettersson, 2007]. 
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 perform 
liver event follow up assessments within 24-72 
• 
Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward trend 
• 
Obtain blood sample for PK analysis, within 
48 hours of last dose4  
• 
Serum CPK and 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: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma globulins. 


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Liver Chemistry Stopping Criteria  
hrs 
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 
• 
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.  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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10.7. 
Appendix 7: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device 
Studies 
• The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and the European MDR 2017/745 for clinical device research (if 
applicable).  
• Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices. 
• The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study (see Section 6.1.1 for the 
list of GSK medical devices). 


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10.7.1. 
Definition of Medical Device AE and ADE 
Medical Device AE and ADE Definition  
• 
A medical device AE is any untoward medical occurrence, in a clinical study 
participant, users, or other persons, temporally associated with the use of study 
intervention whether or not considered related to the investigational medical 
device. 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 an investigational medical device. This 
definition includes events related to the investigational medical device or 
comparator and events related to the procedures involved except for events in 
users or other persons, which only include events related to investigational 
devices. 
• 
An adverse device effect (ADE) is defined as an AE related to the use of an 
investigational medical device. This definition includes any AE resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device 
as well as any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
10.7.2. 
Definition of Medical Device SAE, SADE and USADE 
A Medical Device SAE is any serious adverse event that: 
a. 
Led to death  
b. 
Led to serious deterioration in the health of the participant, that either resulted 
in: 
• A life-threatening illness or injury. 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. 
• A permanent impairment of a body structure or a body function. 
• Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
• Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. 
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SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of an SAE. 
• Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is 
defined as a serious adverse device effect that by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report 
(see Section 2.3). 
 
10.7.3. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequacy of the information supplied by 
the manufacturer. 
10.7.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies 
AE, SAE and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE/device 
deficiency 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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AE, SAE and Device Deficiency Recording 
• 
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. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories:  
• Mild:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate:  Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-
care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden. 
• 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. 
• Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]). 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency. The investigator will use 
clinical judgment to determine the relationship. 
• 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. 
• 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. 


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AE, SAE and Device Deficiency Recording 
• The investigator will also consult the Investigator’s Brochure (IB) in his/her 
assessment. 
• For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AE/SAE/device deficiency 
• 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/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed form. 
• The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.7.5. 
Reporting of SAEs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• The primary mechanism for reporting an 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 table) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 


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SAE Reporting to GSK via an Electronic Data Collection Tool 
• After the study is completed at a given site, the electronic data collection tool will 
be taken offline 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 GSK medical monitor by telephone. 
• Contacts for SAE reporting can be found in the SRM. 
SAE Reporting to GSK via Paper Data CollectionTool 
• Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper 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 paper data collection tool within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in the SRM. 
10.7.6. 
Reporting of SADEs 
SADE Reporting to GSK  
NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency. 
• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
• Refer to the paper medical device deficiency report form for details on transmission 
of this information to the sponsor. 


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10.8. 
Appendix 8: Country-specific Requirements 
None 
 
 


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10.9. 
Appendix 9: COVID-19 
10.9.1. 
Overall Rationale for this Appendix 
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
These measures will remain in place until study completion. 
10.9.2. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrolment and treatment decisions for trial participants. 
Protocol waivers or exemptions are not allowed and every effort should be made to 
adhere to protocol-specified assessments for participants on study intervention, including 
follow up however when not possible, for the duration of these special circumstances, the 
following measures may be implemented for enrolled participants: 
• Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study 
conduct and duration of those changes and indicate which trial participants were 
impacted and how those trial participants were impacted (as per the current local 
COVID-19 related regulatory guidance). 
• Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. 
10.9.3. 
Data Management/Monitoring 
If a situation arises where on-site monitoring is no longer permitted, GSK will consider 
remote 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 


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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 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. 
 


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10.10. 
Appendix 10: Protocol Amendment History  
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE. 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 01 
27 October 2022 
TMF-15074949 
Original Protocol 00 
08 July 2022 
TMF-14593236 
 
Amendment 01: 27 October 2022 
 
Overall Rationale for the Amendment: This amendment has been made in response to 
a request from the Federal Institute of Drugs and Medical Devices (BfArM).  
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1.2: Study 
specific dose escalation 
stopping criteria 
“study” and “if one or 
more of the following 
criteria are met” were 
added to the first paragraph 
as follows. 
“Dose escalation and study 
will be temporarily halted 
and no further participants 
will be dosed until 
completion of a full safety 
review if one or more of 
the following criteria are 
met”  
These edits were made to 
clarify the study stopping 
criteria. 
Section 10.1.9: Study and 
Site Start and Closure 
The following sentence has 
been removed, and reasons 
for study termination have 
been expanded. 
“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” 
This section was amended 
per a request from BfArM 
CTA review.  
 
 


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10.11. 
Appendix 11: Abbreviations and Definitions and Trademarks 
ADE 
Adverse devise effect 
ADL 
Activities of Daily Living 
AE 
adverse event 
ALT 
alanine aminotransferase  
aPTT 
Activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the concentration-time curve 
AUC(0-) 
area under the concentration-time curve from time 0 (predose) 
extrapolated to infinite time 
AUC(0-24) 
area under the concentration-time curve from time 0 (predose) 
to 24 hours post dose administration following the first dose 
AUC(0-t) 
area under the concentration-time curve from time 0 to the time 
of the last quantifiable concentration 
AUC(0-τ) 
area under the concentration-time curve from time 0 (predose) 
to time tau 
BMI 
body mass index 
CA 
Competent Authorities 
CIOMS 
Council for International Organizations of Medical Sciences 
CI 
confidence interval 
Cmax 
maximum observed concentration 
COVID 
Coronavirus disease  
COPD 
Chronic obstructive pulmonary disease  
CPK 
creatine phosphokinase 
CPMS 
Clinical Pharmacokinetics Modelling and Simulation 
CRO 
Contract research organization 
CRF 
Case report form  
CSR 
Clinical Study Report 
CTFG 
Clinical Trial Facilitation Group 
CV 
Cardiovascular 
CYP 
cytochrome P450 
DEC 
Dose escalation committee 
DMPK 
Drug metabolism and Pharmacokinetics 
DoR 
Delegation of Responsibilities 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ERS 
European Respiratory Society 
FEV1 
forced expiratory volume in 1 second 
FPFV 
First Participant First Visit 
FSH 
follicle-stimulating hormone 
FTIH 
First time in human 
FVC 
forced vital capacity 
G 
Gram 


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GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
HBsAg 
hepatitis B surface antigen 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
HRV 
Human rhinovirus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IH 
Inhaled 
IMP 
Investigational Medicinal Product  
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
Intravenous 
Kg 
kilogram  
LDH 
lactate dehydrogenase 
LAM 
lactational amenorrhea method 
m2 
 square meter 
Mcg 
Microgram 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDR 
Medical Device Regulation 
Mg 
Milligram 
mL 
Milliliter 
MSDS 
Material Safety Data Sheet 
MedDRA 
Medical dictionary for regulatory activities 
Msec 
Millisecond 
NIMP 
Non Investigational Medicinal Product  
NOAEL 
No Observed Adverse Effect Level 
NQ 
Non-quantifiable 
OPS 
Output and programming specifications 
PBPK 
Physiologically-based pharmacokinetics 
PCI 
Potential clinical interest  
PEF 
Peak Expiratory Flow 
PI 
Principle investigator  
PK 
pharmacokinetic(s) 
PKPD 
pharmacokinetic/pharmacodynamic modelling 
PopPK 
population PK 
PT 
Prothrombin time 
QC 
Quality check 


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QTc 
corrected QT interval; the measure of time between the start of 
the Q wave and the end of the T wave 
QTcF 
corrected QT interval using the Fridericia formula 
QTL 
quality tolerance limit 
RBC 
Red blood cell count 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SADE 
serious adverse device effects 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic-Pyruvic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SoA 
schedule of activities 
SD 
single dose 
SDR 
Source document review 
SDS 
Safety Data Sheet 
SDV 
Source document verification 
SOP 
Standard operating procedures 
SRM 
Study reference manual 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal phase half-life 
TE 
Target engagement 
Tmax 
time to reach maximum observed plasma concentration 
ULN 
upper limit of normal 
USADE 
Unanticipated serious adverse device event  
WBC 
White blood cell count 
WONCBP 
Wome(a)n of nonchildbearing potential 
WOCBP 
Woman of childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
GastroPlus 
 
 
MedDRA 
 
 
 
 
 
WinNonlin 
CCI


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11. 
REFERENCES 
Global Initiative for Chronic Obstructive Lung Disease (GOLD).  Global Strategy for the 
Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Lung Disease 
(2020 Report). https://goldcopd.org/gold reports/ 
GSK Document Number RPS-CLIN-024977: GSK3923868 Investigator’s Brochure. 
Effective Date 21-Feb-2022. 
GSK Document Number 2020N430088_03.  Protocol 213497: A Randomized Double-
blind, Placebo Controlled, Single Ascending and Repeat Dose, First Time in Human 
Study in Healthy Participants and Stable Asthmatics to Assess Safety, Tolerability and 
Pharmacokinetics of GSK3923868 Inhalation Powder. 
 
GSK Document Number TMF-14737217.  Protocol 213499: A Randomized, Double-
blind, Placebo Controlled, Repeat Dose Phase 1b Study to Assess the Efficacy, Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Inhaled GSK3923868 During 
Experimental Human Rhinovirus Infection in Participants with Mild Asthma. 
 
Hershenson M B. Review Article: Rhino-virus Induced Exacerbations of Asthma and 
COPD. Scientifica. 2013:1-12. 
Pettersson J, Hindorf U, Persson P, et al.  Muscular Exercise Can Cause Highly 
Pathological Liver Function Tests in Healthy Men.  BJCP. 2007, 65(2):253-259. 
Quanjer P H, Stanojevic S, Cole T J, et al. ERS Global Lung Function Initiative. Multi-
ethinc reference values for spirometry for the 3-95yr age range: the global lung function 
2012 equations. Eur Respir J. 2012;40(6):1324-1343. 

SAP_001.pdf: 
Statistical Analysis Plan Amendment 01
Study ID:  214075
Official Title of Study: A randomized, double-blind, placebo controlled, 
single and repeat dose study to assess the safety, tolerability, and 
pharmacokinetics of inhaled GSK3923868 in participants with Chronic 
Obstructive Pulmonary Disease (COPD)
Date of Document: 16-Aug-2023


 
CONFIDENTIAL 
Page 1 of 27 
Information Type: Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title: 
A randomized, double-blind, placebo controlled, single and 
repeat dose study to assess the safety, tolerability, and 
pharmacokinetics of inhaled GSK3923868 in participants with 
Chronic Obstructive Pulmonary Disease (COPD)  
 
 
 
Study Number: 
214075 
 
Compound Number: GSK3923868 
Abbreviated Title: 
The safety, tolerability and PK of GSK3923868 in participants 
with COPD 
 
 
 
Sponsor Name: GSK Research & Development Limited  
Regulatory Agency Identifier Number(s)  
Registry 
ID 
 
 
 
 
 
 
 
 
 
 
Copyright 2023 the GSK group of companies. All rights reserved.  Unauthorised copying 
or use of this information is prohibited. 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Objectives and Endpoints ............................................................................. 5 
1.2. 
Study Design ................................................................................................ 6 
2. 
STATISTICAL HYPOTHESES ................................................................................. 7 
2.1. 
Multiplicity Adjustment .................................................................................. 7 
3. 
ANALYSIS SETS ..................................................................................................... 8 
4. 
STATISTICAL ANALYSES ....................................................................................... 9 
4.1. 
General Considerations ................................................................................ 9 
4.1.1. 
General Methodology .................................................................... 9 
4.1.2. 
Baseline Definition ......................................................................... 9 
4.2. 
Primary Endpoint(s) Analyses ....................................................................... 9 
4.2.1. 
Definition of endpoints ................................................................... 9 
4.2.2. 
Main analytical approach ............................................................. 10 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 12 
4.3.1. 
Key secondary endpoint(s) .......................................................... 12 
4.4. 
Exploratory endpoints Analyses .................................................................. 15 
4.5. 
Safety Analyses .......................................................................................... 15 
4.5.1. 
Extent of Exposure ...................................................................... 15 
4.5.2. 
Adverse Events............................................................................ 15 
4.5.3. 
Additional Safety Assessments .................................................... 16 
4.6. 
Other Analyses ........................................................................................... 16 
4.7. 
Interim Analyses ......................................................................................... 16 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 16 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 16 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 17 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 17 
6.1.1. 
Participant Disposition ................................................................. 17 
6.1.2. 
Demographic and Baseline Characteristics .................................. 17 
6.1.3. 
Protocol Deviations ...................................................................... 17 
6.1.4. 
Prior and Concomitant Medications ............................................. 18 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 19 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 19 
6.2.2. 
Study Period ................................................................................ 22 
6.2.3. 
Study Day and Reference Dates .................................................. 23 
6.2.4. 
Assessment Window ................................................................... 23 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 23 
6.2.6. 
Handling of Partial Dates ............................................................. 23 
6.2.7. 
Abbreviations ............................................................................... 25 
6.2.8. 
Trademarks ................................................................................. 26 
7. 
REFERENCES ....................................................................................................... 27 
 


 
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LIST OF TABLES 
PAGE 
Table 1 
Changes to Protocol Defined Analysis Plan ........................................... 16 
 


 
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VERSION HISTORY 
SAP Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
SAP 
06 Dec 2022 08-Jul-22 
Not Applicable 
Original version 
Amendment 
01 
16 Aug 
2023 
28-Nov-22 
Section 6.2.1 updated 
Discrepancy 
between PCI 
ranges and units 
provided in SAP 
and values 
collected by lab 
Removed wording 
which mentioned 
PEF data would be 
summarised. 
PEF is being 
collected for 
monitoring 
purposes only 
and is not 
recorded in the 
eCRF. 
 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 214075. 
1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and tolerability of 
GSK3923868 following single and 
repeat inhaled administration in 
participants with Chronic Obstructive 
Pulmonary Disease (COPD). 
• Occurrence of adverse events (AEs) and 
serious adverse events (SAEs). 
• Clinically significant changes in laboratory 
values, vital signs,12-lead 
electrocardiogram (ECG) and spirometry 
measurements up to Follow Up. 
Secondary 
• 
To evaluate the plasma 
pharmacokinetics of GSK3923868 
following single and repeat inhaled 
administration in participants with 
COPD. 
Derived pharmacokinetic parameters as data 
permit, including (but not limited to): 
• Area under the plasma-concentration time 
curve (AUC): area under the concentration-
time curve from time 0 (pre-dose) to 24 
hours post dose administration following the 
first dose (AUC[0-24]) or area under the 
concentration-time curve from time 0 to the 
time of the last quantifiable concentration 
(AUC[0-t]) for single dose and area under 
the concentration-time curve from time 0 
(pre-dose) to 6 hours post dose 
administration following the first dose 
(AUC[0-6]) for repeat dose 
• Maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration (Tmax) 


 
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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
 
Design 
Features 
 
This is a single cohort, randomized, double-blind, placebo controlled 
single and repeat dose study designed to assess the safety, tolerability 
and plasma PK of GSK3923868 administered as an inhalation powder 
blend (GSK3923868 
 for inhalation) using the 
 
 inhaler in participants with stable COPD.  This study contains 
two parts, a single ascending dose followed by 14-days repeat dosing. 
The single ascending dose part will assess two dose levels of 
GSK3923868 or placebo across two treatment periods in a single 
crossover cohort of participants. 
The repeat dose part will assess one dose level of GSK3923868 or 
placebo in one treatment period in the same cohort of participants. 
 
Study 
intervention 
The study consists of a single cohort which goes through three treatment 
periods: 
Period 1 is Dose Level 1 of GSK3923868 single dose vs Placebo. 
Screen 
Treatment 
Period 1 
(Dose Level 
1 single 
dose) plus 
washout 
Treatment 
Period 2 
(Dose Level 
2 single 
dose) plus 
washout 
Treatment 
Period 3 
(Dose 
Level 3 
repeat 
dose) 
Follow-up 
Period 
Total 
Duration 
Up to 30 days 
before first 
dose 
6 days (2 
days 
inpatient + 4 
days 
outpatient) 
6 days (2 
days 
inpatient + 4 
days 
outpatient) 
15 days (3 
days 
inpatient + 
12 days 
outpatient) 
7- 14 days 
post-dose 
64 - 71 
days 
 
Period 2 is Dose Level 2 of GSK3923868 single dose vs Placebo. 
Escalation to treatment period 2 (Dose Level 2) will occur on an 
individual participant basis. 
Period 3 is Dose Level 3 of GSK3923868 repeat dose vs Placebo, once 
daily for 14 days. Escalation to treatment period 3 (Dose Level 3) will 
also occur on an individual participant basis. 
CCI
CCI


 
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Overview of Study Design and Key Features 
Study 
intervention 
Assignment 
Participants who meet the study entry criteria will be randomized to 
receive GSK3923868 or placebo before study intervention 
administration on Day 1 of Treatment Period 1. 
Treatment  
Period 
Planned  
Dose 
Cohort 1 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
1 (Single Dose) 
Dose Level 1 GSK3923868 
A 
A 
A 
P 
2 (Single Dose) 
Dose Level 2 GSK3923868 
P 
A 
A 
A 
3 (14-Day Repeat Dose) 
Dose Level 3 GSK3923868 
A 
P 
A 
A 
*Note: A: Active, P: Placebo 
12 Participants will be randomised into one of the four treatment 
sequences described in the table above, to achieve 3:1 ratio of Active to 
Placebo within each period. 
Interim 
Analysis 
There are no formal interim analyses conducted as part of this study. 
 
2. 
STATISTICAL HYPOTHESES  
No formal statistical hypotheses will be tested. The primary objective is to evaluate the 
safety and tolerability of GSK3923868 in participants with COPD. 
2.1. 
Multiplicity Adjustment 
N/A  


 
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3. 
ANALYSIS SETS 
For the purposes of analysis, the following analysis sets are defined: 
 
 
 
Analysis Set 
Definition  
Analyses Evaluated 
Screened 
All participants who were screened for 
eligibility.  
Study Population 
Enrolled 
The All Subjects Enrolled (ASE) 
population will consist of all 
participants who enrolled in the study. 
Note: screening failures (who never 
passed screening even if rescreened) 
and participants screened but never 
enrolled into the study (Reserve, Not 
Used) are excluded from the Enrolled 
analysis set as they did not enter the 
study. 
Study Population 
Randomized 
The randomized population will consist 
of all participants who were 
randomized.  
Study Population 
Safety 
All randomized participants who 
received at least 1 dose of study 
treatment. Participants will be analysed 
according to the treatment they 
received.  
Safety 
Study Population 
Pharmacokinetic 
(PK) 
All randomized participants in the 
Safety population who had at least 1 
dose of GSK3923868 and at least 1 
non-missing PK assessment (Non-
quantifiable [NQ] values will be 
considered as non-missing values). 
• Participants will be analysed 
according to the treatment they 
received. 
PK 


 
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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Confidence intervals (CI) will use 95% confidence levels for both summary statistics and 
statistical analysis, except PK analysis, which will use 90% CI. 
 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
 
4.1.2. 
Baseline Definition 
Unless otherwise specified, baseline will be the last value/assessment before the first dose 
of study treatment (Day 1 pre-dose). If there are multiple assessments collected at the 
same scheduled time, the average of these assessments will be used as the baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
 
4.2. 
Primary Endpoint(s) Analyses 
All safety analyses will be performed on the Safety Analysis set, unless otherwise 
specified. 
Primary Endpoints: 
• 
Adverse events (AEs) and serious adverse events (SAEs). 
• 
Clinically significant changes in laboratory values, vital signs,12-lead ECG, and 
spirometry measurements up to Follow Up. 
 
4.2.1. 
Definition of endpoints 
Adverse events will be coded using the latest standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary).  
 
Grade 1 AEs are defined as mild. Grade 2 or higher AEs are defined as moderate or 
severe. This study will report AEs as mild, moderate, or severe. 


 
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A study intervention-related AE/SAE is defined as an AE/SAE for which the investigator 
classifies the possible relationship to study intervention as “Yes”. A worst-case scenario 
approach will be taken to handle missing relatedness data, i.e., the summary table will 
include events with the relationship to study intervention as ‘Yes’ or missing. 
 
Spirometry assessments are performed in triplicate with the highest value reported. 
 
Whilst all data collected will be summarized, only measurements which are clinically 
significant at any timepoint between randomization and follow up will be reported as part 
of the primary endpoint. 
Clinically significant values are defined as: 
• Values in the potential clinical interest (PCI) ranges for laboratory values, vital 
signs, ECGs and spirometry. 
• Values that achieve the study stopping criteria (protocol Section 7.1.3) for 
spirometry  
 
The PCI ranges will be defined in the Section 6.2.1. 
 
4.2.2. 
Main analytical approach 
4.2.2.1. 
Adverse events and serious adverse events 
An adverse event (AE) is considered study intervention emergent if the AE onset date is 
on or after study intervention start date. All AE summaries will be based on study 
intervention emergent events unless otherwise specified. SAE summaries will be based 
on all SAEs reported regardless of whether they meet the definition of study intervention 
emergent or not.  
Adverse event analysis will be based on GSK Core Data Standards.  
The proportion of participants reporting AEs will be tabulated by study intervention and 
by dose.  
The following displays for Adverse events ((All AEs, Grade 2 or higher, and SAEs)) will 
be generated:  Overview of Adverse Events, Summary of All Adverse Events, Summary 
of Taste Adverse Events, Summary of Drug-Related Adverse Events, Summary of 
Adverse Events Leading to Permanent Discontinuation of Study Treatment, Summary of 
Adverse Events Leading to Withdrawal from Study. These displays will be tabulated by 
by System Organ Class and Preferred Term. 
 Further details of the planned displays will be given in OPS. 


 
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4.2.2.2. 
Laboratory Data, Vital Signs, ECGs 
For haematology, clinical chemistry, urinalysis, vital signs, ECG and spirometry data the 
following information will be summarised: 
1) 
Clinically significant values at each visit 
2) 
Raw and change from baseline values at each visit 
Note: The first table is the only one included as part of the primary endpoint. Urinalysis 
data is only collected when there is an abnormal finding and so it is expected that 
urinalysis tables/listings will be sparse.  
Laboratory Data 
For laboratory data, separate tables for haematology, clinical chemistry and urinalysis 
tests will be produced. Laboratory evaluations including the analyses of Clinical 
chemistry tests, haematology tests and urinalysis, will be based on GSK Core Data 
Standards. Liver biochemical parameters will be included with clinical chemistry tests. 
The details of the planned displays will be given in the OPS. Incidence of clinically 
significant laboratory parameters will be reported. 
Vital Signs 
The analyses of vital signs will be based on GSK Core Data Standards, unless otherwise 
specified.  
In vital sign assessment, pulse rate, respiratory rate, tympanic temperature, and systolic 
and diastolic blood pressure will be assessed. Blood pressure and pulse measurement will 
be taken in the semi supine position. 
Incidence of clinically significant vital sign parameters will be reported. Refer the normal 
ranges of laboratory parameters in the Section 6.2.1 
Further details of the planned displays will be given in OPS. 
ECG 
The QTc data analysis will use the collected values based on Fridericia formula. 
The analysis of 12-lead ECG along with any ECG findings will be reported according to 
GSK Core Data Standards.  
Safety ECGs will be performed in semi-supine position after at least 5 minutes rest. The 
parameters collected are PR, QRS, QT and QTc intervals.  
Incidence of clinically significant ECG parameters will be reported. Refer the normal 
ranges of laboratory parameters in the Section 6.2.1  


 
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Further details of the planned displays will be given in OPS. 
4.2.2.3. 
Lung Function Measurements 
Spirometry 
Spirometry data will include FEV1 measurements. 
For spirometry data the following information will be summarised: 
1) 
Clinically significant values at each visit 
2) 
Raw and change from baseline values at each visit 
4.3. 
Secondary Endpoint(s) Analyses 
All pharmacokinetic analyses will be performed on the PK Population. 
For PK endpoints, all analysis will be performed by Part i.e., Part A (Periods 1 and 2, 
single dose) and Part B (Period 3, repeat dose), except dose proportionality, which will be 
carried out using data from the three periods. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined if data permitting, for each dose of GSK3923868: 
• Treatment period 1 & 2 (single ascending doses): AUC(0-t), AUC(0-24), AUC(0-
6), Cmax and Tmax 
• Treatment period 3 (repeat dose): Cmax, Tmax and AUC(0-6) on Day 1 and Day 
14 
4.3.1. 
Key secondary endpoint(s) 
4.3.1.1. 
Definition of endpoints 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration (C(t)) will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
AUC (0-24) 
Area under the concentration-time curve over the dosing interval. 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data over the dosing interval. 
Tmax 
Time to reach Cmax, determined directly from the concentration-time 
data over the dosing interval/ 
AUC (0-6)  
Area under the concentration-time curve from time 0 to 6-hour post 
dose. 
NOTE: Additional parameters may be included as required. 


 
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4.3.1.2. 
Main analytical approach 
Plasma GSK3923868 concentration-time data will be analyzed by non-compartmental 
methods with WinNonlin. Calculations will be based on the actual sampling times 
recorded during the study. 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarised descriptively.  
4.3.1.3. 
Dose Proportionality 
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data are available (i.e., if more than 5 subjects have well defined plasma profiles). If the 
dose with limited data is at the lower end of the dose range, the data will be excluded, and 
the appropriate analysis conducted on the rest of the data. However, if there are non-
calculable PK parameter data at intermittent doses no statistical analyses will be 
performed.  The assessment of dose proportionality will utilise Period 1,2 and the first 
dose of Period 3 data only.  
Dose proportionality will be assessed using power method as primary, and ANOVA as 
supportive method: 
Pharmacokinetic Statistical Analyses for Dose Proportionality: Power Method 
Endpoint(s) 
• AUC(0-6), Cmax 
• Each endpoint to be assessed separately. 
Model Specification 
• loge(Y) = β × loge(dose) + loge(α) 
where Y is the pharmacokinetic parameter and loge(α) is an intercept term. 
Model Results Presentation 
• The coefficient of the slope with 90% confidence intervals, on the log scale, will be calculated, 
using the pooled estimate of variance, and used to assess dose proportionality.  
• Point estimates and confidence intervals for the slope will be reported to 2 decimal places  
 
Pharmacokinetic Statistical Analyses for Dose Proportionality: ANOVA Method 
Endpoint(s) 
• AUC(0-6), Cmax 
• Each endpoint to be assessed separately. 
Model Specification 
• The PK parameter will be dose-normalised prior to loge-transformation by multiplying by 
reference dose / dose 
• Dose will be fitted as a fixed effect, subject as a random effect using DDFM=KR. 
• The reference dose will be chosen based on the lowest clinically relevant dose over which PK 
can be adequately described, with each other dose as the test doses in the construction of the 
ratio µ(test)/µ(reference). 
Model Results Presentation 


 
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Pharmacokinetic Statistical Analyses for Dose Proportionality: ANOVA Method 
• Point estimates for the adjusted means on the loge scale, the mean difference between each 
dose (test) and the reference dose and associated 90% confidence interval will be constructed 
using the residual variance. These will not be presented. 
• The point estimate and confidence interval will then be exponentially back-transformed to allow 
the presentation of the adjusted (least square) geometric means for each treatment (dose), and 
point estimates and associated 90% confidence intervals for the ratio test/reference. 
• Point estimates and 90% confidence intervals for AUC, Cmax will be reported to 2 decimal 
places. Ratios and 90% CIs will be plotted by dose. 
• Plots will also be provided showing the adjusted geometric mean ratio of test to reference 
treatment (dose) for AUC(0-6), and Cmax together with 90% confidence interval. 
 
4.3.1.4. 
Accumulation Assessment 
The assessment of accumulation will be performed following repeated dosing of 
GSK3923868 in Period 3 only. 
Pharmacokinetic Statistical Analyses 
 
Endpoint(s) 
• AUC(0-6), Cmax on Day 14 compared to Day 1 
• Each endpoint to be assessed separately following a log-transformation. 
Model Specification 
• A mixed effect model will be fitted with day as a fixed effect and subject as a random effect.  
• The Kenward & Roger (KR) degrees of freedom approach will be used. 
• Day 14 will be compared to Day 1 in order to estimate the accumulation ratio(s) 
• The accumulation ratio(s) and 90% confidence interval will be calculated by back-transforming 
the difference between the least square means for the two days and associated 90% 
confidence interval.  
Model Results Presentation 
• Point estimates and confidence intervals for the ratios will be reported to 2 decimal places 
• Scatter plots of each endpoint against day will be produced. The data points for each subject 
will be joined with straight lines 
• Boxplots of each endpoint against day will be produced. Each endpoint will be put on a 
separate page.  
 
4.3.1.5. 
Model Checking Diagnostics 
Model checking diagnostics for dose proportionality and dose accumulation analysis will 
include the following: 
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• An unstructured covariance structure for the R matrix will be used by specifying 


 
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‘type=UN’ on the REPEATED line. 
o In the event that this model fails to converge, alternative correlation structures 
may be considered such as CSH or CS.  
o Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure. 
• 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.  
 
4.3.1.6. 
Population PK Model 
A population PK model (POP PK) may be developed with all available data from this and 
historical studies as appropriate and will be reported separately. 
 
4.4. 
Exploratory endpoints Analyses 
N/A 
4.5. 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
The safety analyses have been detailed in Section 4.2 . 
4.5.1. 
Extent of Exposure 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
Subjects who were randomized but did not report a treatment start date (i.e., were 
randomized in error) will be categorised as having zero days of exposure.  
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
Duration of exposure and cumulative dose will be calculated only for Period 3(Repeat 
dose). 
4.5.2. 
Adverse Events 
Refer to Section 4.2.2.1 


 
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4.5.2.1. 
Adverse Events of Special Interest 
There are no AEs of Special Interest in the study. 
4.5.2.2. 
Impact of COVID-19 Pandemic on Safety Results 
If required, additional COVID-19 displays would be reported if the pandemic has a major 
impact on trial and interpretation of the trial data. 
4.5.3. 
Additional Safety Assessments 
Refer to Section 4.2.2.2 and Section 4.2.2.3 
4.6. 
Other Analyses 
N/A  
4.7. 
Interim Analyses 
No interim analysis has been planned for this study. 
4.8. 
Changes to Protocol Defined Analyses 
Changes from the originally planned statistical analysis specified in the protocol are 
detailed in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
 
5. 
SAMPLE SIZE DETERMINATION 
No formal statistical techniques were used to calculate the sample size for this study.  
The number of participants included is deemed an adequate number to provide an 
assessment of safety and tolerability and pharmacokinetics measurements.  
Sufficient participants with COPD will be screened and randomized to receive 
GSK3923868 or placebo in a 3:1 ratio with the intention of a minimum of 8 and a 
maximum of 12 participants to complete the study.   
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
Spirometry measurements will 
be summarised for FEV1 and 
FVC. 
• 
Spirometry measurements 
will be summarised for 
FEV1 only. 
• 
The changes are 
detailed correctly in SoA 
section of the protocol, 
but not in the Stats 
section of the protocol. 
Hence going by the SoA. 


 
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In total, up to 9 participants are planned to receive each dose of active drug in each 
period. If the true adverse outcome rate is 5%, the chance of observing at least one 
adverse event at a given dose is 37%. If the true adverse outcome rate is 20%, the chance 
of observing at least one adverse event at a given dose level is 87%.  For sample size of 6 
participants on active drug in each period, if the true adverse outcome rate is 5%, the 
chance of observing at least one adverse event at a given dose is 27%. If the true adverse 
outcome rate is 20%, the chance of observing at least one adverse event at a given dose 
level is 74%. 
This level of predictivity is deemed adequate within this phase of development. 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the Enrolled 
Analysis Set. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized. For those who have neither completed nor 
withdrawn, they will be categorized as on study intervention or in follow up.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the scheduled study 
intervention, are ongoing with study intervention, or have discontinued study intervention 
prematurely, as well as primary reasons for discontinuation of study intervention. 
All the data will be summarized based on GSK Core Data Standards. 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, height/weight at 
screening and race will be summarized with descriptive statistics. 
Past medical conditions and current medical conditions as of screening will be 
summarized respectively. 
All the data will be summarized based on GSK Core Data Standards. 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 


 
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Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations (where possible without knowing the study intervention details) are 
captured and categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the latest version of WHO Drug 
dictionaries. The summary of concomitant medications will be provided by ingredient, 
i.e., multi-ingredient medications will be summarized for each individual ingredient 
rather than a combination of ingredients. The summary will be created using ingredient 
base names, i.e., ingredients with the same base name but different salt will appear under 
one base name in the summary. Anatomical Therapeutic Chemical (ATC) classifications 
will not appear in the summary.  
Concomitant medications include any medication that was taken at some point during the 
on-intervention period as defined in Section 6.8 of the protocol. 
 
 
 


 
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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
• Laboratory Values 
 
Haematology 
Laboratory 
Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< 
x) 
High Flag 
(>x) 
Platelet Count 
10^9/L 
 
31 
900 
RBC Count 
10^12/L 
 
4.2 
5.9 
Hemoglobin 
g/L 
Male 
90 
180 
Female 
90 
180 
Hematocrit 
fraction of 1 
 
 
1.5*ULN 
RBC Indices 
MCV 
fL 
 
0.75*LLN 
1.5*ULN 
MCH 
pg 
 
28 
32 
%Reticulocytes 
% 
 
na 
2*ULN 
WBC Count with differentials 
Lymphocytes 
10^9/L 
 
0.6 
6 
Neutrophil Count 
10^9/L 
 
1.5 
12 
Monocytes 
10^9/L 
 
na 
2 
Eosinophils 
10^9/L 
 
na 
0.5 
Basophils 
10^9/L 
 
na 
2*ULN 
 


 
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Clinical Chemistry 
Laboratory 
Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< 
x) 
High Flag 
(>x) 
Albumin 
g/L 
 
32 
50 
Calcium 
mmol/L 
 
2.2 
3.24 
Creatinine 
umol/L 
Male 40-49 
years 
69 
106 
Male 50-59 
years 
67.2 
106 
Male 60-69 
years 
67.2 
106 
Male 70+ years 
59.2 
106 
Female 40-49 
years 
52.2 
106 
Female 50-59 
years 
53 
106 
Female 60-69 
years 
53 
106 
Female 70+ 
years 
55.7 
106 
Glucose 
mmol/L 
 
4.0 
7.8 
BUN 
mmol/L 
 
2.5 
15 
Potassium 
mmol/L 
 
3.5 
5.2 
Sodium 
mmol/L 
 
136 
145 
 
 


 
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Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
Alanine Aminotransferase 
(ALT) / Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
U/L 
High 
2x ULN 
Aspartate Aminotransferase 
(AST) / Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
U/L 
High 
2x ULN 
Alkaline phosphatase 
U/L 
High 
2x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
Direct Bilirubin 
µmol/L 
 
0 – 6 
 
• ECG 
 
ECG Parameters 
Unit 
Clinical Concern range 
 
Lower(<x) 
Upper(>x) 
Absolute 
Absolute QTc Interval 
msec 
 
> 600 
Absolute PR Interval 
msec 
< 85 
> 240 
Absolute QRS Interval 
msec 
< 70 
> 120 
Change from Baseline 
Increase from Baseline 
QTc 
msec 
 
> 60 
 
 
 
 


 
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• Vital Signs 
 
Vital Parameters 
(Absolute) 
Unit 
Clinical Concern range 
 
 
Lower(<x) 
Upper(>x) 
Heart rate 
bpm 
35 
110 
Respiratory Rate 
breaths/pm 
8 
20 
Systolic blood 
pressure 
mmHg 
95 
160 
Diastolic Blood 
Pressure 
mmHg 
55 
100 
Temperature 
°C 
35.6 
37.7 
 
• Spirometry 
 
Any participant experiencing a reduction in FEV1 at the 1-hour post-dose compared 
to daily pre-dose value of > 20%. 
 
6.2.2. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Pre-Intervention is defined as time prior to the first dose of study intervention. 
On-Intervention is defined as time from first dose to last dose date plus 14 days. If time 
of assessment or study intervention is not collected, the following assessment on the first 
dose date will be assumed to be taken prior to the first dose and therefore considered pre-
intervention: ECG, Lab, and vital signs, and first dose date is considered on-intervention 
for AE and concomitant medication. 
Post-Intervention is defined as any time post on-intervention window, i.e., > last dose 
date + 14 days. 


 
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Page 23 of 27 
6.2.3. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
 
6.2.4. 
Assessment Window  
Refer to Section 5 (STUDY ASSESSMENTS AND PROCEDURES) in the Study 
Reference Manual (SRM). 
6.2.5. 
Multiple measurements at One Analysis Time Point 
When triplicate ECG assessments are taken, mean of the measurement will be calculated 
first and summary statistics will be based on the calculated mean. This will apply to both 
baseline and post baseline assessments. 
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from a central lab will be taken over the test from a local lab. If multiple assessments 
are taken from the same type of lab, the worst case will be used. 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary variables 
for sorting data in listings only. In addition, partial dates may be imputed for ‘slotting’ 
data to study phases or for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., time 
since diagnosis). In addition, imputed dates are not used for deriving the last contact 
date in overall survival analysis dataset. 
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start day 
If study intervention start date is missing (i.e. participant did 
not start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 


 
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Element 
Reporting Detail 
• 
If month and year of start date = month and year of study 
intervention start date, then 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date= 1st of month. 
− 
Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e. participant did 
not start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start 
date, then 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date = January 1. 
− 
Else set start date = study intervention start 
date.       
Else set start date = January 1. 
Missing end day  
A '28/29/30/31' will be used for the day (dependent on the 
month and year). 
Missing end day 
and month 
No Imputation 
Completely 
missing start/end 
date 
No imputation 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
Missing start day 
If study intervention start date is missing (i.e. participant did 
not start study intervention), then set start date = 1st of month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of 
study intervention start date, then 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date= 1st of month. 


 
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Page 25 of 27 
Element 
Reporting Detail 
− 
Else set start date = study intervention start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e., participant did 
not start study intervention), then set start date = January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start 
date, then 
− 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date = January 1. 
− 
Else set start date = study. intervention start 
date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the 
month. 
Completely 
missing start/end 
date 
No imputation 
6.2.7. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
BL 
Baseline 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
%CV 
Percent Coefficient of Variation  
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
IA 
Interim Analysis 
MMRM 
Mixed Model Repeated Measures 
OPS 
Output and Programming Specification  
PCI 
Potential Clinical Importance  
PK 
Pharmacokinetic 
PT 
Preferred Term 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
SAP 
Statistical Analysis Plan 


 
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Abbreviation 
Description 
SOC 
System Organ Class 
 
6.2.8. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
WinNonlin 
 
 
 
 
 
 


 
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Page 27 of 27 
7. 
REFERENCES 
GSK Document Number TMF-14593236, A randomized, double-blind, placebo 
controlled, single and repeat dose study to assess the safety, tolerability, and 
pharmacokinetics of inhaled GSK3923868 in participants with Chronic Obstructive 
Pulmonary Disease (COPD). 2020