Clinical trial NCT04585009
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: First time in human Stable asthmatics GSK3923868 Inhalation powder Phosphatidylinositol 4-kinase beta
Sponsor: GlaxoSmithKline
Start date: 2020-10-12; Completion date: 2022-06-16
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a first time in human (FTIH) study designed to evaluate the safety, tolerability and pharmacokinetic (PK) profile of single and repeat doses of GSK3923868 inhalation powder in both healthy participants and asthmatics. This is a 3-part, randomized, double blind, placebo controlled study of GSK3923868, administered as an inhalation powder blend (GSK3923868 capsules for inhalation) via Mono-dose inhaler in healthy participants (Parts A and B) and in participants with asthma (Part C). The duration of study participation for each part A, B and C will be 11, 9 and 8 weeks, respectively.

Detailed description:

Arms: arm 1: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: GSK3923868 50 mcg/Placebo/250 mcg in treatment periods 1, 2 and 3 respectively. There will be at least 10 days of wash-out period between doses for each participant. arm 2: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: GSK3923868 50 mcg/100 mcg/Placebo in treatment periods 1, 2 and 3 respectively. There will be at least 10 days of wash-out period between doses for each participant. arm 3: Healthy participants will receive single ascending doses of GSK3923868 in the planned treatment sequence: GSK3923868 50 mcg/100 mcg/250 mcg in treatment periods 1, 2 and 3 respectively. There will be at least 10 days of wash-out period between doses for each participant. arm 4: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: Placebo/GSK3923868 100 mcg/GSK3923868 250 mcg in treatment periods 1, 2 and 3 respectively. There will be at least 10 days of wash-out period between doses for each participant. arm 5: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: Placebo/GSK3923868 1000 mcg/GSK3923868 3000 mcg. There will be at least 10 days of wash-out period between doses for each participant. arm 6: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: GSK3923868 500 mcg/Placebo/3000 mcg. There will be at least 10 days of wash-out period between doses for each participant. arm 7: Healthy participants will receive single ascending doses of GSK3923868 or placebo in the planned treatment sequence: GSK3923868 500 mcg/1000 mcg/Placebo. There will be at least 10 days of wash-out period between doses for each participant. arm 8: Healthy participants will receive single ascending doses of GSK3923868 in the planned treatment sequence: GSK3923868 500 mcg/1000 mcg/3000 mcg. There will be at least 10 days of wash-out period between doses for each participant. arm 9: Healthy participants will receive planned repeat doses of 3000 mcg (six capsules) GSK3923868 daily for 14 days arm 10: Healthy participants will receive planned repeat doses of 3000 mcg (six capsules) GSK3923868 daily for 14 days arm 11: Participants with stable asthma will receive a planned repeat dosing of 3000 mcg (six capsules) GSK3923868 daily for 7 days
Interventions: intervention 1: GSK3923868 intervention 2: Matching placebo intervention 3: Monodose RS01
Intervention descriptions: intervention 1: GSK3923868 will be available as capsules containing inhalation powder blend to be delivered via Monodose RS01 device. intervention 2: Placebo to match GSK3923868 will be available as capsule containing inhalation powder to be delivered via Monodose RS01 device. intervention 3: Participants will receive GSK3923868 and placebo as capsules containing inhalation powder blend to be delivered via Monodose RS01 device.

Protocol documents:
Prot_000.pdf: 
TMF-13791516 
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TITLE PAGE 
Protocol Title: A randomised 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 
Protocol Number: 213497/ Amendment 04 
Compound Number or Name: 
GSK3923868 
 
Brief Title: Safety, tolerability and pharmacokinetics of GSK3923868 inhalation powder 
in healthy participants and stable asthmatics. 
Study Phase: Phase 1 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s):  
 
EudraCT:  2020-002203-19 
 
Approval Date: 24 Sep 2021 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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SPONSOR SIGNATORY: 
Protocol Title: A randomised 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 
Protocol Number: 213497/ Amendment 04 
Compound Number: 
GSK3923868  
 
 
 
 
 
Nicolas Wisniacki 
VP, Discovery Medicine, CPEM, GSK 
 
Date 
 
 
The signed page is a separate document. 
 
 
 
 
Medical Monitor Name and Contact Information: can be found in the Study 
Reference Manual 
 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE. 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 04 
24 Sep 2021 
TMF-13791516 
Amendment 03 
15-FEB-2021 
2020N430088_03 
Amendment 02 
07-SEP-2020 
2020N430088_02 
Amendment 01 
28-AUG-2020 
2020N430088_01 
Original Protocol 
17-Jul-2020 
2020N430088_00 
 
Amendment [04]: 24 Sep 2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment  
This amendment has been prepared to: 
• Remove the requirement for bronchodilator reversibility for the SABA only using 
mild asthma population; as all participants will have a physician confirmed 
diagnosis of asthma at least 6 months prior to screening. 
• Update to Part C inclusion criteria for SABA only population to also include 
intermittent ICS/LABA use, to align with current treatment guidelines. The regular 
ICS/LABA use population remains unchanged. 
• Increase the maximum age of participation from 50 to 65 years of age, in line with 
the easing of some COVID 19 pandemic restrictions and the availability of safety 
and tolerability data.  Participants over the age of 50 will need to provide proof of 
COVID-19 vaccination before being eligible to participate. 
• Clarification to planned cohort 2, study intervention dose levels. 
• Updated access to unblinded data from complete cohorts to include safety 
endpoints. 
• Document the addition of a PK blood sample at 15 mins in Parts B and C (as per 
Section 8.3.1 Plasma Sample Collection), to support modelling of PK data.  
 
 


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Specific details of the changes are provided below: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of Activities (SoA), 
Parts B & C 
Addition of 15 mins PK 
blood sample. 
To support modelling of PK data. 
Section 4.1 Overall 
Design, 
Part 
C: 
Repeat 
Dose 
in 
Participants 
with 
Asthma 
(Parallel 
Group), 
Updated 
'SABA 
only' 
treatment 
to 
include 
treatment 
with 
‘intermittent’ ICS/LABA 
Population treatment requirements 
updated in line with updated 
treatment guidelines. 
Section 
5.1.2 
Inclusion 
Criteria: 
Part C (Participants 
with 
Asthma), 
number 1 
Increase to maximum age 
of participation, from 50 
years to 65 years. 
Currently, COVID 19 pandemic 
restrictions have been lifted within 
the UK and safety data has been 
generated from healthy participants, 
with no safety concerns identified. 
The increase in maximum age of 
participation is only applicable to 
the asthma population.  Participants 
over the age of 50 will be required 
to provide proof of COVID-19 
vaccination before being eligible to 
participate. 
Section 
5.1.2 
Inclusion 
Criteria: 
Part C (Participants 
with 
Asthma), 
number 3 
Inclusion 
of 
British 
Thoracic 
Society/ 
Scottish 
Intercollegiate 
Guidelines 
Network 
(BTS/SIGN), 
for 
physician 
confirmed 
diagnosis of asthma 
The diagnosis of asthma in the UK 
is likely to be according to 
BTS/SIGN or GINA guidelines. 
Section 
5.1.2 
Inclusion 
Criteria: 
Part C (Participants 
with Asthma) 
Removal 
of 
the 
requirement 
for 
bronchodilator 
reversibility 
as 
an 
inclusion 
criterion 
for 
SABA 
only 
requiring 
population 
In the mild asthma SABA only 
requiring population the ability to 
demonstrate 
bronchodilator 
reversibility is highly variable. 
Therefore, participants in this group 
may now be permitted to be 
included (without demonstration of 
bronchodilator reversibility) if they 
have 
a 
physician 
confirmed 
diagnosis of asthma, at least 6 
months before screening.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 
5.1.2 
Inclusion 
Criteria: 
Part C (Participants 
with 
Asthma), 
number 5 
Updated 
'SABA 
only' 
treatment 
to 
include 
treatment 
with 
‘intermittent’ ICS/LABA 
Population treatment requirements 
updated in line with updated 
treatment guidelines. 
Section 6.1 Study 
Intervention(s) 
administered, Cohort 
2 
Removal of 2000 mcg: 
four capsules, single dose 
This dose level was included in the 
planned study intervention(s) table 
in error. This dose was not one of 
the planned study intervention(s) 
dose levels. 
Section 6.3 Measures 
to Minimize Bias: 
Randomization and 
Blinding 
Updated 
access 
to 
unblinded 
data 
from 
complete 
cohorts 
to 
include safety endpoints  
To allow better interpretation of 
both safety and PK data following 
the completion of each cohort, to 
help the design of future studies. 
Section 8.3.1 Plasma 
Sample Collection 
Reduction in the number 
of plasma PK samples 
that may be collected at 
additional 
time 
points 
during 
the 
study 
if 
warranted 
and 
agreed 
upon 
between 
the 
Investigator 
and 
the 
Sponsor.  
One additional sample at 15 mins 
has been added to the study since 
the last protocol amendment. 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE. .................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of Activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study Rationale .......................................................................................... 31 
2.2. 
Background ................................................................................................ 31 
2.3. 
Benefit/Risk Assessment ............................................................................ 32 
2.3.1. 
Risk Assessment ......................................................................... 33 
2.3.2. 
Benefit Assessment ..................................................................... 36 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 36 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 37 
3.1. 
Objectives and Endpoints: Parts A and B (Healthy Participants) ................. 37 
3.2. 
Objectives and Endpoints: Part C (Participants with Asthma) ..................... 38 
4. 
STUDY DESIGN .................................................................................................... 39 
4.1. 
Overall Design ............................................................................................ 39 
4.2. 
Scientific Rationale for Study Design .......................................................... 41 
4.2.1. 
Participant Input into Design ........................................................ 42 
4.3. 
Justification for Dose .................................................................................. 42 
4.3.1. 
Starting Dose and Dose Escalation.............................................. 43 
4.3.2. 
Safety Margins ............................................................................. 44 
4.3.3. 
Predicted Target Engagement at Steady State ............................ 45 
4.4. 
End of Study Definition ............................................................................... 46 
5. 
STUDY POPULATION ........................................................................................... 46 
5.1. 
Inclusion Criteria: ........................................................................................ 47 
5.1.1. 
Inclusion Criteria: Parts A and B (Healthy Participants) ................ 47 
5.1.2. 
Inclusion Criteria: Part C (Participants with Asthma) .................... 48 
5.2. 
Exclusion Criteria ........................................................................................ 50 
5.2.1. 
Exclusion Criteria: Parts A and B (Healthy Participants) .............. 50 
5.2.2. 
Exclusion Criteria: Part C (Participants with Asthma) ................... 54 
5.3. 
Lifestyle Considerations .............................................................................. 55 
5.3.1. 
Meals and Dietary Restrictions .................................................... 55 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 56 
5.3.3. 
Activity ......................................................................................... 56 
5.4. 
Screen Failures........................................................................................... 56 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 56 
6.1. 
Study Intervention(s) Administered ............................................................. 57 
6.1.1. 
Medical Devices ........................................................................... 59 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 59 
6.2.1. 
Dosing Procedure ........................................................................ 60 
6.2.2. 
Treatment Compliance ................................................................. 60 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 60 


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Pr ot o c ol A m d 0 4  
 
7  
 
6. 4.  
St u d y I nt er v e nti o n C o m pli a n c e  ................................................................... 6 1  
6. 5.  
D o s e M o difi c ati o n  ....................................................................................... 6 1  
6. 5. 1.  
P h ar m a c o ki n eti c Crit eri a f or D o s e M o difi c ati o n  ............................ 6 1  
6. 5. 2.  
D o s e E s c al ati o n St o p pi n g Crit eri a  ............................................... 6 2  
6. 6.  
Tr e at m e nt of O v er d o s e  ............................................................................... 6 2  
6. 7.  
C o n c o mit a nt T h er a p y .................................................................................. 6 2  
6. 7. 1.  
R e s c u e M e di ci n e  ......................................................................... 6 3  
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ..................................................................... 6 4  
7. 1.  
Di s c o nti n u ati o n of St u d y I nt er v e nti o n  .......................................................... 6 4  
7. 2.  
St o p pi n g Crit eri a  ......................................................................................... 6 4  
7. 2. 1.  
St u d y St o p pi n g Crit eri a  ................................................................ 6 4  
7. 2. 2.  
P h ar m a c o ki n eti c St o p pi n g Crit eri a  ............................................... 6 4  
7. 2. 3.  
Li v er C h e mi str y St o p pi n g Crit eri a  ................................................ 6 4  
7. 2. 4.  
Q T c St o p pi n g Crit eri a  .................................................................. 6 5  
7. 2. 5.  
S pir o m etr y St o p pi n g Crit eri a  ........................................................ 6 6  
7. 2. 6.  
A st h m a E x a c er b ati o n St o p pi n g Crit eri a ( P art C O nl y)  .................. 6 6  
7. 2. 7.  
T e m p or ar y Di s c o nti n u ati o n  .......................................................... 6 6  
7. 2. 8.  
R e c h all e n g e  ................................................................................. 6 6  
7. 3.  
P arti ci p a nt Di s c o nti n u ati o n/ Wit h dr a w al fr o m t h e St u d y  ............................... 6 6  
7. 4.  
L o st t o F oll o w U p  ........................................................................................ 6 7  
7. 5.  
M a n a g e m e nt of P arti ci p a nt s w h o D e v el o p C O VI D -1 9 S y m pt o m s 
D uri n g t h e St u d y  ......................................................................................... 6 7  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 6 8  
8. 1.  
S af et y A s s e s s m e nt s  ................................................................................... 6 8  
8. 1. 1.  
P h y si c al E x a mi n ati o n s  ................................................................. 6 8  
8. 1. 2.  
Vit al Si g n s  .................................................................................... 6 9  
8. 1. 3.  
El e ctr o c ar di o gr a m s  ...................................................................... 6 9  
8. 1. 3. 2.  
1 2 -L e a d S af et y E C G s  ................................................. 6 9  
8. 1. 3. 3.  
T el e m etr y M o nit ori n g  .................................................. 7 0  
8. 1. 4.  
L u n g F u n cti o n  .............................................................................. 7 0  
8. 1. 5.  
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s  ...................................... 7 0  
8. 1. 6.  
Pr e g n a n c y T e sti n g  ....................................................................... 7 1  
8. 2.  
A d v er s e E v e nt s ( A E s), S eri o u s A d v er s e E v e nt s ( S A E s) a n d Ot h er 
S af et y R e p orti n g  ......................................................................................... 7 1  
8. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n ................................................................................... 7 2  
8. 2. 2.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 7 2  
8. 2. 3.  
F oll o w -u p of A E s a n d S A E s  ......................................................... 7 2  
8. 2. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s  ............................. 7 2  
8. 2. 5.  
Pr e g n a n c y  ................................................................................... 7 3  
8. 2. 6.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  ................................................ 7 3  
8. 2. 7.  
M e di c al D e vi c e D efi ci e n ci e s  ........................................................ 7 4  
8. 2. 7. 1.  
Ti m e P eri o d f or D et e cti n g M e di c al D e vi c e 
D efi ci e n ci e s  ................................................................ 7 4  
8. 2. 7. 2.  
F oll o w -u p of M e di c al D e vi c e D efi ci e n ci e s  ................... 7 4  
8. 2. 7. 3.  
Pr o m pt R e p orti n g of M e di c al D e vi c e 
D efi ci e n ci e s t o S p o n s or  .............................................. 7 4  
C CI
C CI


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8. 2. 7. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or 
M e di c al D e vi c e I n ci d e nt s  ............................................ 7 5  
8. 3.  
P h ar m a c o ki n eti c s  ....................................................................................... 7 5  
8. 3. 1.  
Pl a s m a S a m pl e C oll e cti o n  ........................................................... 7 5  
8. 4.  
G e n eti c s a n d/ or P h ar m a c o g e n o mi c s  .......................................................... 7 6  
8. 5.  
Bi o m ar k er s  ................................................................................................. 7 6  
8. 6.  
I m m u n o g e ni cit y A s s e s s m e nt s ..................................................................... 7 6  
8. 7.  
H e alt h E c o n o mi c s  ....................................................................................... 7 7  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 7 7  
9. 1.  
St ati sti c al H y p ot h e s e s ................................................................................. 7 7  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ........................................................................ 7 7  
9. 3.  
A n al y si s S et s  .............................................................................................. 7 9  
9. 4.  
St ati sti c al A n al y s e s  ..................................................................................... 7 9  
9. 4. 1.  
Pri m ar y E n d p oi nt( s)  ..................................................................... 7 9  
9. 4. 1. 1.  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ............. 8 0  
9. 4. 1. 2.  
L a b or at or y v al u e s, vit al si g n s, 1 2 -l e a d 
el e ctr o c ar di o gr a m a n d S pir o m etr y  .............................. 8 0  
9. 4. 2.  
S e c o n d ar y E n d p oi nt( s)  ................................................................ 8 0  
9. 5.  
I nt eri m A n al y si s .......................................................................................... 8 1  
9. 5. 1.  
D o s e E s c al ati o n C o m mitt e e ( D E C)  .............................................. 8 1  
9. 5. 2.  
I n str e a m A n al y si s of P K D at a ...................................................... 8 1  
1 0.  S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L  
C O N SI D E R A TI O N S  ............................................................................................... 8 3  
1 0. 1.  A p p e n di x 1: R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht 
C o n si d er ati o n s  ............................................................................................ 8 3  
1 0. 1. 1.  
R e g ul at or y a n d Et hi c al  C o n si d er ati o n s  ........................................ 8 3  
1 0. 1. 2.  
Fi n a n ci al Di s cl o s ur e  ..................................................................... 8 3  
1 0. 1. 3.  
I nf or m e d C o n s e nt Pr o c e s s .......................................................... 8 4  
1 0. 1. 4.  
D at a Pr ot e cti o n  ............................................................................ 8 4  
1 0. 1. 5.  
C o m mitt e e s Str u ct ur e  .................................................................. 8 5  
1 0. 1. 5. 1.  D o s e E s c al ati o n C o m mitt e e  ....................................... 8 5  
1 0. 1. 6.  
Di s s e mi n ati o n of Cli ni c al St u d y D at a  ........................................... 8 5  
1 0. 1. 7.  
D at a Q u alit y A s s ur a n c e  ............................................................... 8 6  
1 0. 1. 8.  
S o ur c e D o c u m e nt s  ...................................................................... 8 7  
1 0. 1. 9.  
St u d y a n d Sit e St art a n d Cl o s ur e  ................................................. 8 7  
1 0. 1. 1 0.  P u bli c ati o n P oli c y  ......................................................................... 8 8  
1 0. 2.  A p p e n di x 2: Cli ni c al L a b or at or y T e st s  ......................................................... 8 9  
1 0. 3.  A p p e n di x 3: A E s a n d S A E s: D efi niti o n s a n d Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, F oll o w -u p, a n d R e p orti n g  ....................................... 9 1  
1 0. 3. 1.  
D efi niti o n of A E  ............................................................................ 9 1  
1 0. 3. 2.  
D efi niti o n of S A E  .......................................................................... 9 2  
1 0. 3. 3.  
D efi niti o n of C ar di o v a s c ul ar E v e nt s  ............................................. 9 3  
1 0. 3. 4.  
R e c or di n g a n d F oll o w -U p of A E a n d S A E  .................................... 9 4  
1 0. 3. 5.  
R e p orti n g of S A E t o G S K  ............................................................. 9 6  
1 0. 4.  A p p e n di x 4: C o ntr a c e pti v e G ui d a n c e  .......................................................... 9 7  
1 0. 4. 1.  
D efi niti o n s:  ................................................................................... 9 7  
1 0. 4. 2.  
C o ntr a c e pti o n G ui d a n c e:  ............................................................. 9 8  
C CI
C CI


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1 0 . 5. A p p e n di x 5: Li v er S af et y: R e q uir e d A cti o n s a n d F oll o w -u p 
A s s e s s m e nt s  ............................................................................................ 1 0 0  
1 0. 6.  A p p e n di x 6: A E s, A D E s, S A E s, S A D E s, U S A D E s a n d D e v i c e 
D efi ci e n ci e s: D efi niti o n a n d Pr o c e d ur e s f or R e c or di n g, E v al u ati n g, 
F oll o w -u p, a n d R e p orti n g i n M e di c al D e vi c e St u di e s  ................................ 1 0 2  
1 0. 6. 1.  
D efi niti o n of M e di c al D e vi c e A E a n d A D E  .................................. 1 0 3  
1 0. 6. 2.  
D efi niti o n of M e di c al D e vi c e S A E, S A D E a n d U S A D E  ............... 1 0 3  
1 0. 6. 3.  
D efi niti o n of D e vi c e D efi ci e n c y  ................................................... 1 0 4  
1 0. 6. 4.  
R e c or di n g a n d F oll o w -U p of A E a n d/ or S A E a n d D e vi c e 
D efi ci e n ci e s  ............................................................................... 1 0 4  
1 0. 6. 5.  
R e p orti n g of S A E s  ..................................................................... 1 0 6  
1 0. 6. 6.  
R e p orti n g of S A D E s  ................................................................... 1 0 7  
1 0. 8.  A p p e n di x 8: C o vi d -1 9  ............................................................................... 1 1 0  
1 0. 8. 1.  
O v er all R ati o n al e f or t hi s A p p e n di x  ............................................ 1 1 0  
1 0. 8. 2.  
St u d y Pr o c e d ur e s  D uri n g C O VI D -1 9 P a n d e mi c  ......................... 1 1 0  
1 0. 8. 3.  
Pr ot o c ol D efi n e d Pr o c e d ur e s/ Vi sit s:  ........................................... 1 1 0  
1 0. 8. 4.  
D at a M a n a g e m e nt/ M o nit ori n g:  ................................................... 1 1 1  
1 0. 9.  A p p e n di x 9: A b br e vi ati o n s a n d D efi niti o n s a n d Tr a d e m ar k s  ..................... 1 1 2  
1 0. 1 0.  A p p e n di x 1 0: Pr ot o c ol A m e n d m e nt Hi st or y  ............................................... 1 1 6  
1 1.  R E F E R E N C E S  ..................................................................................................... 1 2 2  
 
 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomised 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 
Brief Title: Safety, tolerability and pharmacokinetics of GSK3923868 inhalation powder 
in healthy participants and stable asthmatics. 
Rationale: This is a first time in human (FTIH) study designed to evaluate the safety, 
tolerability and pharmacokinetic (PK) profile of single and repeat doses of GSK3923868 
inhalation powder in both healthy participants and asthmatics.  The study will use the 
Monodose RS01 inhaler for drug delivery. This study aims to provide evaluate the safety 
and tolerability profile of the molecule and will obtain preliminary information regarding 
PK to support future clinical development. 
Phosphatidylinositol 4-kinase beta (PI4KB) is a human intracellular lipid kinase that 
catalyses the formation of phosphatidylinositol-4-phosphate (PI4P), a key component of 
the Golgi and trans-Golgi network membranes and regulator of trafficking to and from the 
Golgi body.   
PI4KB is host factor required for the replication of multiple picornaviruses, including 
human rhinovirus (HRV).  Following cell entry, HRV proteins produced by translation of 
viral RNA recruit PI4KB to the Golgi membrane, where increased synthesis of PI4P drives 
membrane cholesterol enrichment.  The role of PI4KB is crucial for viral polyprotein 
processing and for the formation of replication organelles where viral replication takes 
place. 
HRV are small, non-enveloped, positive sense RNA viruses belonging to the family 
Picornaviridae and genus Enterovirus.  The characteristic clinical manifestation of HRV 
infection is the common cold, for which HRV is responsible for approximately 50% of 
cases, though during seasonal peaks in autumn and spring, incidence can be up to 80%.   
The symptoms related to HRV infection are generally limited to the upper respiratory tract 
(e.g. rhinorrhoea, sore throat, sneezing) and of minimal clinical concern.  However, in the 
context of chronic respiratory diseases, such as COPD and asthma, HRV has been shown 
to induce lower respiratory tract symptoms (e.g. cough, wheeze and shortness of breath) 
and is the predominant viral stimulus leading to exacerbations.  Furthermore, HRV 
infection may increase host susceptibility to secondary bacterial infection through 
upregulation of cell surface receptors, disruption of normal epithelial barrier function and 
through impairment of macrophage response following exposure to bacterial toll-like 
receptors.   
Preclinical data support the use of GSK3923868 in the treatment of HRV infection.  In air-
liquid interface cultures of fully differentiated human bronchial epithelial cells, 
GSK3923868 has been shown to exhibit potent and slowly reversible inhibition of HRV 
replication (t1/2 ~ 50 h via washout protocol).  In vitro data also indicates that 


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GSK3923868 is a potent inhibitor of viral replication in a broad number of HRV strains 
from both major and minor groups (HRV-A and HRV-B species, IC50 range 0.3 to 3.9 nM 
respectively).  In other experiments, HRV-C species have also been shown to be sensitive 
to PI4KB inhibition.   
There are currently no licensed treatments or vaccines for HRV, with previous treatments 
generally targeting virus-specific factors including capsid binding and cell entry or 
inhibition of viral enzymes (e.g. 3C protease) necessary for viral genome processing and 
replication.  The failure to develop an effective treatment has been attributed to the 
antigenic diversity of HRV which has over 160 serotypes and also the rapid emergence of 
drug resistance.  As PI4KB inhibition is a host target, it is expected to exhibit a comparably 
higher barrier to resistance. 
As a selective and potent inhibitor of PI4KB, GSK3923868 has the potential to inhibit viral 
replication whilst permitting normal immune mediated clearance of the virus. This could 
lead to reduced symptoms, prevention of HRV driven exacerbations and prevention of 
secondary bacterial infections.   


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 2  
 
O bj e cti v e s a n d E n d p oi nt s: P art s A a n d B ( H e alt h y p arti ci p a nt s)  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o ev al uat e t he s afety an d tol er a bility of 
G S K 39 2 38 68 f oll o wi ng si n gl e a nd r e pe at 
i n h al ed a d mi nistr ati o n in h ealt hy 
p artici p a nts.  
•  
A dv ers e ev e nts ( A Es) an d serio us a dv ers e 
ev e nts ( S A Es).  
•  
Cli nic ally si g nific a nt l ab or atory v al u es, vit al 
si g ns, 1 2-l e a d el ectr ocar di ogr a m ( E C G) 
a n d spiro m etry m e asur e m ents up t o D ay 2 
of t h e fi nal tr e at m e nt p erio d i n P art A, an d 
D ay 1 8 in P art B . 
S ec o nd ary  
•  
T o ev al uat e t he pl as m a p har mac oki n etics 
of G S K 3 92 38 6 8 f oll o wi n g si n gl e a n d 
r e p e at i n hal e d a d mi nistr ati on i n h e althy 
p artici p a nts.  
D eriv e d p har mac oki netic p ar a m et ers as d ata 
p er mit, i ncl u di ng ( but not li mit e d t o):  
Si n gl e d os e ( P art A, C o h orts 1 & 2):  
•  Ar e a u n der t h e pl as m a G S K 3 9 23 86 8 
c o nc entr ati on v ers us ti m e curv e fr o m ti me 
z er o t o last qu antifi a bl e c o nc e ntr ati on 
( A U C( 0-t)) a n d fr o m ti m e z er o t o i nfinity 
( A U C( 0-∞)) (if d et er mi n e d).  
•  M axi mu m o bs erv e d G S K3 92 3 86 8 pl as m a 
c o nc entr ati on ( C max). 
•  Ti me t o m axi mu m o bserv e d pl as m a dr ug 
c o nc entr ati on ( T max). 
R e p e at e d d ose ( P art B, C oh orts 3 & 4):  
•  A U C( 0 -) o n D ay 1 a nd D ay 1 4 (= 2 4 h f or 
o nc e a d ay d osi n g re gi me n) (if d et er mi n e d).  
•  C max a n d T m ax o n D ay 1 a n d D ay 1 4.  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 3  
 
O bj e cti ve s  
E n d p oi nt s  
 
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Objectives and Endpoints: Part C (Participants with Asthma) 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and tolerability of 
GSK3923868 following repeat inhaled 
administration in participants with 
asthma. 
• 
AE and SAEs 
• 
Clinically significant laboratory values, vital 
signs, 12-lead ECG and spirometry 
measurements up to Day 8. 
Secondary 
• 
To evaluate the plasma 
pharmacokinetics of GSK3923868 
following repeat inhaled administration in 
participants with asthma. 
• 
AUC(0-) on Day 1 and Day 7 (=24h for 
once a day dosing regimen) (if 
determined). 
• 
Cmax and Tmax on Day 1 and Day 7. 
 
Overall Design: 
This is a 3-part, randomised, double-blind, placebo controlled, study designed to assess the 
safety, tolerability and PK of GSK3923868 administered as an inhalation powder blend 
(GSK3923868 capsules for inhalation) via the Monodose inhaler in healthy participants 
(Parts A and B) and in participants with asthma (Part C). 
In all parts, participants who meet the criteria for study entry will be randomised to receive 
GSK3923868 (active) or placebo before study intervention administration on Day 1. 
As this study represents the first administration of GSK3923868 to humans, sentinel dosing 
will be utilised for each increasing dose level in Part A (if the selected dose level is below 
the previous dose level, sentinel dosing may still be applied) and before initiating full 
cohort repeat dosing in Part B.  Each sentinel sub-cohort will consist of two participants 
receiving GSK3923868 or placebo (i.e. one will receive active and one will receive 
placebo).  The decision to dose the remaining participants in each cohort will be based on 
the review of safety and tolerability data (i.e. AE/SAE, clinical safety laboratory 
assessments, vital signs, 12-lead safety ECGs and spirometry) from the sentinel sub-cohort 
by the Principal Investigator (PI) or appropriately qualified delegate, in consultation with 
the Medical Monitor.  For Part A this will include data up to 24 hours post-dose and in Part 
B will include all data up Day 14, 24 hours. 
 In addition, a Dose Escalation Committee (DEC) will be responsible for the review of 
emerging safety, tolerability and plasma PK results to determine the progression of single 
ascending dose levels in each treatment period in Part A and the progression to repeat dose 
levels in Parts B and C.   
 
 


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Brief Summary:  
For Part A, sufficient healthy adult participants will be screened to ensure a total of 24 
participants are randomised in Cohorts 1 and 2 with the aim to achieve approximately 24 
completed.  Cohorts 1 and 2 will each consist of 12 healthy participants receiving study 
intervention in treatment periods 1 to 3 and 4 to 6 (9 active and 3 placebo per period), 
respectively.   
In Part B, sufficient healthy adult participants will be screened to ensure 8 healthy 
participants are randomised to each of the two cohorts, with the aim to achieve 
approximately 8 completed in each cohort.  A total of 16 healthy participants will be 
randomised in Part B to achieve 16 completers, 12 on active and 4 on placebo (6 active and 
2 placebo in each of Cohorts 3 and 4). 
For Part C, sufficient participants with asthma will be screened to ensure 16 participants 
are randomised, with the aim to achieve 16 completers, 12 on active and 4 on placebo. 
If participants prematurely discontinue the study, they will be replaced at the discretion of 
the sponsor Medical Monitor in consultation with the Principal Investigator.  In Part A, the 
replacement participant will be assigned to the same treatment sequence and may start the 
treatment period where the last participant prematurely discontinued.  In Parts B and C 
participants will be assigned to same treatment as the last participant prematurely 
discontinued. 
Each participant may only be randomised to one cohort and may only participate in one 
part of the study. 
Number of Participants: 
A total of approximately 56 participants will be enrolled across the entire study, comprising 
of 40 healthy participants (in Parts A and B) and 16 participants with asthma (in Part C). 
Note: "Enrolled" means a participant's, agreement to participate in the 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 
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Intervention Groups and Duration: 
The total duration of study participation in each part of the study is summarised in the 
table below: 
Part 
Screening 
Treatment Period 
Washout Period 
Follow-Up 
Total 
Duration 
A 
Up to 30 days 
before the first 
dose. 
Cohort 1 will be comprised of three 
treatment periods (3days each) 
with a follow up phone call at 48 
hours after each dose. 
Will be at least 10 
days between doses 
for each participant. 
Between 7 to 14 
days following 
the final dose. 
Approx. 
11 
weeks 
A 
Cohort 2 will be comprised of three 
treatment periods (4 days each). 
B 
Each participant will  
receive up to 14 days of treatment 
with additional observation up to 
96 hours after their final dose. 
N/A 
Approx. 
 9 weeks 
C 
Each participant will receive up to 
7 days of treatment. 
N/A 
Approx. 
8 weeks 
 
Each participant may only be randomised to one cohort and may only participate in one 
part of the study. 
Part A: Single Dose Escalation in Healthy Participants (Crossover) 
In Part A, single ascending doses of GSK3923868 will be assessed in two sequential 
crossover cohorts (Cohorts 1 and 2) of healthy participants, each with up to three treatment 
periods.  In each cohort, 12 participants will be randomised to one of four treatment 
sequences.  Across the three treatment periods, 9 participants will receive placebo in one 
of the periods, whereas 3 participants will receive an active dose in all periods (see below 
table for further details). 
 
Treatment Period 
Cohort 1 
Cohort 2 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
(n=3) 
1 
A 
A 
A 
P 
- 
2 
P 
A 
A 
A 
- 
3 
A 
P 
A 
A 
- 
4 
- 
P 
A 
A 
A 
5 
- 
A 
P 
A 
A 
6 
- 
A 
A 
P 
A 
 
The planned dose levels in each treatment period outlined in Section 4.3.1 will be 
conducted only if it is supported by safety, tolerability and plasma PK results (from a 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 7  
 
mi ni m u m of 5 partici pa nts o n acti ve treat me nt) fr o m t he prece di n g d os e le vel(s) a n d ma y 
be m o dif ie d base d o n e mer gi n g d ata. 
A mi ni m u m of 1 0 da ys was h o ut is re q uire d b et w ee n eac h treat me nt peri o d.  
P art B: R e p e at D o s e i n H e alt h y P arti ci p a nt s ( P ar all el Gr o u p)  
Part B will ass ess re p eat d oses of G S K 3 9 2 3 8 6 8 f or 1 4 da ys acr oss t w o p arallel c o h orts 
( C o h orts 3 a n d 4) of 8 healt h y partici p a nts (t otal 1 6 partici pa nts i n Part B).  T he d ose 
selecte d f or Part B will b e base d o n t h e f ull re vi e w of safet y, t olera bilit y a n d plas ma P K 
data  i n Part A.  T h e d ose f or Part B will n ot e x cee d t he t o p d ose use d i n Part A.  I n a d diti o n, 
t he pre dicte d stea d y stat e s yste mic e x p os ure i n Part B will n ot i nte nti o nall y e x cee d t he 
pre deter mi ne d s yst e mic e x p os ure st o p pi n g criteria ( Secti o n 6. 5 ).  B ot h c o h orts i n Part B 
are pr o p os e d t o recei ve t he sa me d ose.  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 8  
 
P art C: R e p e at D o s e i n P arti ci p a nt s wit h A st h m a ( P ar all el Gr o u p)  
I n Part C, f urt h er re peat d osi n g of G S K 3 9 2 3 8 6 8 f or 7 d a ys will be assesse d i n a si n gle 
parallel c o h ort ( C o h ort 5) of 1 6 partici pa nts wit h sta ble ast h ma.  T he d ose f or Part C will 
be base d o n t he re vie w of safet y, t olera bilit y a n d plas ma P K data i n Part B  u p t o Da y 1 4, 
2 4 h o urs (fr o m a mi ni m u m of 1 0 partici pa nts o n acti ve treat me nt) . T h e d os e le vel i n Part 
C will n ot  e x cee d t he d ose use d i n Part B .  
. 
Partici pa nts i n Part C will be recr uite d bas e d o n t heir ast h ma se verit y, s uc h t hat 8 
partici pa nts will be mil d or i nter mitte nt ast h matics re q uiri n g o nl y treat m e nt wit h s h ort -
acti n g b eta a g o nist ( S A B A)  a n d/or i nter mittent i n hale d c ortic oster oi d ( I C S)/l o n g-acti n g 
beta a g o nist ( L A B A)  c o m bi nati o n a n d 8 partici pa nts will ha ve m o derat e ast h ma re q uiri n g 
re g ular tr eat me nt wit h I C S or I C S/ L A B A.  Ra n d o misati o n will be stratifie d t o e ns ure 6 
partici pa nts usi n g S A B A  a n d/or i nter mitte nt I C S/ L A B A a n d 6 p artici pa nts ta ki n g re g ul ar 
I C S or I C S/ L A B A will be o n acti ve tr eat me nt.  
D at a 
M o nit ori n g / Ot h er C o m mittee:  N o Data 
M o nit ori n g C o m mittee.  A D os e 
Escalati o n C o m mittee: Yes  
A d ose escal ati o n c o m mittee ( D E C) will be res p o nsi ble f or o n -g oi n g m o nit ori n g d uri n g 
t he st u d y.  
As t his st u d y re pres e nts t he first a d mi nistrati o n of G S K 3 9 2 3 8 6 8 t o h u ma ns, a d ose 
escalati o n c o m mittee ( D E C) will be res p o nsi ble f or re vie wi n g all a vaila ble safet y, 
t olera bilit y a n d P K data t o deter mi ne pr o gressi n g d ose le vels i n Part A a n d bef ore i nitiati n g 
re peat d osi n g i n Parts B a n d C. 
T he D E C will at a mi ni m u m c o nsist of t he f oll o wi n g:  
•  Pri nci pal I n v esti gat or ( or s uita bl y q ualifie d d ele gate)  
•  Fr o m G S K:  
o  Me dical M o nit or  
o  Cli nical P har mac ol o g y, M o delli n g a n d Si m ulati o n re pres e ntati ve 
o  Safet y a n d Me dic al G o ver na nce re prese ntati ve  
o  Statisticia n  
T o mi ni mise t he ris k of u n bli n di n g d uri n g D E C meeti n gs, i n di vi d ual P K data will be 
scra m ble d s uc h t hat t he bli n d is mai ntai ne d.  S u m mar y statistics will als o be pr o vi de d f or 
p las ma P K para meters ( C ma x a n d A U C) .  T he data ma y be u n bli n de d s h o ul d a safet y 
c o ncer n arise d uri n g t h e bli n de d re vie w.  
F urt her details o n t he d ose escalati o n pr ocess , d ose m o dificati o n a n d escalati o n st o p pi n g 
criteria a n d t he D E C are o utli ne d i n t he  pr ot oc ol a n d  D ose Escal ati o n Pla n.  
 
 
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1.2. 
Schema 
Part A: Single Ascending Dose | Healthy Participants 
 
 
 
 
 
Part B: Repeat Dose | Healthy Participants 
 
 
Part C: Repeat Dose | Participants with Asthma 
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1.3. 
Schedule of Activities (SoA)  
• 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. 
 
 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
2 1  
 
P art s A, B a n d C: S cr e e ni n g a n d F oll o w U p  
Pr oc e d ur e  
Scr e e ni n g  
( u p t o -3 0 d ays  
b ef or e D ay 1)  
F oll o w U p  
( 7 t o 1 4 d ays  
p ost l ast d os e)  
O ut p ati e nt Visit  
X  
 
T el e p h o n e C all  
 
X  
I nf or m e d C o ns e nt 
X  
 
R evi e w I ncl usi o n a n d Excl usi o n Crit eri a 
X  
 
D e m o gr a p hy  
X  
 
M e dic al Hist ory (i ncl u d es s u bst a nc e us a g e, s m oki n g st at us a n d m e dic ati o n 
hist ory)  
X  
 
F ull P hysic al Ex a mi n ati o n  
(i ncl u d es h ei g ht, w ei g ht  a n d B MI ) 
X  
 
A E R evi e w  
 
X  
S A E R evi e w  
X  
X  
C o nc o mit a nt M e dic ati o n R evi e w  
X  
X  
S pir o m etry 1 
X  
 
P e ak Ex pir at ory Fl o w ( P E F)  Tr ai ni n g 2 
X  
 
P E F 2 
X  
 
Vit al Si g ns 3 
X  
 
1 2 -L e a d S af ety E C G 4 
X  
 
S af ety L a b or at ory Ass ess m e nt 6 
X  
 
HI V, H e p atitis B a n d C Scr e e ni n g  
X  
 
C O VI D -1 9  T est 7 
X  
 
-h C G Pr e g n a ncy/ Estr a di ol/ F S H T ests  
X  
 
Alc o h ol a n d S m oki n g Br e at h T est  
X  
 
Uri n e Dr u g Scr e e n  
X  
 
1.  M e as ure f orc ed expir at ory v olu m e i n 1 s ec o n d ( F E V 1) a n d forc e d vit al c a p acity ( F V C) i n tri plic at e.  
2.  F or P art C o nly –  Tri plicat e meas ur e me nts an d tr ai ni n g of t h e p artici p a nt i n h o w t o t ak e 
m e as ure m e nts will occ ur at scr e e ni n g.  
3.  I ncl u des systolic a n d di ast olic bl o o d pressur e, h e art r at e, r espir ati o n r at e a nd ty m p a nic 
t e m p er atur e. 
4.  Scr e e ni ng E C G t o be p erf or me d i n triplic at e.  
6.  Cli nic al C h e mistry, H a e m at ol ogy, C o a g ul a ti on a n d Urin alysis. 
7.  T o b e p erf or m e d accor di n g t o l oc al sit e pr oce d ur es.  A d diti on al a d hoc t esti ng m ay b e 
i m pl e m e nt ed b ase d o n l ocal sit e pr oc ed ur es. 
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 2  
 
P art A: Si n gl e A s c e n di n g D o s e | H e alt h y P arti ci p a nt s ( C o h ort 1)  
Pr oc e d ur e  
Tr e at m e nt P eri o ds 1 t o 3  
D ay -1  
D ay 1  
D ay 2  
( D 1+ 2 4 h)  
D ay 3  
( D 1+  4 8 h)  
Pr e -d os e  
0  
5 m  
3 0 m  
4 5 m  
1 h  
2 h  
4 h  
6 h  
8 h  
1 2 h  
1 6 h  
A d missi o n t o Cli nic al U nit  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc h ar g e  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
P h o n e C all  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Bri ef P hysic al Ex a mi n ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
I n h al er Tr ai ni n g1 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol a n d S m oki n g Br e at h T est  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n e Dr u g Scr e e n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9  T est 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
Uri n e Pr e g n a ncy  T est  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o mis ati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Tr e at m e nt A d mi nistr ati o n 3 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
A E R evi e w  
 
 
 
S A E R evi e w  
 
C o nc o mit a nt M e dic ati o n R evi e w  
 
 
 
S pir o m etry ( F E V 1 a n d F V C) 4 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
Vit al Si g ns 5 
X  
X  
 
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
1 2 -L e a d S af ety E C G 6 
X  
X  
 
X  
X  
 
X  
 
X  
 
 
X  
 
X  
 
T el e m etry 7 
 
 
 
 
 
 
 
L a b or at ory S af ety Ass ess m e nt 9 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
P K Bl o o d S a m pl e  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 3  
 
F o ot n ot e s t o  P art A: Si n gl e A s c e n di n g D o s e |  H e alt h y P arti ci p a nt s ( C o h ort 1)  
1.  Day -1 i n hal er tr ai ni ng m ay b e p erf or m e d o n D ay 1 if ne e d e d a n d b ef ore  a d mi nistr atio n of th e  first d os e.  A d diti o n al tr ai nin g m ay b e pr ovi d ed as n e e d ed a n d 
acc or di n g t o I nv esti gat or discreti o n.  
2 . T o b e p erf or m e d accor di n g t o l oc al sit e pr oce d ur es.  A d diti on al a d hoc t esti ng m ay b e i m ple m e nt e d b ase d o n l oc al sit e pr oc e d u r es. 
3 . No m e als fr o m 2 h o urs b ef ore d osi n g u ntil 2 h ours p ost d os e.  
4 . P erf or m i n tri plic at e a n d inclu des F E V 1 a n d F V C.  
5 . I ncl u des systolic a n d di ast olic bl o o d pressur e, h e art r at e, r espir ati o n r at e a nd ty m p a nic t e mp er at ur e. 
6 . O n D ay 1 pr e -d os e  of eac h treat m e nt peri o d,  tri plic ate E C G m e as ure m e nts will b e c oll ect ed, a n d t he m e an v al u es will be us e d t o c alc ulat e b as elin e.  At all 
ot h er ti m e p oints si n gl e E C Gs will b e tak e n.  
7 . Car di ac t el e m etry t o st art ap proxi m at ely 1 -h o ur pr e -d ose a n d c o nti nu o usly until 6 h o urs p ost d o s e. 
9 . Cli nic al C h e mistry a n d H a e m at ol o gy o nly.  
    
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 4  
 
P art A: Si n gl e A s c e n di n g D o s e | H e alt h y P arti ci p a nt s ( C o h ort 2)  
Pr oc e d ur e  
Tr e at m e nt P eri o ds 4  t o 6 
D ay -1  
D ay  1  
D ay 2  
( D 1 + 2 4 h) 
D ay 3  
( D 1 + 4 8 h) 
Pr e -d os e  
0  
5 m  
3 0 m  
4 5 m  
1 h  
2 h  
4 h  
6 h  
8 h  
1 2 h  
1 6 h  
A d missi o n t o Cli nic al U nit  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disc h ar g e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
P h o n e C all  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bri ef P hysic al Ex a mi n ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
I n h al er Tr ai ni n g1 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol a n d S m oki n g Br e at h T est  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n e Dr u g Scr e e n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C O VI D -1 9 T est 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Uri n e Pr e g n a ncy  T est  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o mis ati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Tr e at m e nt A d mi nistr ati o n 3 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
A E R evi e w  
 
 
 
S A E R evi e w  
 
C o nc o mit a nt M e dic ati o n R evi e w  
 
 
 
S pir o m etry ( F E V 1 a n d F V C) 4 
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
 
Vit al Si g ns 5 
X  
X  
 
 
X  
 
X  
 
X  
 
 
X  
 
X  
 
1 2 -L e a d S af ety E C G 6 
X  
X  
 
X  
X  
 
X  
 
X  
 
 
X  
 
X  
 
T el e m etry 7 
 
 
 
 
 
 
 
L a b or at ory S af ety Ass ess m e nt 9 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
P K Bl o o d S a m pl e  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 5  
 
F o ot n ot e s t o  P art A: Si n gl e A s c e n di n g D o s e |  H e alt h y P arti ci p a nt s ( C o h ort 2)  
1.  Day -1 i n hal er tr ai ni ng m ay b e p erf or m e d o n D ay 1 if ne e d e d a n d b ef ore a d mi nistr atio n of th e first d os e.  A d diti o n al tr ai nin g m ay b e pr ovi d ed as n e e d ed a n d 
acc or di n g t o I nv esti gat or discreti o n.  
2.  T o b e p erf or m e d accor di n g t o l oc al sit e pr oce d ur es.  A d diti on al a d hoc t esti ng m ay b e i m p le m e nt e d b ase d o n l oc al sit e pr oc e d ur es. 
3.  No m e als fr o m 2 h o urs b ef ore d osi n g u ntil 2 h ours p ost d os e.  
4.  P erf or m i n tri plic at e a n d inclu des F E V 1 a n d F V C.  
5.  I ncl u des systolic a n d di ast olic bl o o d pressur e, h e art r at e, r espir ati o n r at e a nd ty m p a nic t e mp er at ur e. 
6.  O n D ay 1 pr e -d os e of eac h treat m e nt peri o d, tri plic ate E C G m e as ure m e nts will b e c oll ect ed, a n d t he m e an v al u es will be us e d t o c alc ulat e b as elin e.  At all 
ot h er ti m e p oints si n gl e E C Gs will b e tak e n.  
7.  Car di ac t el e m etry t o st art ap proxi m at ely 1 -h o ur pr e -d ose a n d c o nti nu o usly until 6 h o urs p ost d os e.  
9 . Cli nic al C h e mistry a n d H a e m at ol o gy o nly.  
 
C CI
C CI


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Part B: Repeat Dose | Healthy Participants (Cohorts 3 and 4) 
Procedure 
Inpatient Period 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
(D14+ 
24h) 
D16 
(D14+ 
48h) 
D17 
(D14+ 
72h) 
D18 
(D14+ 
96h) 
Admission to 
Clinical Unit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Brief Physical 
Examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Inhaler Training1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and 
Smoking Breath 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Test2 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Urine Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
AE Review 
 
 
SAE Review 
 
Concomitant 
Medication 
Review 
 
 
Spirometry (FEV1 
& FVC) 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
 
 
 
Vital Signs4 
X 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X 
 
 
X 
12-Lead Safety 
ECG6 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Telemetry 
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 7  
 
Pr oc e d ur e  
I n p ati e nt Peri o d 
D -1  
D 1  
D 2  
D 3  
D 4  
D 5  
D 6  
D 7  
D 8  
D 9  
D 1 0  D 1 1  D 1 2  D 1 3  
D 1 4  
D 1 5  
( D 1 4+  
2 4 h)  
D 1 6  
( D 1 4+  
4 8 h)  
D 1 7  
( D 1 4+  
7 2 h)  
D 1 8  
( D 1 4+  
9 6 h)  
L a b or at ory S af ety 
Ass ess m e nt 9 
X  
 
X 5 
 
X 5 
 
X 5 
 
X 5 
 
X 5 
 
X 5 
 
X 5 
X  
 
 
X  
P K Bl o o d S a m pl e  
 
X 1 0 , 
1 6 
X 5 
X 5 
X 5 
X 5 
X 5 
X 5 , 
1 1 
X 5 
X 5 
X 5 
X 5 
X 5 
X 5 
X 1 0 , 
1 6 
X  
X  
X  
X  
 
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
 
 
2 8  
 
F o ot n ot e s t o P art B: R e p e at D o s e R e p e at D o s e | H e alt h y P arti ci p a nt s ( C o h ort s 3 a n d 4)  
1.  Day -1 i n hal er tr ai ni ng m ay b e p erf or m e d o n D ay 1 if ne e d e d a n d b ef ore a d mi nistr atio n of th e first d os e.  A d diti o n al tr ai nin g m ay b e pr ovi d ed as n e e d ed a n d 
acc or di n g t o I nv esti gat or discreti o n.  
2.  T o b e p erf or m e d accor di n g t o l oc al sit e pr oce d ur es.  D ay 4 to 6 t est is r eq uir e d f or C o h ort 4 o nly a h e a d of br o nc h osc o py o n D ay 7.  D ay 1 2 to 1 4 test is 
r e q uir e d for Co h ort 3 o nly a h ea d of bro nc h osc o py o n D ay 1 5.  A d diti on al ad h oc t esti n g m ay b e i m pl e m e nt ed b ase d o n l oc al sit e pr oc e d ures.  
3.  Pr e d os e a nd 1 -h our p ost -d os e o nly.  
4.  I ncl u des systolic a n d di ast olic bl o o d pressur e, h e art r at e, r espir ati o n r at e a nd ty m p a nic t e mp er at ur e. 
5.  Pr e d os e.  
6.  O n tr e at m e nt days E C Gs will b e c oll ecte d at pre d ose a n d 6 -h o urs p ost -d os e.  O n D ay 1 pre d os e, tri plic at e m e as ur e me nts will be c oll ect e d, an d t h e m ea n 
v al u es will b e us e d t o c alc ul ate b as eli n e.  At all ot h er ti m es si n gle E C Gs c a n be t ake n.  
7.  Car di ac t el e m etry t o st art ap proxi m at ely 1 -h o ur pr e -d ose a n d c o nti nu o usly until 6 h o urs p ost d os e.  
9.  Cli nic al C h e mistry a n d H a e m at ol o gy at all visits.  C o a g ul ation will b e ass ess e d o n D ay 4 f or b ot h c oh orts.  
1 0.  At pr e -d os e, 5 mi n, 3 0 mi n, 4 5 mi n, 1 h, 2 h, 4 h, 6 h, 8 h, 1 2 h a n d 1 6 h.  
1 6.  At 1 5 mi n.  
C CI
C CI


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Part C: Repeat Dose | Asthma (Cohort 5) 
Procedure 
Inpatient Period 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
(D7+ 24h) 
Admission to Clinical Unit 
X 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
X 
Review Inclusion and Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Brief Physical Examination 
X 
 
X 
 
 
 
 
 
X 
Inhaler Training1 
X 
 
 
 
 
 
 
 
 
Alcohol and Smoking Breath Test 
X 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
COVID-19 Test2 
X 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
 
AE Review 
 
 
SAE Review 
 
Concomitant Medication Review 
 
 
Spirometry (FEV1 & FVC) 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X 
PEF4 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
X 
12-Lead Safety ECG8 
X 
X 
X 
 
X 
 
X 
X 
X 
Telemetry 
 
X9 
 
 
 
 
 
 
 
Laboratory Safety Assessment10 
X 
 
X7 
 
X7 
 
X7 
 
X 
PK Blood Sample 
 
X11 
X7 
X7 
X7 
X7 
X7 
X11 
X 


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Footnotes to Part C: Repeat Dose | Asthma (Cohort 5) 
1. Day -1 inhaler training may be performed on Day 1 if needed and before administration of the first dose.  Additional training may be provided as needed and 
according to Investigator discretion. 
2. To be performed according to local site procedures.  Additional ad hoc testing may be implemented based on local site procedures. 
3. Predose and 30 min only. 
4. 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 evening until 
discharge on Day 8.  Clinical site staff will complete and record the PEF measurements at each time point.   
5. Provide PEF device refresher training if necessary. 
6. Includes systolic and diastolic blood pressure, heart rate, respiration rate and tympanic temperature. 
7. Predose only 
8. On treatment days ECGs will be collected at predose and 6-hours post-dose.  On Day 1 predose, triplicate measurements will be collected, and the mean 
values will be used to calculate baseline.  At all other times single ECGs can be taken. 
9. Cardiac telemetry to start approximately 1-hour pre-dose and continuously until 6 hours post dose. 
10. Clinical Chemistry and Haematology only. 
11. At pre-dose, 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 16 h 
 
 


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2. 
INTRODUCTION 
Phosphatidylinositol 4-kinase beta (PI4KB) is a human intracellular lipid kinase that 
catalyses the formation of phosphatidylinositol-4-phosphate (PI4P), a key component of 
the Golgi and trans-Golgi network membranes and regulator of trafficking to and from the 
Golgi body.   
PI4KB is a host factor required for the replication of multiple picornaviruses, including 
human rhinovirus (HRV).  Following cell entry, HRV proteins produced by translation of 
viral RNA recruit PI4KB to the Golgi membrane, where increased synthesis of PI4P drives 
membrane cholesterol enrichment.  The role of PI4KB is crucial for viral polyprotein 
processing and for the formation of replication organelles where viral replication takes 
place [Hsu, 2010; Altan-Bonnet, 2012; Roulin, 2014]. 
GSK3923868 is a selective and potent inhibitor of PI4KB being developed for respiratory 
disease and specifically the treatment of rhinovirus associated exacerbations of chronic 
obstructive pulmonary disease (COPD) and asthma.  GSK3923868 is not an 
immunomodulatory drug. 
2.1. 
Study Rationale  
This is a first time in human (FTIH) study designed to evaluate the safety, tolerability and 
pharmacokinetic (PK) profile of single and repeat inhaled doses of GSK3923868 in both 
healthy participants and asthmatics.  The study will use the Monodose RS01 inhaler for 
drug delivery. This study aims to evaluate the safety and tolerability profile of the molecule 
and will also obtain preliminary information regarding PK to support future clinical 
development. 
2.2. 
Background 
HRV are small, non-enveloped, positive sense RNA viruses belonging to the family 
Picornaviridae and genus Enterovirus.  The characteristic clinical manifestation of HRV 
infection is the common cold, for which HRV is responsible for approximately 50% of 
cases, though during seasonal peaks in autumn and spring, incidence can be up to 80% 
[Turner, 2007].   
The symptoms related to HRV infection are generally limited to the upper respiratory tract 
(e.g. rhinorrhoea, sore throat, sneezing) and of minimal clinical concern.  However, in the 
context of chronic respiratory diseases, such as COPD and asthma, HRV has been shown 
to induce lower respiratory tract symptoms (e.g. cough, wheeze and shortness of breath) 
and is the predominant viral stimulus leading to exacerbations [Hershenson, 2013].  
Furthermore, HRV infection may increase host susceptibility to secondary bacterial 
infection by upregulation of cell surface receptors, disruption of normal epithelial barrier 
function and through impairment of macrophage response following exposure to bacterial 
toll-like receptors [Jacobs, 2013].   
Preclinical data support the use of GSK3923868 in the treatment of HRV infection.  In air-
liquid interface cultures of fully differentiated human bronchial epithelial cells, 
GSK3923868 has been shown to exhibit potent and slowly reversible inhibition of HRV 


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replication (t1/2 ~ 50 h via washout protocol).  In vitro data also indicates that 
GSK3923868 is a potent inhibitor of viral replication in a broad number of HRV strains 
from both major and minor groups (HRV-A and HRV-B species, IC50 range 0.3 to 3.9 nM).  
In other experiments, HRV-C species have also been shown to be sensitive to PI4KB 
inhibition [Mello, 2014].   
There are currently no licensed treatments or vaccines for HRV, with previous treatments 
generally targeting virus-specific factors including capsid binding and cell entry or 
inhibition of viral enzymes (e.g. 3C protease) necessary for viral genome processing and 
replication.  The failure to develop an effective treatment has been attributed to the 
antigenic diversity of HRV which has over 160 serotypes and also the rapid emergence of 
drug resistance [Casanova, 2018].  As PI4KB inhibition is a host target, it is expected to 
exhibit a comparably higher barrier to resistance. 
As a selective and potent inhibitor of PI4KB, GSK3923868 has the potential to inhibit viral 
replication whilst permitting normal immune mediated clearance of the virus. This could 
lead to reduced symptoms, prevention of HRV driven exacerbations and prevention of 
secondary bacterial infections.   
A detailed description of the chemistry, preclinical pharmacology, efficacy and safety of 
GSK3923868 is provided in the Investigator’s Brochure [GSK Document Number 
2020N427621_00]. 
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 2020N427621_00]. 
 


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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.  Inclusion/Exclusion criteria: In Parts A and B 
healthy participants with an FEV1 and an FVC < 
80% of predicted normal value will be excluded. 
In Part C only participants with mild to moderate 
asthmatics with a pre-bronchodilator FEV1 > 
65% of predicted normal value will be recruited.  
Monitoring: All doses of study treatment will be 
administered in the clinical pharmacology 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 
Appropriate safety margin: Maximum clinical 
exposure at 3 mg are expected to be below the 


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
3 4  
 
P ot e nti al Ri sk of Cli ni cal Si g nifi c a n ce  
 
S u m m ar y of D ata/ R ati o n ale f or Ri s k  
 
Miti g ati o n Str at e g y  
 
t h e 
br o nchi ol o alve ol ar ju ncti on 
at 
20 60 
µ g/k g/ d ay.   In ad diti on, a n incr e as e d i nci d enc e of 
i nfl a m m at ory c ell i nfiltr at e ( mi ni m al or sli g ht 
s ev erity),  
c o m p ose d  
pr e d o mi na ntly  
of 
gr a n ul ocyt es, of t h e peri br onc hi ol ar/ periv asc ul ar 
i nt erstiti u m w as als o s e en at 2 0 60 µ g/kg/ d ay. 
Mi ni m al or sli g ht i nfl a m m at ory c ell i nfiltr at e w as 
s e e n at a hi gh er th an co ntr ol inci d e nce in 
f e m al es  
giv en  
20 6 0  
µ g/kg/ d ay 
o nly.   H o w ev er,  n o microsc opic fi n din gs i n d og I H 
a n d r at I V s t u di es. 
N O A E L ex pos ur e m ar gi ns ( A U C:  1 5 -fol d; C max: 
5 -f ol d; l un g d ep ositi o n: 5-fol d). 
M o nit or i n g: r espirat ory A Es will b e m o nit or e d a n d 
spiro m etry will b e c on d uct e d pr e - a n d post -
d osi n g  i n all t hr e e parts of th e st u dy.  I n ad diti on, 
p e ak expirat ory flo w ( P E F ) m o nit orin g will be 
i mpl e m e nt e d f or ast h m atics i n P art C. 
S e nti nel d osin g will b e us e d at eac h dos e 
esc al ati on  ( P art A), an d als o f or o n e of t h e r e pe at 
d os e c oh orts ( P art B). Esc al ati on will only 
pr oc e ed aft er a bli n de d r evi e w of saf ety, 
t ol er a bility a n d pl as m a P K  o bt ain e d i n at le ast 5 
p articip a nts o n activ e tr e at m e nt  at t h e prior d ose 
l ev el.  
St u d y Pr o c e d ure s   
S pir o m etry ass ess me nts  
S h ort ness of bre at h, c ou ghi n g, li ght h e ad ed n ess 
or f ai nti ng, an d/ or ch est ti g ht n ess d uring t h e 
s piro m etry ass ess m ents. 
As s p ecifi ed i n th e i nf or me d c o ns ent f or m for t his 
st u dy, if any of t h ese sy m pt o ms s h o ul d occur, t h e 
p articip a nt 
will r ec eiv e a p pr opriat e 
m edic al 
tr e at m e nt. 
C CI


T M F -1 3 7 9 1 5 1 6  
 
C O N FI D E N TI A L  
 
 
 
 
 
2 1 3 4 9 7  
 
 
Pr ot o c ol A m d 0 4  
3 5  
 
P ot e nti al Ri sk of Cli ni cal Si g nifi c a n ce  
 
S u m m ar y of D ata/ R ati o n ale f or Ri s k  
 
Miti g ati o n Str at e g y  
 
 
C CI


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2.3.2. 
Benefit Assessment 
No clinical benefit is expected for the healthy participants or asthma patients enrolled in 
this FTIH 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 human rhinovirus infection. 
However, participants may benefit in the knowledge that they are contributing to the 
process of developing new therapies in an area of unmet need.  Participants may also 
benefit from the thorough medical assessments they receive during the course of the study. 
2.3.3. 
Overall Benefit: Risk Conclusion 
This study will be conducted in a fully equipped clinical pharmacology unit with access to 
hospital emergency facilities.  Considering the measures taken to minimise the potential 
risks associated with participation in this study, the enrolment of healthy participants and 
stable asthma patients is considered justified by the anticipated benefits that may be 
afforded to participants with COPD and Asthma in the future. 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
3 7  
 
3.  
O B J E C TI V E S A N D E N D P OI N T S  
3. 1.  
O bj e cti v e s a n d E n d p oi nt s: P art s A a n d B ( H e alt h y 
P arti ci p a nt s)  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  
T o ev al uat e t he s afety an d tol er a bility of 
G S K 39 2 38 68 f oll o wi ng si n gl e a nd r e pe at 
i n h al ed ad mi nistr ati o n in h ealt hy 
p artici p a nts.  
•  
A dv ers e ev e nts ( A Es) an d serio us a dv ers e 
ev e nts ( S A Es).  
•  
Cli nic ally si g nific a nt l ab or atory v al u es, vit al 
si g ns,12 -l e a d el ectr ocar di ogr a m ( E C G) 
a n d spiro m etry m e asur e m ents up t o D ay 2 
of t h e fi nal tr e at m e nt p erio d i n P art A, an d 
D ay 1 8 in P art B . 
S ec o nd ary  
•  
T o ev al uat e t he pl as m a 
p h ar mac oki netics of G S K 3 92 3 86 8 
f oll o wi n g si ngl e an d re p eat in h al ed 
a d mi nistr ati o n i n h e althy p artici p a nts.  
D eriv e d p har mac oki netic p ar a m et ers as d ata 
p er mit, i ncl u di ng ( but not li mit e d t o):  
Si n gl e d os e ( P art A, C o h orts 1 & 2):  
•  Ar e a u n der t h e pl as m a G S K 3 9 23 86 8 
c o nc entr ati on v ers us ti m e curv e fr o m ti me 
z er o t o last qu antifi a bl e c o nc e ntr ati on 
( A U C( 0-t)) a n d fr o m ti m e z er o t o i nfinity 
( A U C( 0-∞)) (if d et er mi n e d).  
•  M axi mu m o bs erv e d G S K3 92 3 86 8 pl as m a  
c o nc entr ati on ( C max). 
•  Ti me t o m axi mu m o bserv e d pl as m a dr ug 
c o nc entr ati on ( T max). 
R e p e at e d d ose ( P art B, C oh orts 3 & 4):  
•  A U C( 0 -) o n D ay 1 a nd D ay 1 4 (= 2 4 h f or 
o nc e a d ay d osi n g re gi me n) (if d et er mi n e d).  
•  C max a n d T m ax o n D ay 1 a n d D ay 1 4.  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
3 8  
 
O bj e cti ve s  
E n d p oi nt s  
 
3. 2.  
O bj e cti v e s a n d E n d p oi nt s: P art C ( P arti ci p a nt s wit h A st h m a)  
O bj e cti ve s  
E n d p oi nt s  
Pri m ary  
•  T o ev al uat e t he s afety an d tol er a bility of 
G S K 39 2 38 68  f oll o wi ng r e peat i n h al e d 
a d mi nistr ati o n i n p artici p a nts wit h 
ast h m a.  
•  
A E a n d S A Es  
•  
Cli nic ally si g nific a nt l ab or atory v al u es, vit al 
si g ns, 12 -l e a d E C G an d spir o m etry  
m e as ur e m e nts up t o D ay 8 . 
S ec o nd ary  
•  
T o ev al uat e t he pl as m a 
p h ar mac oki netics of G S K 3 92 3 86 8 
f oll o wi n g r ep e at i n h al e d a d mi nistr ati o n i n 
p artici p a nts wit h ast h m a.  
•  
A U C( 0 -) o n D ay 1 a nd D ay 7 (= 2 4 h f or 
o nc e a d ay d osi n g re gi me n) (if 
d et er mi n e d).  
•  
C max a n d T m ax o n D ay 1 a n d D ay 7.  
C CI


TMF-13791516 
CONFIDENTIAL 
 
 
 
213497 
 
Protocol Amd 04 
39 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a 3-part, randomised, double-blind, placebo controlled, study designed to assess the 
safety, tolerability and PK of GSK3923868 administered as an inhalation powder blend 
(GSK3923868 capsules for inhalation) via Monodose inhaler in healthy participants (Parts 
A and B) and in participants with asthma (Part C). 
In all parts, participants who meet the criteria for study entry will be randomised to receive 
GSK3923868 (active) or placebo before study intervention administration on Day 1. 
As this study represents the first administration of GSK3923868 to humans, sentinel dosing 
will be utilised for each increasing dose level in Part A (if the selected dose level is below 
the previous dose level, sentinel dosing may still be applied) and before initiating full 
cohort repeat dosing in Part B.  Each sentinel sub-cohort will consist of two participants 
receiving GSK3923868 or placebo (i.e. one will receive active and one will receive 
placebo).  The decision to dose the remaining participants in each cohort will be based on 
the review of safety and tolerability data (i.e. AE/SAE, clinical safety laboratory 
assessments, vital signs, 12-lead safety ECGs and spirometry) from the sentinel sub-cohort 
by the Principal Investigator (PI) or appropriately qualified delegate, in consultation with 
the Medical Monitor.  For Part A this will include data up to 24 hours post-dose and in Part 
B will include all data up Day 14, 24 hours. 
 
In addition, a Dose Escalation Committee (DEC) will be responsible for the review of 
emerging safety, tolerability and plasma PK results to determine the progression of single 
ascending dose levels in each treatment period in Part A and the progression to repeat dose 
levels in Parts B and C.  Dose modification and escalation stopping criteria are outlined in 
Section 6.5 and the DEC committee structure is outlined in Section 10.1.5.  Further 
information on the dose escalation process is outlined in the Dose Escalation Plan.  
The total duration of study participation in each part of the study is summarised in Table 
1. 
Table 1 
Summary of study duration for study Parts A, B and C  
Part 
Screening 
Treatment Period 
Washout Period 
Follow-Up 
Total 
Duration 
A 
Up to 30 days 
before the first 
dose. 
Cohort 1 will be comprised of 
three treatment periods (3 days 
each) with a follow up phone call 
at 48 hours after each dose. 
Will be at least 10 
days between doses 
for each participant. 
Between 7 to 14 
days following 
the final dose. 
Approx. 
11 weeks 
A 
Cohort 2 will be comprised of 
three treatment periods (4 days 
each). 
B 
Each participant will  
receive up to 14 days of treatment 
with additional observation up to 
96 hours after their final dose. 
N/A 
Approx. 
 9 weeks 
C 
Each participant will receive up to 
7 days of treatment. 
N/A 
Approx. 
8 weeks 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 0  
 
 
Eac h partici p a nt ma y o nl y be ra n d o mise d t o o ne c o h ort a n d ma y o nl y p artici pate i n o ne 
part of t he st u d y.  
P art A: Si n gl e D o s e E s c al ati o n i n H e alt h y P arti ci p a nt s ( Cr o s s o v er)  
I n Part A, si n gl e asce n di n g d oses of G S K 3 9 2 3 8 6 8 will be assesse d i n t w o se q ue ntial 
cr oss o ver c o h orts ( C o h orts 1 a n d 2) of h ealt h y partici pa nts, eac h wit h u p t o t hree tr eat me nt 
peri o ds.  I n eac h c o h ort, 1 2  partici pa nts will be ra n d o mise d t o o ne of f o ur treat me nt 
se q ue nces.  Acr oss t he t hree tr eat me nt peri o ds, 9  partici pa nts will recei ve place b o i n o n e 
of t he p eri o ds, w hereas 3  partici pa nts will recei ve a n acti ve d ose i n all peri o ds (see Ta ble 
2  f or f urt her details). 
T a bl e 2  
E x a m pl e tr e at m e nt s e q u e n c e r a n d o mi s ati o n f or P art A  
Tr e at m e nt P eri o d  
C o h ort 1  
C o h ort 2  
( n =3 ) ( n =3 ) ( n =3 ) ( n =3 ) ( n =3 ) ( n =3 ) ( n =3 ) ( n =3 ) 
1  
A  
A  
A  
P  
- 
2  
P  
A  
A  
A  
- 
3  
A  
P  
A  
A  
- 
4  
- 
P  
A  
A  
A  
5  
- 
A  
P  
A  
A  
6  
- 
A  
A  
P  
A  
 
T he pla n ne d d ose le v els i n eac h treat me nt peri o d o utli ne d i n Secti o n 4. 3. 1  will be 
c o n d ucte d o nl y if it is s u p p orte d b y safet y, t olera bilit y a n d plas ma P K res ults (fr o m a 
mi ni m u m of 5 partici pa nts o n acti ve treat me nt) fr o m t he prece di n g d os e le vel(s) a n d ma y 
be m o dif ie d base d o n e mer gi n g d ata. 
A mi ni m u m of 1 0  da ys was h o ut is re q uire d b et w ee n eac h treat me nt peri o d.  
P art B: R e p e at D o s e i n H e alt h y P arti ci p a nt s ( P ar all el Gr o u p)  
Part B will ass ess re p eat d oses of G S K 3 9 2 3 8 6 8 f or 1 4 da ys acr oss t w o p arallel c o h orts 
( C o h orts 3 a n d 4) of 8 healt h y partici p a nts  (t otal 1 6 partici pa nts i n Part B).  T he d ose 
selecte d f or Part B will b e base d o n t h e f ull re vi e w of safet y, t olera bilit y a n d p las ma P K 
data  i n Part A.  T h e d ose f or Part B will n ot e x cee d t he t o p d ose use d i n Part A.  I n a d diti o n, 
t he pre dict e d ste a d y stat e s yste mic e x p os ure i n Part B will n ot i nte nti o n all y e x cee d t h e 
pre deter mi ne d s yst e mic e x p os ure st o p pi n g criteria ( Secti o n 6. 5 ).  B ot h c o h orts i n Part B 
are pr o p os e d t o recei ve t he sa me d ose.  
P art C: R e p e at D o s e i n P arti ci p a nt s wit h A st h m a ( P ar all el Gr o u p)  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 1  
 
I n Part C, f urt h er re peat d osi n g of G S K 3 9 2 3 8 6 8 f or 7 d a ys will be as sesse d i n a si n gle 
parallel c o h ort ( C o h ort 5) of 1 6 partici pa nts wit h sta ble ast h ma.  T he d ose  f or Part C will 
be base d o n t he re vie w of safet y, t olera bilit y a n d plas ma P K data i n Part B  u p t o Da y 1 4, 
2 4 h o urs (fr o m a mi ni m u m of 1 0 partici pa nts o n acti ve t reat me nt).  T h e d ose le vel i n Part 
C will n ot e x cee d t he  d ose use d i n Part B .  
 
Partici pa nts i n Part C will be recr uite d bas e d o n t heir ast h ma se verit y, s uc h t hat 8 
partici pa nts will be mil d or i nter mitte nt ast h matics re q uiri n g o nl y treat m e nt wit h s h ort -
acti n g b eta a g o nist ( S A B A) a n d/or i nter mitte nt i n hale d c ortic oster oi d (I C S)/l o n g-acti n g 
beta a g o nist ( L A B A) c o m bi nati o n a n d 8 partici pa nts will ha ve m o derat e ast h ma re q uiri n g 
re g ular tr eat me nt wit h I C S or I C S/ L A B A.  Ra n d o misati o n will be stratifie d t o e ns ure 6 
partici pa nts usi n g i nter mitte nt S A B A or i nter mitte nt I C S/ L A B A a n d 6 partici pa nts ta ki n g 
re g ular I C S or I C S/ L A B A will be o n acti ve treat me nt. 
4. 2.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
T his st u d y has bee n desi g ne d i n acc or da n ce wit h re g ul at or y g ui d a nce f or t he c o n d uct of 
First Ti me i n H u ma n ( F TI H) st u dies.  Precli nical assess me nts of G S K 3 9 2 3 8 6 8 c o ntri b ute 
t o t he n u m ber a n d ti mi n g of safet y ass ess me nts a n d m o nit ori n g d uri n g t he st u d y. 
T his st u d y will be t he first a d mi nistrati o n of G S K 3 9 2 3 8 6 8 t o h u ma ns.  T his st u d y ai ms t o 
ge n erat e safet y, t olera bilit y  a n d  P K  data of G S K 3 9 2 3 8 6 8 i n h u ma ns.  A place b o c o ntr ol 
ar m has b ee n i nc or p orat e d i nt o eac h p art of t his st u d y t o all o w f or v ali d e val uati o n of safet y 
a n d t olera bilit y a n d t o all o w assess me nt of a d verse e ve nts t hat are attri b uta ble t o treat me nt, 
vers us t h ose n ot attri b uta ble t o  treat me nt. 
Parts A ( C o h orts 1 a n d 2) a n d B ( C o h orts 3 a n d 4) will be recr uiti n g healt h y partici pa nts 
t o all o w i nitial assess me nt of t he safet y a n d t olera bilit y of G S K 3 9 2 3 8 6 8, bef ore 
pr o gressi o n t o treat me nt of partici pa nts wit h sta bl e ast h ma i n Part C ( C o h ort 5).  
As t his is a F TI H st u d y, a se nti nel d osi n g a p pr oac h will be e m pl o ye d f or a n y d ose le vel 
n ot pre vi o usl y a d mi nistere d t o h u ma ns (i.e. eac h i ncreasi n g d ose le vel i n Part A a n d first 
re peat d osi n g i n Part B).  T his will per mit earl y ass ess ment of t h e safet y a n d t olera bilit y of 
G S K 3 9 2 3 8 6 8 i n 2 partici pa nts ( 1 acti ve a n d 1 place b o), bef ore t he re m ai ni n g partici p a nts 
i n t he c o h orts recei ve st u d y tr eat me nt.  A n y escalati o n of d oses, i ncl u di n g d efi niti o n of t he 
ne xt d ose, will be ma de b y t he D E C b ase d u p o n t he re vie w of all a vaila ble safet y, 
t olera bilit y a n d plas ma P K data.  
Part A will e m pl o y a mi ni m u m was h o ut peri o d of 1 0  d a ys bet w ee n treat me nt peri o ds t o 
e ns ure s uffi cie nt ti me f or t he res ults of a vaila ble 2 4  h p ost -d ose safet y data a n d all o w f or 
t he re vie w a n d a n y a dj ust me nt nee de d o n t h e basis of e mer gi n g s afet y, t olera bilit y a n d P K 
i nf or mati o n.  T h e w as h o ut peri o d is b ase d o n t he pre dicte d t ar get e n ga ge m e nt at t h e 
pla n ne d si n gle d os es of G S K 3 9 2 3 8 6 8 , w hic h is a ntici pate d  t o be bel o w 5 % aft er 1 0 da ys 
fr o m t he ti me of d osi n g, t h us it is c o nsi dere d s ufficie nt was h o ut  bet wee n treat me nt peri o ds .  
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 2  
 
I n b ot h c o h orts of Part B, partici pa nts will be a d mi nistere d treat me nt f or 1 4  da ys.  T he 
treat me nt d urati o n will e ns ure a  t h or o u g h assess m e nt of safet y a n d t olera bilit y i n t he l u n g 
(tar get or ga n) a n d ali g ns wit h t he pr o p ose d treat m e nt d urati o n i n f ut ure pati e nt st u dies. 
Part C will pr o gress o nce t he res ults fr o m Part B has bee n re vie we d. Part C is c o nsi dere d 
nec essar y t o i nf or m o n t he earl y safet y a n d t olera bilit y pr ofile of G S K 3 9 2 3 8 6 8 i n sta ble 
ast h matics bef ore pr o gressi o n t o efficac y st u dies 
w here ast h matics 
will recei v e 
G S K 3 9 2 3 8 6 8 o n a bac k gr o u n d of H R V i nf ecti o n.  Part C  will recr uit t w o strata of 
ast h matics : 1)  S A B A a n d/or  i nter mitte nt I C S/ L A B A users w h o are t he pri m ar y p o p ulati o n 
of i nterest i n earl y cli nical trials , a n d 2)  R e g ular I C S or  I C S/ L A B A users t o s u p p ort f ut ure 
cli nical st u dies a n d assess o verall safet y i n treate d ast h ma . 
4. 2. 1.  
P arti ci p a nt I n p ut i nt o D e si g n  
T here w as n o s pecific eli citati o n of partici pa nt i n p ut i nt o t he desi g n of t his st u d y.  
4. 3.  
J u stifi c ati o n f or D o s e  
F or t his M o n o d ose de vice, t he ter m “ d ose” refers t o t he n o mi nal c o nte nt of acti ve 
p har mace utical i n gre die nt c o ntai ne d wit hi n t he G S K 3 9 2 3 8 6 8 ca ps ules f or i n h alati o n, 
a d mi nistere d usi n g t he M o n o d ose i n haler.  
A m o del -bas e d a p pr oac h was utilize d t o pr o vi de t h e d ose j ust ificati o n f or t his F TI H st u d y. 
A P h ysi ol o gic al l y Bas e d P har mac o ki netic ( P B P K) m o del usi n g Gastr o Pl us  S oft ware  was 
de vel o pe d, i n w hic h t he p h ysic o -c he mical pr o perties of t he c o m p o u n d, i n vitr o a n d i n viv o 
data fr o m rats (I V a n d I H) a n d d o gs  (I V) P K a n d t o xi c o-ki netics ( T K) data were utilise d 
[ G S K D oc u me nt N u m ber 2 0 1 9 N 4 1 9 5 0 1 _ 0 1 ]. T he i n vitr o p ul m o nar y de p ositi o n of 
G S K 3 9 2 3 8 6 8 aer os olise d via t he  M o n o d ose 
i n haler was f o u n d t o b e 
, w he n  
c haracterise d usi n g t he Electr o nic L u n g breat hi n g si m ulat or a n d s u bse q ue nt i n silic o L u n g 
De p ositi o n M o delli n g usi n g t he M ulti ple -Pat h Particle D osi metr y ( M P P D) m o del [ G S K 
D oc u me nt N u m ber 2 0 2 0 N 4 3 7 0 7 8 _ 0 1 ]. T his val ue was use d as i n p ut i nt o Nasal-P ul m o nar y 
C o m part me ntal A bs or pti o n a n d Tra nsit ( N P C A T) m o del m o d ule i n Gastr o Pl us t o acc o u nt 
f or t he a bs or pti o n fr o m l u n gs f oll o wi n g i n halati o n.  
 
T he h u ma n P B P K m o del was deter mi ne d bas e d o n t he p h ysic o -c he mical i n p uts use d i n t he 
rat a n d d o g m o delli n g f oll o wi n g t he pre-cli nical i n viv o v erificati o n. H u ma n i ntri nsic 
plas ma cleara nce ( 3 7 L/ h) was esti mate d usi n g t h e rat a n d d o g u n b o u n d cleara n ce w hic h 
C CI
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 3  
 
were scal e d t o h u ma n usi n g restricti ve li ver bl o o d fl o w scali n g or si n gle s pecies all o metr y 
met h o ds d ue t o t he a bs e n ce of a r o b ust i n vitr o / i n viv o c orrelati o n. T he h u ma n v ol u me of 
distri b uti o n at stea d y st ate ( 5 1 L)  was cal c ulate d usi n g t he m ec ha nistic L u c o k o va e q uati o n 
use d i n Gastr o Pl us [ Gastr o Pl us v 9. 6 User Ma n ual , 2 0 1 8 ].  
 
H u ma n P K e x p os ure pr ofiles i n s ys te mic circ ul ati o n a n d l u n g were ge n erate d fr o m t he 
P B P K m o del, s pecificall y f or l u n g, t he e x p os ure was t he t otal p ul m o nar y c o m p art me nt 
re pres e nte d b y t he br o nc hi olar, br o nc hi oles a n d al ve olar i nterstitial. T he N O A E L data 
o btai ne d fr o m t he precli nical s peci es (rats a n d d o gs) [ Secti o n 4 of I B] was a p plie d t o deri v e 
t he safet y mar gi ns i n b ot h t he l u n g a n d s yste mic c o m part me nts.  I n a d diti o n, t he P B P K 
m o del pre dicte d l u n g e x p os ure pr ofile was t he n i nc or p orat e d i nt o t he P K P D m o del [G S K 
D oc u me nt N u m ber 2 0 1 9 N 4 1 9 5 0 1 _ 0 1 ] w hic h use d t he PI 4 K B e nz y m e ki netics data  
(acc o u nte d f or c o m petiti ve bi n di n g wit h A T P ) ( Secti o n 4. 2 of I B) t o deri ve t he tar get 
e n ga ge me nt of G S K 3 9 2 3 8 6 8 t o s u p p ort d ose selecti o n.  
 
4. 3. 1.  
St arti n g D o s e a n d D o s e E s c al ati o n  
T he pr o p ose d starti n g d ose i n Part A ( S A D p orti o n) of t he st u d y is 5 0 mc g. T his d ose was 
selecte d u n der t he ass u m pti o n t hat 1 0 0 % of t he i n hale d d ose w o ul d de p osit i nt o t he l u n gs, 
a n d t he pre dicte d ma xi m u m PI 4 K B tar get e n ga ge me nt at t his d ose is < 2 0 %  (see Ta ble 3 ). 
Base d o n t he c urre nt k n o wle d ge o n t he mec h a nis m of acti o n of t his c o m p o u n d, a p ote nt 
i n hi bit or of PI 4 K B, a 2 0 % tar get e n ga ge me nt is c o nsi dere d a p pr o priate as mi ni m u m 
a ntici pate d bi ol o gic al e ffecti ve le vel ( M A B E L) [F D A , 2 0 0 5].  
I n a d diti o n, t he ass u me d 1 0 0 % l u n g d e p ositi o n f oll o wi n g i n halati o n, as re q uir e d b y 
re g ulat or y a ge n cies, is kn o w n t o be c o nser vati ve. I n vitr o a n d i n silic o c haracterizati o n of 
G S K 3 9 2 3 8 6 8 
aer os olise d via  t he M o n o d ose i n haler ( G S K 
D oc u me nt 
N u m ber 
2 0 2 0 N 4 3 7 0 7 8 _ 0 1 ) s u g gests a p pr o xi matel y 
 of n o mi nal d ose is li kel y t o be d e p osite d 
i nt o t he l u n gs. Gi ve n t his pre dicte d l u n g de p ositi o n, t he ma xi m u m tar get e n ga ge me nt wit h 
a si n gle 5 0  mc g  d os e  is e x pecte d t o be l o wer t ha n 1 0 %  (see T a ble 3 ).   
T he pla n ne d d os es f or d ose escal ati o n i n Part A after t he first c o h ort wit h 5 0  mc g  are 1 0 0, 
2 5 0, 5 0 0, 1 0 0 0, a n d 3 0 0 0 mc g.  T he pre dicte d ma xi m u m tar get e n ga ge me nt after eac h 
pla n ne d d ose i n Part A is o utli ne d i n  see Ta ble 3 . At 3 0 0 0 mc g ( ma xi m u m pla n ne d d ose) 
t he pre dicte d ma xi m u m tar get en ga ge me nt is 9 7 %  
 base d o n 1 0 0 %  
 l u n g 
de p ositi o n.  
F oll o wi n g eac h d ose, t he s yste mic P K ( u p t o 2 4  h p ost d ose) , s afet y a n d t olera bilit y d ata 
will be e val uate d. T he s yste mic e x p os ure, C ma x a n d A U C ( u p t o 2 4  h) ( w here data per mit) 
will be calc u late d f or t he c urre nt d ose a n d pre di cte d f or t he ne xt d ose le vel ass u mi n g li near 
P K. T he pre dicte d C ma x a n d A U C will be c o m pare d wit h t he N O A E L fr o m I V i n rats a n d 
I H i n d o gs. T he pr o p ose d d ose f or t he ne xt c o h ort ma y be m o difie d if necessar y, s o t hat 
t he pre dicte d C ma x a n d A U C are wit hi n t he N O A E L fr o m I V d os e i n  rats. 
C CI
C CI
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 4  
 
T a bl e 3  
Pr e di ct e d m a xi m u m t ar g et e n g a g e m e nt f or pl a n n e d si n gl e d o s e s of 
G S K 3 9 2 3 8 6 8  at 1 0 0 %  
 d e p o siti o n  
Pl a n n e d si n gl e d o s e l e v el s ( µ g)  
Pre di ct e d M a xi m u m T ar g et E n g a g e m e nt ( %)  
1 0 0 % D e p ositi o n  
5 0  
1 3  
1 0 0  
2 4  
2 5 0  
4 7  
5 0 0  
6 9  
1 0 0 0  
8 6  
3 0 0 0  
9 7  
 
At  t hese pla n ne d si n gle d oses of G S K 3 9 2 3 8 6 8 a d mi nistere d via t he M o n o d ose i n haler , t he 
pre dicte d tar get e n ga ge me nt w o ul d be e x pecte d  t o be bel o w 1 0 % after se ve n da ys, a n d 
bel o w 5 % after 1 0 da ys fr o m t he ti me of d osi n g. T his s u g gests t hat 1 0  da ys of was h o ut 
bet wee n eac h tr eat me nt p eri o d  i n Part A is e x pecte d t o be s ufficie nt. 
T he selecti o n of a safe d ose f or Part B will be perf or me d u p o n c o nsi derati o n of a v aila ble 
safet y, t olera bilit y a n d s yste mic P K data fr o m Part A, a n d t he selecti o n of a safe d ose f or 
Part C will be perf or me d u p o n c o nsi derati o n of a vaila ble safet y, t olera bilit y a n d s yste mic 
P K data fr o m Part B.  T h e d ose c h ose n will n ot e x cee d t he ma xi m u m well t olerate d d os e 
i de ntifie d i n t he prece di n g Part, a n d d oses ma y be a dj uste d d o w n war ds if n ecessar y. 
4. 3. 2.  
S af et y M ar gi n s  
T he pla n n e d t o p d os e of G S K 3 9 2 3 8 6 8 i n t his st u d y is 3 0 0 0 mc g. T his d ose was selecte d 
base d o n t he a ni mal t o h u ma n o vera ge i n l u n gs, u n der t he f oll o wi n g ass u m pti o ns: 1) 1 0 %, 
2 5 %, 1 0 0 % (as s u g geste d b y re g ulat or y a ge n cies) de p osite d d ose i n t he l u n gs f or rats, d o gs 
a n d h u ma ns, res pecti vel y; 2) mea n h u ma n b o d y wei g ht of 7 0  k g a n d l u n g wei g ht of 1  k g; 
3) N O A E L i n r ats a n d  d o gs f oll o wi n g 4 -wee k t o xic ol o g y st u dies ( Secti o n 4 I B).  
T he calc ulati o n of s yst e mic e x p os ure safet y mar gi ns is base d o n t he m o del pre dicte d 
s yste mic e x p os ure i n h u ma ns f or t he gi ve n d oses of G S K 3 9 2 3 8 6 8 , a n d t he t o xic ol o g y 
st u dies f oll o wi n g I V a n d I H i n rats a n d I H i n d o gs.  
Ta ble 4  bel o w s h o ws t he l u n g de p ositi o n a n d s yste mic e x p os ure safet y mar gi ns.  
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Table 4 
Predicted GSK3923868 systemic PK parameters and safety coverage 
in lung and systemic following single doses of GSK3923868 
Propose
d daily 
dose to 
humans 
(µg) 
Human 
deposite
d lung 
dose a 
(µg/g) 
Predicted 
human 
AUC 
(ng.h/mL
) 
Predicte
d human 
Cmax 
(ng/mL) 
Ratio of 
animal:huma
n deposited 
lung dose 
Ratio of 
animal:human 
AUC 
Ratio of 
animal:human 
Cmax 
Rat b 
Dog c 
Rat 
Do
g 
Rat 
Do
g 
IH d 
IV e 
IH f 
IH 
g 
IV h 
IH i 
50 
0.05 
0.19 
0.24 
312 
386 
19
8 
312
1 
889 
7
5 
239
6 
280 
100 
0.1 
0.38 
0.48 
156 
193 
99 
156
1 
445 
3
7 
119
8 
140 
250 
0.25 
0.95 
1.2 
62 
77 
40 
624 
178 
1
5 
479 
56 
500 
0.5 
1.9 
2.4 
31 
39 
20 
312 
89 
7 
240 
28 
1000 
1 
3.8 
4.8 
16 
19 
10 
156 
44 
4 
120 
14 
3000 
3 
11.4 
14.4 
5 
6 
3 
52 
15 
1 
40 
5 
Key: 
IH = Inhaled, IV = Intravenous. 
a = assuming lung weight of 1000 g and 100% of inhaled dose is deposited in lungs. 
b = actual mean body weight of 0.328 kg, actual mean lung weight of 1.305 g and assuming 10% of inhaled dose is 
deposited in lungs.  NOAEL = 620 µg/kg/week. 
c = actual mean body weight of 9.07 kg, actual mean lung weight of 96.9 g and assuming 25% of inhaled dose is 
deposited in lungs.  NOAEL = 826 µg/kg/week. 
d = gender-average AUC on Day 28 of 4-week inhalation toxicity study at NOAEL = 37.7 ng.h/mL. 
e = gender-average AUC on Day 29 of 4-week intravenous toxicity study at NOAEL = 593 ng.h/mL. 
f = gender-average AUC on Day 28 of 4-week inhalation toxicity study at NOAEL = 169 ng.h/mL. 
g = gender-average Cmax on Day 28 of 4-week inhalation toxicity study at NOAEL = 17.9 ng/mL. 
h = gender-average Cmax on Day 29 of 4-week intravenous toxicity study at NOAEL = 575 ng/mL. 
i = gender-average Cmax on Day 28 of 4-week inhalation toxicity study at NOAEL = 67.1 ng/mL. 
 
4.3.3. 
Predicted Target Engagement at Steady State 
Under the once daily dosing regimen, the steady state target engagement is predicted from 
the PBPK model and the PKPD model for a range of doses within the dose range proposed 
for this study (50-3000 mcg) as shown in Figure 1.  


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
4 6  
 
Si m ulati o ns s h o w t hat f oll o wi n g o nce dail y ( Q D ) d osi n g, t he pre dicte d tar get e n ga ge m e nt 
pr ofile reac h es stea d y state after a b o ut f o ur da ys of d osi n g. At stea d y state, t he pea k tar get 
e n ga ge me nt is 
 f or d ose of 3 0 0 0 mc g Q D, w hile at tr o u g h ( 2 4 h p ost d ose), t here is 
a b o ut  
tar get e n ga ge me nt wit h t his d ose re gi me n.  
Alt h o u g h t here is n o esta blis he d relati o ns hi p of h o w m uc h tar get e n ga ge m e nt is re q ui re d 
t o pr o vi de p ote ntial effi cac y i n H R V, a m uri ne pr o p h ylactic m o del of c o xsac kie vir us -
i n d uce d pa ncreatitis (a vir us t hat als o re plicates t hr o u g h PI 4 K B) s h o w e d t hat cli nical 
effic ac y m a y p ote ntiall y be ac hie ve d at a relati v el y l o wer le vel (a b o v e 5 0 %) of tar get 
e n ga ge me nt [G S K D oc u me nt N u m ber 2 0 1 9 N 4 1 9 5 0 1 _ 0 1 ]. It is a ntici pate d t he pr o p ose d 
d ose ra n ge i n t his st u d y will ac hie ve 5 0 % or greater PI 4 K B t ar get e n ga ge me nt.  
4. 4.  
E n d of St u d y D efi niti o n  
T he e n d of t he st u d y is defi ne d as t he d ate of t he last  visit of t he l ast partici p a nt i n t he st u d y . 
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if h e/s he has c o m plete d all p hases 
of t he st u d y i ncl u di n g t he last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of Acti vities.  
5.  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o 
k n o w n as pr ot oc ol wai v ers or e x e m pti o ns, is n ot per mitte d.  
C CI
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5.1. 
Inclusion Criteria: 
5.1.1. 
Inclusion Criteria: Parts A and B (Healthy Participants) 
Participants are eligible to be included in the study only if all of the following criteria apply: 
AGE 
1.  Between 18 and 50 years of age inclusive, at the time of signing the informed consent. 
 
TYPE OF PARTICIPANT 
2. Participants who are generally healthy as determined by medical evaluation based on 
screening medical history, physical examination, vital signs, ECG assessment, pulmonary 
function testing, laboratory tests and cardiac monitoring. 
• Note: Fully resolved childhood asthma is acceptable. 
• Note: A participant with a clinical abnormality or laboratory parameter(s) not 
specifically listed in the exclusion or exclusion criteria that is outside the reference 
range for the population being studied may be included only if the investigator, in 
consultation with the Medical Monitor (if required), agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures or outcomes. 
 
WEIGHT 
3. Body weight at least 50.0 kg (110 lbs) and body mass index (BMI) within the range 18.5 to 
32.0 kg/m2 (inclusive). 
 
SEX 
4. Males and female participants, as follows: 
• Male Participants: A male participant is eligible to participate if they agree to the 
following during the intervention period and for at least 10 days after the last dose 
of study intervention: 
o Refrain from donating sperm. 
o Plus either: 
▪ Be abstinent from heterosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and 
agree to remaining abstinent. 
OR 
▪ Must agree to use contraception as detailed below when having 
sexual intercourse with a woman of childbearing potential who is 
not currently pregnant: 
• Agree to use a male condom. 
• AND female partner to use an additional highly effective 
contraceptive method (see Appendix 4) with a failure rate 
of < 1 % per year.  The participant should also be 


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advised of the benefit for a female partner as a condom 
may break or leak. 
• Female Participants: A female participant is eligible to participate if she is not 
pregnant or breastfeeding and is a woman of non-childbearing potential 
(WONCBP) as defined in Appendix 4. 
 
INFORMED CONSENT 
5. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
 
5.1.2. 
Inclusion Criteria: Part C (Participants with Asthma) 
AGE 
1.  Between 18 and 65 years of age inclusive, at the time of signing the informed consent. 
• Note: Participants over the age of 50 will need to provide proof of completed 
COVID-19 vaccination to be eligible to participate. 
 
TYPE OF PARTICIPANT 
2. Participants who are otherwise healthy (other than the acceptable condition of asthma and 
other mild atopic diseases, including allergic rhinitis and atopic dermatitis) as determined 
by medical evaluation based on screening medical history, physical examination, vital 
signs, ECG assessment, pulmonary function testing, laboratory tests and cardiac 
monitoring. 
• Note: A participant with a clinical abnormality or laboratory parameter(s) not 
specifically listed in the exclusion or exclusion criteria that is outside the reference 
range for the population being studied may be included only if the investigator, in 
consultation with the Medical Monitor (if required), agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.   
3. A current confirmed physician diagnosis of asthma (as defined by the British Thoracic 
Society/ Scottish Intercollegiate Guidelines Network (BTS/SIGN, 2019), or the Global 
Initiative for Asthma (GINA, 2020 guidelines)) at least 6 months before screening.  The 
reason for diagnosis of asthma should be documented in the participant’s source data, 
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4. A screening pre-bronchodilator FEV1 ≥ 65% predicted normal value. 
Note: Predicted values based on European Respiratory Society (ERS) guidelines 
[Quanjer, 2012]. 
5. Participants with maintained control of their asthma using the permitted medications listed 
below, will be recruited as follows: 
 
Permitted Medication Use 
Number of Participants 
SABA use and/or intermittent ICS/LABA 
use. 
n=8 
Regular treatment with ICS or ICS/LABA 
(including use of Leukotriene Receptor 
Agonist (LTRA)) 
n=8 
 
 
WEIGHT 
6. Body weight at least 50.0 kg (110 lbs) and body mass index (BMI) within the range 18.5 to 
32.0 kg/m2 (inclusive). 
 
SEX 
7. Males and female participants: 
• Male Participants: A male participant is eligible to participate if they agree to the 
following during the intervention period and for at least 10 days after the last dose 
of study intervention: 
o Refrain from donating sperm. 
o Plus either: 
▪ Be abstinent from heterosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and 
agree to remaining abstinent. 
OR 
▪ Must agree to use contraception as detailed below when having 
sexual intercourse with a woman of childbearing potential who is 
not currently pregnant: 
• Agree to use a male condom. 
• AND female partner to use an additional highly effective 
contraceptive method (see Appendix 4) with a failure rate 
of < 1 % per year.  The participant should also be 
advised of the benefit for a female partner as a condom 
may break or leak. 
• Female Participants: A female participant is eligible to participate if she is not 
pregnant or breastfeeding and is a woman of non-childbearing potential 
(WONCBP) as defined in Appendix 4 
 


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INFORMED CONSENT 
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
5.2.1. 
Exclusion Criteria: Parts A and B (Healthy Participants) 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the study 
intervention or interfering with the interpretation of data. 
2. Alanine transaminase (ALT) and Aspartate Aminotransferase (AST) above upper limit of 
normal (ULN)1. 
3. Total Bilirubin above ULN (isolated bilirubin above ULN is acceptable if total bilirubin is 
fractionated and direct bilirubin <35%)1. 
4. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with 
the exception of Gilbert's syndrome or asymptomatic gallstones). 
5. QTcF > 450 msec at screening visit based on the average of triplicate ECGs. 
6. Screening ECG measurements meets the following criteria for exclusion: 
Parameter 
Males 
Females 
Heart Rate 
< 45 or > 100 bpm 
< 50 or > 100 bpm 
PR Interval 
< 120 or > 220 msec 
QRS duration 
< 70 or > 120 msec 
QTcF 
> 450 msec 
• Note: A heart rate from 100 to 110 bpm can be rechecked by ECG or vital signs 
within 30 minutes to verify eligibility. 
7. Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of 
long QT syndrome. 
8. Evidence of previous myocardial infarction (does not include ST segment changes 
associated with re-polarization). 
9. Signs and symptoms suggestive of COVID-19. 
• Note: Assessments will be performed in accordance with local site procedure. 
 
1 May be repeated once before first dose. 
 
 
 


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PRIOR/CONCOMITANT THERAPY 
10. Past or intended use of over-the-counter or prescription medication, including vitamins, 
herbal and dietary supplements (including St John’s Wort) within 7 days before the first 
dose of study intervention, unless in the opinion of the Investigator and the GSK Medical 
Monitor, the medication will not interfere with the study procedures or compromise 
participant safety. 
• Note: Use of paracetamol or acetaminophen, at doses ≤ 2 g/day and/or use of 
simple analgesics is acceptable. 
 
PRIOR/CONCOMITANT CLINICAL STUDY EXPERIENCE 
11. Participation in this study would result in loss of blood or blood products in excess of 500 
mL within 56 days. 
12. Exposure to more than 4 new chemical entities within 12 months before the first dosing 
day. 
13. Current enrolment or past participation in a clinical trial and has received an investigational 
product within the following time 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).  
 


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DIAGNOSTIC ASSESSMENTS 
14. FEV1 and FVC < 80% predicted normal value. 
• Note: Predicted values based on European Respiratory Society (ERS) guidelines 
[Quanjer, 2012]. 
15. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to 
first dose of study intervention. 
16. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose 
of study intervention.  
• Note:  Subjects with positive hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained 
17. Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of 
study intervention. 
• Note: Test is optional and subjects with negative hepatitis C antibody test are not 
required to also undergo hepatitis C RNA testing 
18. Positive pre-study drug/alcohol screen. 
19. Positive human immunodeficiency virus (HIV) antibody test. 
20. Positive test for COVID-19 infection. 
• Note: Testing will be according to site procedures. 
21. Current or history of drug abuse. 
22. Any conduction abnormality (including but not specific to left or right complete bundle 
branch block, AV block [2nd degree or higher], Wolff-Parkinson-White (WPW) syndrome). 
23. Sinus Pauses > 3 seconds. 
24. Any significant arrhythmia which, in the opinion of the Investigator or GSK Medical 
monitor, will interfere with the safety for the individual participant. 
25. Non-sustained or sustained ventricular tachycardia (with more than 3 consecutive 
ventricular ectopic beats). 
 


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OTHER EXCLUSIONS 
26. Regular alcohol consumption within 6 months prior to the study defined as: 
• An average weekly intake of > 14 units for both males and females.  
• One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass 
(125 mL) of wine or 1 (25 mL) measure of spirits. 
27. Current or previous use of tobacco- or nicotine-containing products (e.g. cigarettes, 
nicotine patches or electronic devices) within 6 months before screening and/or have a 
smoking pack history of > 5 pack years. 
• Note: 1 pack year = 20 cigarettes per day for 1 year or 5 cigarettes per day for 4 
years. 
28. Positive breath carbon monoxide test indicative of recent smoking at screening or each in-
house admission to the clinical research unit. 
29. Sensitivity to any of the study interventions, or components thereof (including lactose and 
magnesium stearate (MgSt)), or drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates participation in the study. 
30. Participants with known COVID-19 positive contacts in the past 14 days. 
 


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5.2.2. 
Exclusion Criteria: Part C (Participants with Asthma) 
MEDICAL CONDITIONS 
1. Any asthma exacerbation requiring systemic corticosteroids within 8 weeks of screening, 
or that resulted in overnight hospitalization requiring additional treatment for asthma within 
3 months of screening. 
2. A history of life-threatening asthma, defined as an any asthma episode that required 
admission to a high-dependency or intensive therapy unit. 
3. Significant pulmonary diseases, other than asthma, including (but not limited to): 
pneumonia previously requiring hospital admission, bronchiectasis, pulmonary fibrosis, 
bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive 
pulmonary disease, or other significant respiratory abnormalities. 
4. ALT and AST above upper limit of normal (ULN)1  
5. Bilirubin above ULN (isolated bilirubin above x ULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%)1. 
6. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with 
the exception of Gilbert's syndrome or asymptomatic gallstones). 
7. QTcF > 450 msec at screening visit based on the average of triplicate ECGs. 
8. Signs and symptoms suggestive of COVID-19. 
• Note: Assessments will be performed in accordance with local site procedure. 
 
1 May be repeated once before first dose. 
 
PRIOR/CONCOMITANT THERAPY 
9. Past or intended use of over-the-counter or prescription medication, including vitamins, 
herbal and dietary supplements (including St John’s Wort) within 7 days before the first 
dose of study intervention, unless in the opinion of the Investigator and the GSK Medical 
Monitor, the medication will not interfere with the study procedures or compromise 
participant safety. 
• Note: Use of SABA, ICS and low dose ICS/LABA and LTRA is permitted for 
control of Asthma, and use of paracetamol or acetaminophen, at doses ≤ 2 g/day 
and/or simple analgesics is acceptable. 
 
PRIOR/CONCOMITANT CLINICAL STUDY EXPERIENCE 
10. Participation in this study would result in loss of blood or blood products in excess of 500 
mL within 56 days. 
11. Exposure to more than 4 new chemical entities within 12 months before the first dosing 
day. 
12. Current enrolment or past participation in a clinical trial and has received an investigational 
product within the following time 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). 
 
 


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DIAGNOSTIC ASSESSMENTS 
13. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to 
first dose of study intervention. 
14. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose 
of study intervention.  
• Note:  Subjects with positive hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained. 
15. Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of 
study intervention. 
• Note: Test is optional and subjects with negative hepatitis C antibody test are not 
required to also undergo hepatitis C RNA testing. 
16. Positive pre-study drug/alcohol screen. 
17. Positive human immunodeficiency virus (HIV) antibody test. 
18. Positive test for COVID-19 infection. 
• Note: Testing will be according to site procedures. 
19. Current or history of drug abuse. 
 
OTHER EXCLUSIONS 
20. Regular alcohol consumption within 6 months prior to the study defined as: 
• An average weekly intake of > 14 units for males and females.  
• One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass 
(125 mL) of wine or 1 (25 mL) measure of spirits. 
21. Current or previous use of tobacco- or nicotine-containing products (e.g. cigarettes, 
nicotine patches or electronic devices) within 6 months before screening and/or have a 
smoking pack history of > 5 pack years. 
• Note: 1 pack year = 20 cigarettes per day for 1 year or 5 cigarettes per day for 4 
years. 
22. Positive breath carbon monoxide test indicative of recent smoking at screening or each in-
house admission to the clinical research unit. 
23. Sensitivity to any of the study interventions, or components thereof (including lactose and 
magnesium stearate (MgSt)), or drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates participation in the study. 
24. Participants with known COVID-19 positive contacts in the past 14 days. 
 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids from 7 days before the start of study 
intervention until discharge from the unit.  


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• No water is allowed until 2 hours after dosing, water is allowed ad libitum at all 
other times.  
• Participants must fast overnight until 2 hours after each dose. 
 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, cola drinks, and chocolate) for 12 hours 
before the start of dosing until after collection of the final pharmacokinetic (PK) 
sample. 
• During each dosing session, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample.  
• Participants who use tobacco or nicotine-containing products are not eligible for this 
study, See Section 5.2. 
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. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, any protocol deviations and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once. 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. 
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. 


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6.1. 
Study Intervention(s) Administered 
ARM Name 
Cohort 1 
Cohort 2 
Cohort 3,4 
Cohort 5 
Cohorts 1-5 
Intervention 
Name 
GSK3923868 
Capsules for 
Inhalation 
GSK3923868 
Capsules for 
Inhalation 
 
GSK3923868 
Capsules for 
Inhalation 
 
GSK3923868 
Capsules for 
Inhalation 
 
Placebo to 
match  
GSK3923868 
Capsules for 
Inhalation 
Type  
Drug 
Drug 
Drug 
Drug 
Placebo  
Dose 
Formulation  
Capsule 
containing 
Inhalation 
powder blend 
Delivered via 
Monodose RS01 
device 
Capsule 
containing 
Inhalation 
powder blend 
Delivered via 
Monodose RS01 
device 
Capsule 
containing 
Inhalation 
powder blend 
Delivered via 
Monodose RS01 
device 
Capsule 
containing 
Inhalation 
powder blend 
Delivered via 
Monodose RS01 
device 
Capsule 
containing 
Inhalation 
powder blend 
Delivered via 
Monodose RS01 
device 
Unit Dose 
Strength(s)  
50 mcg 
500 mcg 
500 mcg 
500 mcg 
N/A 
Dosage 
Level(s)1 
50 mcg: one 
capsule, single 
dose 
100 mcg: two 
capsules, single 
dose 
250 mcg: five 
capsules, single 
dose 
500 mcg: one 
capsule, single 
dose 
1000 mcg: two 
capsules, single 
dose 
3000 mcg: six 
capsules, single 
dose 
Planned dose:  
3000 mcg: six 
capsules, daily 
for 14 days 
Planned dose:  
3000 mcg: six 
capsules, daily 
for 7 days 
Number of 
capsules to 
match active 
treatment  
Route of 
Administration 
Inhalation 
Inhalation 
Inhalation 
Inhalation 
Inhalation 
Use 
Experimental 
Experimental 
Experimental 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 


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ARM Name 
Cohort 1 
Cohort 2 
Cohort 3,4 
Cohort 5 
Cohorts 1-5 
Packaging and 
Labelling 
 
Study 
Intervention will 
be provided in a 
HDPE (high 
density 
polyethylene) 
bottles. 
Each bottle 
contains 21 
capsules and 
one 8 g 20%RH 
maintaining 
desiccant 
sachet. 
Each bottle will 
be labelled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
HDPE bottles.   
Each bottle 
contains 32 
capsules and 
one 8 g 20%RH 
maintaining 
desiccant 
sachet. 
Each bottle will 
be labelled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
HDPE bottles. 
Each bottle 
contains 32 
capsules and 
one 8 g 20%RH 
maintaining 
desiccant 
sachet. 
Each bottle will 
be labelled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
HDPE bottles. 
Each bottle 
contains 32 
capsules and 
one 8 g 20%RH 
maintaining 
desiccant 
sachet. 
Each bottle will 
be labelled as 
required per 
country 
requirement. 
Study Placebo 
will be provided 
in HDPE bottles.   
Each bottle 
contains 32 
capsules and 
one 8 g 20%RH 
maintaining 
desiccant 
sachet. 
Each bottle will 
be labelled as 
required per 
country 
requirement. 
Current Name 
N/A 
N/A 
N/A 
N/A 
N/A 
1 Any unplanned doses of GSK3923868 will be administered using combinations of 50 and 500 mcg capsules as 
necessary. 


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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 the Monodose RS01 (manufacturer 
Plastiape S.p.A)  
• Instructions for medical device use are provided in the Study Reference Manual 
(SRM). 
• All device deficiencies, (including malfunction, use error and inadequate labelling) 
shall be documented, and reported by the Investigator throughout the clinical 
investigation (see Section 8.2.7) and appropriately managed by the Sponsor. 
6.2. 
Preparation/Handling/Storage/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. 
• Capsules should be kept in their primary packaging until dispensing into participant 
dosing bottles. 
• Monodose RS01 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 SRM.  
• Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the Monitor, Medical Monitor and/or 
GSK Study Delivery Lead. 
• A Safety Data Sheet (SDS)/equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, 
where this is required by local laws, or is available upon request from GSK. 
• Precaution will be taken to avoid direct contact with the study intervention.  A 
Safety Data Sheet (SDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator. In the case of 


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unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
6.2.1. 
Dosing Procedure 
Please refer to the SRM for dosing procedure. 
6.2.2. 
Treatment Compliance 
Full details of treatment compliance will be provided in the SRM. 
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. In Part A (Cohorts 1 and 2), Part B 
(Cohorts 3 and 4) and Part C (Cohort 5) participants will be randomized in a 3:1 ratio to 
receive study treatment (active drug: placebo).  
This will be a double-blind study with participants and the site staff blinded. The site 
pharmacy will be unblinded. For dose escalation, the Sponsor study team physicians, 
statisticians, clinical safety and clinical pharmacokinetic staff and/or their delegates will 
have access to unblinded data, if necessary. Other Sponsor staff will remain blinded unless 
unblinding becomes necessary.  
Once each cohort is complete, selected members of the sponsor staff may have access to 
unblinded PK and safety data for the given cohort, to enable the PK analysis and modelling 
and to support the planning of future studies.   
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 if the participant’s treatment code is unblinded by the 
Investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF. 


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GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
6.4. 
Study Intervention Compliance 
• When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• When participants are dosed at the site, they will receive study intervention directly 
from the Investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering 
the study intervention.   
• A record of the quantity of GSK3923868 dispensed to and administered to 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 
As this is a first time in human study, doses may be modified on the basis of emerging 
safety, tolerability and PK data.  The dose escalation committee (DEC) will be responsible 
for dose selection and/or modification.  See Section 10.1.5 for more information on the 
committee structure. 
Specific PK criteria are outlined in Section 6.5.1 and dose escalation stopping criteria are 
outlined in Section 6.5.2. 
6.5.1. 
Pharmacokinetic Criteria for Dose Modification 
This protocol allows some alteration from the currently outlined dosing schedule, however 
in this study the maximum total daily dose will not exceed 3000 g GSK3923868 and the 
maximum daily exposure of GSK3923868 is not intended to exceed the gender averaged 
steady-state exposure at the NOAEL in the 4-week rat intravenous  toxicology study 
(AUC(0-24h) 593 ng.h/mL; Cmax 575 ng/mL).  See Section 4.3 for further details. 
The following dose modification and PK stopping criteria will be used: 
• 
If exposure in a participant is predicted to reach 593 ng.h/mL for AUC(0-24h) and/or 
575 ng/mL for Cmax, the dose for next cohort will be modified. 
• 
If exposure in a participant reaches 593 ng.h/mL for AUC(0-24h) and/or 575 ng/mL for 
Cmax, the dose escalation will be paused, and no further participants will be dosed at 
that level or at any higher dose level. 


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6.5.2. 
Dose Escalation Stopping Criteria 
Further dosing at the current dose level stops and that dose and no higher dose may be used 
if any of the following occur: 
• Any 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. 
• Three participants meet liver chemistry stopping criteria outlined in Section 7.2.3. 
• Three participants meet QTc stopping criteria outlined in Section 7.2.4. 
• Three participants meet spirometry stopping criteria outlined in Section 7.2.5. 
• Three participants experience any adverse event considered clinically important by 
the Investigator. 
6.6. 
Treatment of Overdose 
For this study, any dose of GSK3923868 greater than the planned nominal dose for the 
treatment period or cohort within a 24-hour time period up to minus 1 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 (or the 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 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. 
6.7. 
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 


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• 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 the 
acceptability of concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) within 7 days before the 
first dose of study intervention until completion of the follow-up visit, unless, in the 
opinion of the Investigator and Medical Monitor, the medication will not interfere with the 
study procedures or compromise participant safety.  
Paracetamol/Acetaminophen, at doses of  2 grams/day, and/or use of simple analgesics is 
permitted for use any time during the study. Other concomitant medication may be 
considered on a case-by-case basis by the Investigator in consultation with the Medical 
Monitor. 
In Part C, depending on asthma severity participants will also be permitted to use SABA, 
ICS, ICS/LABA or LTRA to control their asthma.   
GSK3923868 is not expected to perpetrate a drug-drug interaction (DDI) on the 
pharmacokinetics of these therapies; GSK3923868 is considered to pose a low risk of a 
systemic DDI with substrates of CYP3A4, OATP1B1 or MATE1. Montelukast is 
metabolised by CYP2C8. Currently there is no information on whether GSK3923868 is an 
inhibitor of CYP2C8, however, from the montelukast SPC coadministration of gemfibrozil 
(a strong CYP2C8 inhibitor) with montelukast (a sensitive CYP2C8 substrate) does not 
result in a clinically relevant DDI and dose adjustment is not recommended.  
GSK3923868 is not expected to be a victim to a DDI with these therapies as they are not 
clinically relevant inhibitors/inducers of CYP450 or inhibitors of drug transporters. 
6.7.1. 
Rescue Medicine 
For asthmatics in Part C of this study SABA (e.g. salbutamol) 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. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will be 
withdrawn from the study and will be asked to complete study discharge procedures as 
described listed in Section 7.3. 
7.2. 
Stopping Criteria 
7.2.1. 
Study Stopping Criteria 
If one or more of the following criteria are met, the study will be temporarily paused, and 
all available safety data will be reviewed by the Sponsor and Investigator: 
• A SAE occurring in 1 or more participants receiving GSK3923868 that is 
considered at least possibly related to the study drug; 
• Two or more severe AEs occurring in a group of participants receiving 
GSK3923868 that are 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. 
7.2.2. 
Pharmacokinetic Stopping Criteria 
This protocol allows some alteration from the currently outlined dosing schedule, please 
refer to Section 6.5. 
7.2.3. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event aetiology. 
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.  


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Figure 2 
Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm 
 
 
Abbreviations: ALT = alanine transaminase; AST = aspartate transaminase; INR = international normalized 
ratio; SAE = serious adverse event; ULN = upper limit of normal. 
7.2.4. 
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 
Baseline QTcF will be based on the average of 3 predose ECGs collected on Day 1 (in Part 
A, Day 1 predose for each treatment period should be considered as baseline). 
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. 


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7.2.5. 
Spirometry Stopping Criteria 
Any participant experiencing a reduction in FEV1 at the 1-hour post-dose time point 
compared to daily predose value of > 25% in Parts A and B and > 20% in Part C will be 
withdrawn from the study. 
7.2.6. 
Asthma Exacerbation Stopping Criteria (Part C Only) 
Any participant experiencing an exacerbation of asthma must be withdrawn from the study.  
An asthma exacerbation is defined as follows: 
• Episodes characterised by a progressive increase in symptoms of shortness of 
breath, cough, wheezing or chest tightness and progressive decrease in lung 
function1, i.e. they represent a change from the patient’s usual status that is 
sufficient to require a change in treatment [GINA, 2020]. 
• 
1A progressive decrease in lung function is defined as sustained drop in PEF of > 
20 % from baseline (Day 1, predose) maintained for ≥ 3 days.  In the absence of 
PEF 
measurements, 
Investigator 
judgement 
will 
be 
applied. 
 
7.2.7. 
Temporary Discontinuation 
Participant withdrawn from the study treatment will be withdrawn from the study. 
7.2.8. 
Rechallenge 
Study intervention restart or rechallenge after stopping criteria are met by any participant 
in this study is not allowed. 
7.3. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, or compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, the procedures outlined in 
the SOA on the day of discharge from the clinical unit should be completed (i.e. 
Days 2, 3, 18 and 8 for Parts A Cohort 1, A Cohort 2, B and C respectively). 
• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a withdrawal 
of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records. 
• If participants prematurely discontinue in the study, they may be replaced at the 
discretion of the Medical Monitor in consultation with the Principal Investigator.  


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In Part A, the replacement participant will be assigned to the same treatment 
sequence and may start the treatment period where the last participant prematurely 
discontinued.  In Parts B and C participants will be assigned to same treatment as 
the participant prematurely discontinued. 
7.4. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 
1. 
7.5. 
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 Part A (SAD portion of the study), 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 Part B and C (Repeat dose of the study in HV and asthma patients), study 
treatment should be halted for any participants who develop a high clinical index 
of suspicion for COVID-19 disease; they should be isolated and tested for COVID-
19 in accordance with site procedures. 
• 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 


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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 8 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 time frame defined in the SoA. 
• Individual PK data that could unblind the study will not be reported to investigative 
sites 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 8. 
8.1. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.1.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
skin, eyes, cardiovascular, respiratory, gastrointestinal and neurological systems.  
• Height (at screening only) and weight will also be measured and recorded.  BMI 
will be calculated. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
6 9  
 
•  I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relat e d t o pre vi o us 
seri o us ill nesses. 
•  Refer t o t he S R M f or f urt her i nf or mati o n.  
8. 1. 2.  
V it al Si g n s 
•  Vital si g ns will be me as ure d i n se mi -s u pi ne p ositi o n after at least 1 0  mi n utes rest 
a n d will i ncl u de s yst olic a n d diast olic bl o o d press ure , heart rate, res pirat or y rate 
a n d t y m pa ni c te m perat ur e. 
•  Bl o o d press ur e a n d p ulse meas ure m e nts will be assesse d  wit h a  c o m pletel y 
a ut o mate d de vi ce. M a n u al tec h ni q ues will be use d o nl y if a n a ut o mate d d e vice is 
n ot a vaila ble.  
•  Refer t o t he S R M f or f urt her i nf or mati o n.  
8. 1. 3.  
El e ctr o c ar di o gr a m s  
8. 1. 3. 2.  
1 2 -L e a d S af et y E C G s  
•  Safet y E C Gs will be perf or me d i n se mi -s u pi ne p ositio n after at least 1 0 mi n utes 
rest. 
•  All safet y E C Gs m ust be o btai ne d usi n g a n E C G mac hi ne t hat a ut o maticall y 
calc ulates t he h eart rate a n d meas ures, P R, Q R S, Q T a n d Q T c F i nter vals. 
•  Safet y E C Gs will be pri nte d a n d i nter prete d o n -site b y t h e I n v esti gat or t o ens ure 
partici pa nt safet y.  Safet y 
E C Gs 
ma y als o be pri nte d fr o m t he Gl o bal 
I nstr u me ntati o n ( Ma nli us, N Y, U S A) 
M 1 2 R E C G c o nti n u o us 1 2 lea d di gital 
rec or der use d f or c o nti n u o us car diac m o nit ori n g (see Secti o n 8. 1. 3. 4 ). At ti me 
p oi nts w here tri plicate E C Gs are re q uir e d, t he E C Gs will be o btai ne d at least 2 
mi n utes a part a n d o ver a rec or di n g p eri o d of u p t o 1 0 mi n utes.  
•  Baseli ne Q Tc F will be base d o n t he a vera ge of 3 pre d ose E C Gs c ollecte d o n Da y 1 
(i n Part A, Da y 1 pre d ose f or eac h treat me nt peri o d s h o ul d be c o nsi dere d as 
baseli ne).  
•  Refer t o Secti o n 7. 2. 4  f or Q Tc s pecifi c st o p pi n g criteria. 
•  Refer t o t he S R M f or f urt her i nf or mati o n.  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
7 0  
 
8. 1. 3. 3.  
T el e m etr y M o nit ori n g  
•  I n a d diti o n t o 1 2-lea d safet y E C Gs, partici pa nts will be m o nit ore d o n tele metr y f or 
eac h tr eat me nt peri o d i n Part A a n d f or t h e first d ose i n Parts B a n d C.  
8. 1. 4.  
L u n g F u n cti o n  
•  Pea k E x pirat or y F l o w ( P E F) ( Part C o nl y) a n d s pir o metr y assess me nts will be 
perf or me d as o utli ne d i n t he S R M.  
8. 1. 5.  
Cli ni c al  S af et y L a b or at or y A s s e s s m e nt s  
•  See  A p pe n di x 2  f or t he list of cli nical la b orat or y tests t o be perf or m e d a n d t o t he 
S o A f or t he ti mi n g a n d fre q ue nc y.  
•  T he In v esti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d 
rec or d a n y cli nicall y si g nifica nt c ha n ges o cc urri n g d uri n g t he st u d y as a n A E. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts.  
C CI


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• In Part C, 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 aetiology 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 SRM 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 may be recorded in the eCRF. 
8.1.6. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• If a pregnancy is reported then the Investigator should inform GSK within 2 weeks 
of learning of pregnancy and should follow the procedures outlined in Section 8.2.5. 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the Investigator or as required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the study. 
8.2. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AE or SAEs can be found in Section 10.3. 
The definitions of device-related safety events, (adverse device effects [ADEs] and serious 
adverse device effects [SADEs]), can be found in Section 10.6.  Device deficiencies are 
covered in Section 10.6. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up. 
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. 


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8.2.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• All SAEs will be collected from the start of screening until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
• All AEs will be collected from the start of intervention until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as Medical History/Current Medical Conditions not 
as AEs. 
• All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the Investigator must promptly notify the Sponsor. 
8.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.4). Further information on follow-up procedures is given in Appendix 3. 
8.2.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
• An Investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
Sponsor will review and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 


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• Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and Sponsor 
policy and forwarded to Investigators as necessary 
8.2.5. 
Pregnancy 
• This study will recruit only female participants meeting the criteria of a woman of non-
childbearing potential, so pregnancies are not expected.  However, if a pregnancy does 
occur then procedure outlined here should be followed. 
• 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 
after the final dose.  
• Follow up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of the foetal status 
(presence or absence of anomalies) or indication for procedure. 
• 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, foetal 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 
8.2.4. 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 
discontinue study intervention or be withdrawn from the study. 
8.2.6. 
Cardiovascular and Death Events 
The requirements outlined in this section do not apply to healthy participants in Parts A 
and B. 
For Part C, any cardiovascular (CV) events detailed in Appendix 3 Section 10.3.3 and all 
deaths, whether or not they are considered SAEs, specific Cardiovascular and Death 


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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. 
8.2.7. 
Medical Device Deficiencies 
Medical devices are 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 
devices.  
The definition of a Medical Device Deficiency can be found in Section 10.6. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 10.3 of the protocol.  
8.2.7.1. 
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 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 Incidents is provided in Section 10.6. 
8.2.7.2. 
Follow-up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those who discontinue study 
intervention or the study. 
• 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. 
8.2.7.3. 
Prompt Reporting of Medical Device Deficiencies to 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. 


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•  T he Me dic al De vic e D eficie nc y  Re p ort F or m will be se nt t o t h e s p o ns or b y facsi mile 
tra ns missi o n. If facsi mile tra ns missi o n is u na vaila ble, t he n n otificati o n b y t ele p h o ne is 
acce pta ble f or i nci d e nts, wit h a c o p y of t he " M e dical De vice I nci de nt Re p ort F or m" 
se nt b y o v er ni g ht mail.    
•  T he S p o ns or  will be t he c o ntact f or t h e recei pt of de vice deficie nc y re p orts. 
8. 2. 7. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or M e di c al D e vi c e I n ci d e nt s  
•  T he In v esti gat or will pr o m ptl y re p ort all defici e nc ies occ urri n g wit h a n y me dical 
de vice pr o vi de d f or use i n t he st u d y i n or der f or t he S p o ns or t o f ulfil t he le gal 
res p o nsi bilit y t o n otif y a ppr o priate re g ulat or y a ut h orities a n d ot her e ntities a b o ut 
certai n safet y i nf or mati o n relati n g t o me di cal de vi ces bei n g use d i n cli nical st u dies.  
•  T he I n vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire me nts (e. g., t he hea d 
of t he 
me dical i nstit ut i o n), 
will c o m pl y 
wit h t he a p plica bl e l ocal re g ulat or y 
re q uire me nts r elati n g t o t he re p orti n g of d e vice d eficie ncies t o t he I R B/I E C. 
8. 3.  
P h ar m a c o ki n eti c s  
8. 3. 1.  
Pl a s m a S a m pl e  C oll e cti o n  
Plas ma sa m ples 
will be c ollecte d f or 
meas ure me nt of plas ma c o nce ntrati o ns of 
G S K 3 9 2 3 8 6 8  as s pecifi e d i n t he S o A  ( Secti o n 1. 3 ). Detai ls of s a m ple c ollecti o n will be 
pr o vi de d i n t he S R M.   
•  A ma xi m u m of  2  sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts d uri n g t he 
st u d y if warra nte d a n d a gree d u p o n bet w ee n t he In vest i gat or a n d t h e S p o ns or. T he 
ti mi n g of plas ma P K sa m ples ma y be altere d d uri n g t he c o urse of t he st u d y bas e d 
o n ne wl y a vaila ble d ata (e. g., t o o btai n data cl oser t o t he ti me of pea k plas ma 
c o nce ntr ati o ns  or l o n ger t ha n 2 4-h o ur p ost d ose ) t o e ns ure a p pr o priate m o nit ori n g 
a n d c haracterisati o n of G S K 3 9 2 3 8 6 8 plas ma P K pr ofile.  
•  I nstr u cti o ns f or t h e c ollecti o n a n d ha n dli n g of bi ol o gical s a m ples will be pr o vi de d 
b y t he S p o ns or. T he act u al date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will 
be rec or de d.  
•  Sa m ples c ollecte d f or a n al yses of G S K 3 9 2 3 8 6 8  plas ma c o nce ntr ati o n ma y als o be 
use d t o e val uate safet y or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after 
t he st u d y. 
•  Ge netic a nal ys es will n ot be perf or me d o n t hese plas ma  sa m ples. Partici pa nt 
c o nfi de ntial it y will be mai ntai ne d. I nter v e nti o n c o n ce ntrati o n i nf or mati o n t hat ma y 
u n bli n d t he st u d y will n ot be re p orte d t o i n vesti gati ve sites or bli n de d p ers o n nel 
u ntil t he st u d y h as bee n u n bli n de d.  
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8. 4.  
 G e n eti c s a n d/ or P h ar m a c o g e n o mi c s  
Ge netics are n ot e v al uate d i n t his st u d y.  
8. 5.  
Bi o m ar k er s  
Bi o mar kers are n ot e val u ate d i n t his st u d y.  
8. 6.  
I m m u n o g e ni cit y A s s e s s m e nt s 
I m m u n o ge nicit y is n ot e val uate d i n t his st u d y. 
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8.7. 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
Statistical analyses will be performed by, or under the direct auspices of, Biostatistics, 
GlaxoSmithKline. 
Reporting of study data will be performed in accordance with applicable GSK and/or 
contract research organization (CRO) standards. Complete details of the planned statistical 
analyses will be provided in the Statistical and Analysis Plan (SAP). 
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 
Given this study is the FTIH for GSK3923868, no formal statistical hypotheses will be 
tested. The primary objective is to evaluate the safety and tolerability of GSK3923868 in 
healthy participants and stable asthmatics. 
9.2. 
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, and thereby to 
allow progression to larger clinical studies.  
A minimum of 5 participants receiving each dose of active drug (either as a single or repeat 
dose) are required for the dose escalation meetings. With 5 participants, if the true adverse 
outcome rate is 5%, the chance of not observing any adverse events at a given dose is 77%. 
If the true adverse outcome rate is 20%, the chance of not observing any adverse events at 
a given dose level is 33%. 
For Part A, sufficient healthy adult participants will be screened to ensure a total of 12 
participants per cohort are randomised with the aim to achieve approximately 12 per cohort 
completed.   
In total for Part A, 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 not observing any adverse 
events at a given dose is 63%. If the true adverse outcome rate is 20%, the chance of not 
observing any adverse events at a given dose level is 13%.  
In Part B, sufficient healthy adult participants will be screened to ensure 8 participants are 
randomised to each of the two cohorts, with the aim to achieve approximately 8 completed 
in each cohort.   


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F or Part C, s ufficie nt partici pa nts wit h ast h ma will be scree ne d t o e ns ure 1 6 partici pa nts 
are ra n d o mise d, wit h t he ai m t o ac hie ve 1 6 c o m pleters.  Part C will be ra n d o mise d 
acc or di n g t o t w o str ata, S A B A a n d/ or i nter mitte nt i n hale d c ortic oster oi d (I C S)/l o n g -acti n g 
beta a g o nist ( L A B A) c o m bi nati o n  users a n d I C S or I C S/ L A B A users.  
I n Parts B a n d C, 1 2 partici pa nts are pla n ne d t o recei v e eac h d ose of acti ve dr u g. T h e 
c orres p o n di n g pr o ba bilities f or 1 2 parti ci pa nts wit h tr ue e ve nt rates of 5 % a n d 2 0 % are 
5 4 % a n d 7 %, res pecti vel y.  
T his le vel of pre dicti vit y is dee me d a de q u ate wit hi n t his p hase of de vel o p m e nt.  
 
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For Parts A, B and C if participants prematurely discontinue in the study, they will be 
replaced at the discretion of the sponsor Medical Monitor in consultation with the 
Principal Investigator.   
9.3. 
Analysis Sets 
 
Participant Analysis Set 
Description 
Screened 
All participants who were screened for eligibility.  
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. 
Randomized 
The randomized population will consist of all participants who 
were randomized. A participant who is recorded as a screen 
failure and was also randomized will be considered as 
randomized in error provided that they have not performed any 
study assessments.  
Safety 
All randomized participants who received at least 1 dose of study 
intervention. Participants will be analysed according to the 
treatment they received.  
Pharmacokinetic (PK) 
All randomized participants in the Safety population who had at 
least 1 non-missing PK assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
Participants will be analysed according to the treatment they 
received. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database release and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.4.1. 
Primary Endpoint(s) 
All safety analyses will be performed on the Safety Population and details will be provided 
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9.4.1.1. 
Adverse Events and Serious Adverse Events 
The proportion of participants reporting AEs will be tabulated by study intervention and 
by cohort and dose for participants on GSK3923868, except for Part B for which data from 
cohorts 3 and 4 will be combined (the cohorts are identical in every aspect apart from the 
timing of the bronchoscopy assessment). 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 by study intervention. 
9.4.1.2. 
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 randomisation 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 haematology, 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 and FVC 
9.4.2. 
Secondary Endpoint(s) 
All pharmacokinetic analyses will be performed on the Pharmacokinetic Population.  
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modelling and Simulation (CPMS) department within GlaxoSmithKline.  
Plasma GSK3923868 concentration-time data will be analysed 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: 


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•  Part A, C o h orts 1 & 2:  A U C( 0 -t), A U C( 0 -∞), C ma x a n d T ma x 
•  Part B, C o h orts 3 & 4: C ma x, T ma x  a n d A U C ( 0-) o n Da y 1 a n d Da y 1 4 ( = 2 4 h 
f or o nce a da y d osi n g re gi me n)  
•  Part C, C o h ort 5: C ma x, T ma x  a n d A U C( 0 -) o n Da y 1 a n d Da y 7 (= 2 4 h f or o nce 
a da y d osi n g re gi me n.   
If A U C(0 -) is n ot calc ul ata ble d ue t o n o n -q u a ntifi a ble plas ma G S K 3 9 2 3 8 6 8 data, A U C( 0 -
t’) ma y be calc ulate d i nstea d. t’ is t he c o m m o n ti mep oi nt  f or all s u bjects f or t he 
c orres p o n di n g d ose  or c o h ort . 
P har mac o ki netic d ata will be pres e nte d i n gra p hical a n d/ or ta b ular f or m a n d will be 
s u m marise d descri pti vel y. A nal ysis of d ose pr o p orti o nalit y ( Part A) a n d d ose acc u m ulati o n 
( Parts B a n d C) will be c o n d ucte d. A p o p ulati o n P K m o del ( P O P P K) ma y b e de vel o p e d 
wit h all a vaila ble data as a p pr o priate a n d ma y be re p orte d se paratel y. F urt h er details of t he 
a nal ysis pla n a n d met h o ds will be defi ne d wit hi n t he S A P . 
9. 5.  
I nt eri m A n al y s i s 
T here are n o f or mal i nteri m a nal yses c o n d u cte d as part of t his st u d y, h o we ver t he f oll o wi n g 
i n-strea m a nal ys es will be perf or me d. 
9. 5. 1.  
D o s e E s c al ati o n C o m mitt e e ( D E C)  
A re vi e w of preli mi nar y safet y , t olerabilit y  a n d pl as ma P K  d ata will b e c o n d ucte d b y t h e 
D E C  pri or t o eac h d os e le vel i n Part A , bef ore i nitiati n g re peat d osi n g i n Part B, a n d bef ore 
re peat d osi n g ast h matics i n Part C. 
Safet y  a n d t olera bilit y data will be pr o vi de d b y t h e site at t he e n d of eac h d osi n g sessi o n, 
al o n g wit h a n al ysis of t h e plas ma P K data w hic h will be perf or me d usi n g n o mi nal sa m pli n g 
ti mes. 
T o mi ni miz e t he ris k of u n bli n di n g d uri n g D E C meeti n gs, i n di vi d ual P K data will be 
scra m ble d s uc h t hat t he bli n d is mai ntai ne d.  S u m mar y statistics will als o be pr o vi de d f or 
plas ma P K para meters ( C ma x a n d A U C).  T he data ma y be u n bli n de d s h o ul d a safet y 
c o ncer n arise d uri n g t h e bli n de d re vie w . 
A d diti o nal details are a v aila ble i n t he D ose Escal ati o n Pla n . 
9. 5. 2.  
I n str e a m A n al y si s of P K D at a  
O nce C o h ort 3 has c o m plete d, selecte d me m bers of t he G S K s p o ns or staff tea m will be 
f or mall y u n bli n de d t o t he treat me nt all ocati o ns of partici pa nts w h o c o m plet e d t he st u d y  t o 
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enable the analysis and modelling of PK data to start. Once Cohort 4 has completed, the 
same sponsor staff will also be unblinded to the treatment allocations of the completed 
participants from Cohort 4 to incorporate their data into the ongoing PK analysis and 
modelling. Access to unblinded subject-level data will be restricted to members of the 
Statistics and Programming and Clinical Pharmacology Modelling and Simulation teams. 
The aim of this analysis is to inform internal decision making around dose selection for 
future studies in the development plan of this compound. This analysis will not impact the 
conduct or the design of the current study.  
 
 
 
 


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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: 
o Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
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 to the 
participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants will 
be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study centre.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days of their first dose. 
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 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 the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 


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10.1.5. 
Committees Structure 
10.1.5.1. 
Dose Escalation Committee 
As this study represents the first administration of GSK3923868 to humans, a dose 
escalation committee (DEC) will be responsible for reviewing all available safety, 
tolerability and PK data to determine progressing dose levels in Part A and before initiating 
repeat dosing in Parts B and C. 
The DEC will at a minimum consist of the following: 
• Principal Investigator (or suitably qualified delegate) 
• From GSK: 
o Medical Monitor 
o Clinical Pharmacology, Modelling and Simulation representative 
o Safety and Medical Governance representative 
o Statistician 
To minimise the risk of unblinding during DEC meetings, individual PK data will be 
scrambled such that the blind is maintained.  Summary statistics will also be provided for 
plasma PK parameters (Cmax and AUC).  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 and DEC 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 trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. Requests 
for access may be made through www.clinicalstudydatarequest.com. 
• GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 


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• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will be 
in accordance with GSK Policy. 
• GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. 
• 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 electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in the eCRF Completion 
Guidelines Document Veeva Vault Location. 
• Quality tolerance limits (QTLs) 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.  
• 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 final 
Clinical Study Report (CSR) / equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records 


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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. 
• Data reported 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 
Document Agreement (SDA) template as per SOP52563: provided by CRA to 
outline what will be regarded as source data per study.  SDA is finalised by CWM 
(on behalf of the PI) and CRA (on behalf of the sponsor) and stored in the SIF.  
• 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 
GSK or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but 
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For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract 
research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The investigator 
shall promptly inform the subject and should assure appropriate participant therapy 
and/or follow-up 
10.1.10. 
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 5 will be performed by the local and central labs.  
• 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 5 
Protocol Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
Urea 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose  
non-fasting 
Calcium2 
Alkaline 
phosphatase 
 
Coagulation 
Prothrombin time 
(PT) 
Activated partial 
thromboplastin 
time (aPTT) 
 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood, protein or leukocyte is abnormal) 
Pregnancy 
testing 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test. 


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Laboratory 
Assessments 
Parameters 
Other 
Screening 
Tests3 
• Follicle-stimulating hormone and oestradiol (as needed in women of non-
childbearing potential only). 
• Alcohol Breath Test 
• Breath Carbon Monoxide Test 
• Urine drug screen4 (to include at minimum: amphetamines, 
methamphetamine, barbiturates, cocaine, opiates, cannabinoids, 
benzodiazepines, methadone, phencyclidine and tricyclic 
antidepressants). 
• Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody). 
• COVID-19 testing will be in line with local 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 7.2.3 and Section 10.5 All events of ALT or AST 3 × upper limit of 
normal (ULN) and total bilirubin 2 × ULN (>35% direct bilirubin) or ALT or AST 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. 
Corrected Calcium 
3. 
The investigative site may assess other laboratory parameters as needed, according to standard site practice 
and results will be recorded in source documents. 
4. 
The investigative site may screen for additional drugs of abuse as part of standard site practice and will be 
recorded in source documents. The study eCRF will only collect drug screen results of those that are positive 
. 
 


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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 hospitalisation, or emergency room visit, or visit to/by a health care 
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 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 
participant will be collected during interview with the participants and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined local at the injection site 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. 


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• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected 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 which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
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 serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
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“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Possible Hy’s Law case: ALT or AST≥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 


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• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
 


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


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10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor 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 SRM. 
 


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10.4. 
Appendix 4: Contraceptive Guidance  
10.4.1. 
Definitions: 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
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 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 must discontinue 
HRT to allow confirmation of postmenopausal status before study enrolment. 
 
 
 
 
 
 
 
 


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10.4.2. 
Contraception Guidance: 
All male participants must agree to using a male condom when having sexual intercourse 
with a female partner of childbearing potential who is not currently pregnant 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 table 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 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview. 
Highly Effective Methodsb That Are User Dependent 
• Combined (oestrogen- 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 


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a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
 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. 


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event aetiology  
Phase 1 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria  
 
ALT or AST -
absolute 
 
ALT or AST ≥3xULN 
If ALT or AST ≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention 
 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver 
chemistries resolve, stabilise, or return to 
within baseline (see MONITORING below) 
MONITORING: 
If ALT or AST ≥3xULN AND bilirubin  
2xULN or INR >1.5 
• Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 24 h of  last 
dose4  
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 


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Liver Chemistry Stopping Criteria  
 
If ALT or AST ≥3xULN AND bilirubin < 
2xULN and INR ≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours 
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
 
If ALT or AST ≥3xULN AND bilirubin  
2xULN or INR >1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding 
week) [James, 2009]. NOTE: not 
required in China. 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that subject if ALT or AST  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 or AST  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT or AST  3xULN and 
INR>1.5, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving 
anticoagulants 
3. Includes: Hepatitis A immunoglobulin (gM) antibody; HBsAg and HBcAb; Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing) and Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and 
Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
 


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10.6. 
Appendix 6: 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 European Medical Device Regulation (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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10.6.1. 
Definition of Medical Device AE and ADE 
Medical Device AE and ADE Definition  
• 
An 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 unfavourable 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. 
• 
An adverse device effect (ADE) is 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. 
 
10.6.2. 
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 foetal distress, foetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product 
SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 


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• 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 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). 
 
10.6.3. 
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 information supplied by the manufacturer. 
10.6.4. 
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. 
• 
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 


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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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; both AEs and SAEs can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe. 
• 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 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB, 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 assess causality for every event before the 
initial transmission of the SAE data to GSK. 


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• The investigator may change his/her opinion of causality considering 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, if conducted. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.6.5. 
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. 
• 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/SAE coordinator by telephone. 
• Contacts for SAE reporting can be found in study reference manual (SRM). 
 


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SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE 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 SRM. 
10.6.6. 
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 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.  
• 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. 
• Contacts for SAE reporting can be found in SRM. 
 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
1 0 8  
 
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 0 9  
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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10.8. 
Appendix 8: Covid-19  
10.8.1. 
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. 
 
10.8.2. 
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. 
As outlined in Section 8, Protocol waivers or exemptions are not allowed and every effort 
should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up however when not possible, for the duration of these 
special circumstances, the following measures may be implemented for enrolled 
participants: 
• 
Clinical investigators should document in site files and in participant notes as 
appropriate how restrictions related to COVID-19 led to the changes in study conduct 
and duration of those changes and indicate which trial participants were impacted and 
how those trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance). 
• 
Missing protocol required data/visits due to COVID-19 should be noted in participant 
notes and recorded as a COVID-19 protocol deviation. 
 
10.8.3. 
Protocol Defined Procedures/Visits: 
• The protocol defined interval for the collection of samples during the Follow-up 
visit (see Section 1.3 Schedule of Activities), may be extended up to a maximum 
length of 14 days.  


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10.8.4. 
Data Management/Monitoring: 
• 
If a situation arises where on-site monitoring is no longer permitted, GSK will consider 
remote Source Data Verification/Source Document Review (SDV/SDR) where 
permitted by the clinical site/institution. Remote SDV/SDR will be proposed to study 
sites to meet a participant and/or critical quality need, e.g., to assess participant safety 
or to ensure data integrity. In case of remote SDV/SDR, GSK will work with the site 
to ensure participant privacy. 
• 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and consistent 
with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The PI may 
sign/re-sign the eCRF from any computer/location by accessing InForm (or other eDC 
platform) using his/her unique eCRF log-in credentials. The PI may delegate this 
activity to another medically qualified and trained sub-investigator and this must be 
documented on the Delegation of Responsibilities (DoR) Log. It is recommended that 
the PI identifies a sub-investigator as a back-up for eCRF signatures. The sub-
investigator must be appropriately trained on the protocol and eCRF requirements 
(with training documented), and the DoR log updated accordingly. 
Essential Document Sign Off Process: If an investigator is unable to print and sign essential 
documents such as Protocol /Amendment signature page then Email approval can be 
accepted by replying to the relevant email that is sent by GSK. 
 
 
 
 
 
 
 
 
 
 
 
 
 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 1 2  
 
1 0. 9.  
A p p e n di x 9 : A b br e vi ati o n s a n d D efi niti o n s a n d Tr a d e m ar k s  
A D E  
A dv ers e d evis e effect  
A E  
a dv ers e ev ent  
A L T  
al a ni ne a mi n otr a nsfer as e  
a P T T  
Activ at e d p arti al t hr o m bo pl asti n ti me  
A S E  
All s u bj ects e nr oll ed  
A S T  
as p art at e a mi n otr ansf er ase  
A T P  
a d en osi ne trip hos p hat e  
A U C  
ar e a u n der t he c o nce ntrati on-ti m e c urv e 
A U C( 0 -) 
ar e a u n der t he c o nce ntrati on -ti m e c urv e fr o m ti me 0 ( pre d ose) 
extr a p olat e d t o i nfi nit e ti me  
A U C( 0 -2 4)  
ar e a u n der t he c o nce ntrati on -ti m e c urv e fr o m ti me 0 ( pre d ose) 
t o 2 4 h o urs post dos e a d ministr ati o n f oll o wi n g t he first d os e  
A U C( 0 -t) 
ar e a u n der t he c o nce ntrati on -ti m e c urv e fr o m ti me 0 to th e ti me 
of t h e l ast q ua ntifi abl e co nce ntr ati on  
A U C( 0 -τ) 
ar e a u n der t he c o nce ntrati on -ti m e c urv e fr o m ti me 0 ( pre d ose) 
t o ti me ta u 
A V  
atri ov e ntric ul ar  
B MI  
b o dy m ass i n dex  
b p m  
b e ats p er mi n ut e  
B T S  
Britis h T h or acic Soci ety  
C A  
C o m p et e nt Aut h oriti es  
CI O M S  
C o u ncil f or Int er nati on al Org a niz ati o ns of M edic al Sci enc es  
CI  
c o nfi de nc e int erv al 
C m ax  
m axi mu m o bs erv e d c o nce ntr ati o n  
C O VI D  
C or o n avirus dis e as e   
C O P D  
C hr o nic o bstr uctiv e p ul mo nary dis e ase   
C P E M  
Cli nic al P h ar mac ol ogy a n d Ex p eri m e ntal M e dici n e  
C P K  
cr e ati n e p hos p hoki n ase 
C P M S  
Cli nic al P h ar mac oki netics M o d elli n g a n d Si mul ati on  
C R A  
Cli nic al r es e arc h 
C R O  
C o ntr act r ese arc h or g aniz ati o n  
C R F  
C as e r e port f or m  
C S R  
Cli nic al St u dy Re p ort  
C T F G  
Cli nic al Tri al F acilit ati o n Gr ou p  
C V  
C ar di ov asc ul ar  
C W M  
Cli nic al w ar d m a n ag er  
C Y P  
cyt oc hr o m e P 4 50 
D DI  
dr u g -dr u g i nt eracti o n  
D E C  
D os e escal ati o n c o m mitt e e  
D M P K  
Dr u g m et a b olis m a nd P har m ac oki n e tics 
E C  
Et hics C o m mitt e e  
E C G  
el ectr oc ar di ogr a m  
e C R F  
el ectr o nic cas e r ep ort for m  
C CI


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 1 3  
 
E R S  
E ur o pe a n R es piratory S ociety  
F E V 1  
f orc e d ex pirat ory vol u m e i n 1 s ec on d 
F S H  
f ollicl e-sti m ul ati n g h or mo n e 
F TI H  
First ti m e i n h u m an  
F V C  
f orc e d vital c a pacity 
g  
Gr a m  
G C P  
G o o d Cli nic al Pr actic e  
G C S P  
Cli nic al S af ety a nd Ph ar mac ovi gil a nc e  
GI N A  
Gl o b al Initi ativ e f or Asth m a  
G S K  
Gl ax o S mit h Kli ne  
H Bs A g  
h e patitis B surf ac e a ntig e n  
H D P E  
hi g h -d ensity p oly et hyle n e  
HI P A A  
H e alt h Ins ur anc e Port ability a n d Acc ou nta bility Act  
HI V  
h u m a n i m m u no defici e ncy vir us  
H P L C  
hi g h p erf or ma nce li q ui d c hro m at o gra p hy  
H R  
H e art r at e  
H R T  
h or mo n e r e pl ace m e nt t h er apy  
H R V  
H u m a n r hi novirus  
I B 
I nv esti gat or’s Br och ur e 
I bs 
p o un ds  
I C F 
i nf or me d c o ns ent for m 
I C H 
I nt er nati o nal C o u ncil f or H ar m o nis ati o n  
I C S 
i n h al ed c ortic oster oi d 
I E C 
I n d ep en d ent Et hics C o m mitt e e 
I H 
I n h ale d 
I M P 
I nv esti gati o nal M e dici nal Pro d uct  
I N R 
i nt er n atio n al n or maliz e d ratio 
I R B 
I nstit utio n al R evie w B oar d 
I U D 
i ntr a ut erine d evic e 
I U S 
i ntr a ut erine hor mo n e -r el easi n g syst e m 
I V 
i ntr av e no us 
k g 
kil o gr a m  
L D H  
l act at e d ehy dr og e nas e 
L A B A  
l o n g-acti ng b et a a go nist  
L A M  
l act ati on al a m en orrh ea m eth o d 
L T R A  
L e ukotri e n e R ec ept or Ag onist  
m 2 
 s q u ar e m et er 
M A B E L  
mi ni m u m a ntici p at e d biol o gic al effectiv e l evel  
M A T E  
m ulti dr u g a n d toxi n extr usi on  
mc g  
micr o gr a m  
M C H  
m e a n c orp usc ul ar h e m ogl obi n  
M C V  
m e a n c orp usc ul ar vol u m e  
M D R  
M e dic al D evic e R eg ul ati o n  
m g  
milli gr a m  
M g St  
m a g n esi u m ste ar at e  
C CI


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mL 
milliliter 
mm 
millimeter 
msec 
millisecond 
mV 
Megavolt  
n 
number 
NIMP 
Non Investigational Medicinal Product  
NOAEL 
No Observed Adverse Effect Level 
NQ 
Non-quantifiable 
PBPK 
Physiologically-based pharmacokinetics 
PCI 
Potential clinical interest  
PEF 
Peak Expiratory Flow 
PI 
Principle investigator  
PK 
pharmacokinetic(s) 
PKPD 
pharmacokinetic/pharmacodynamic modelling 
PT 
Prothrombin time 
QD 
once a day 
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 
RH 
Relative humidity 
SABA 
short-acting beta agonist 
SAE 
serious adverse event 
SADE 
serious adverse device event  
SAP 
Statistical and Analysis Plan 
SD 
Standard deviation 
SDA 
Source Document Agreement 
SGOT 
Serum Glutamic-Pyruvic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SIGN 
Scottish Intercollegiate Guidelines Network 
SoA 
schedule of activities 
SD 
single dose 
SDS 
Safety Data Sheet 
SOP 
Standard operating procedures 
SPC 
Summary of product characteristics 
SRM 
Study reference manual 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
terminal phase half-life 
Tmax 
time to reach maximum observed plasma concentration 
QC 
Quality check 
ULN 
upper limit of normal 
USADE 
Unanticipated serious adverse device event  
Vz/F 
apparent volume of distribution 
WBC 
White blood cell count 


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WONCPB 
Wome(a)n of nonchildbearing potential 
WPW 
Wolff-Parkinson-White 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
GastroPlus 
 
 
MedDRA 
 
 
RS01 Monodose dry powder inhaler 
 
 
WinNonlin 
 
 


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10.10. 
Appendix 10: Protocol Amendment History 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE. 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 04 
24 Sep 2021 
TMF-13791516 
Amendment 03 
15-FEB-2021 
2020N430088_03 
Amendment 02 
07-SEP-2020 
2020N430088_02 
Amendment 01 
28-AUG-2020 
2020N430088_01 
Original Protocol 
17-Jul-2020 
2020N430088_00 
 
Amendment [03]: 15-FEB-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
Overall Rationale for the Amendment  
This amendment has been prepared to: 
• Extend the PK sampling period from 24 hours to 48 hours in Part A Cohort 2 to 
enable a better estimation of the drug terminal half-life and prediction of repeat 
dose PK profile.  The participants in this cohort will also be discharged on Day 3 
(48 hours post dose). 
• Update the dose modification criteria and maximum daily exposure limits to align 
with the NOAEL in the 4-week rat intravenous study.  To date, the 50 and 100 mcg 
treatment periods in Part A (SAD) have been completed with no notable safety or 
tolerability findings. 
• Allow the unblinding of data following the completion of each cohort in Part B to 
enable analysis and modelling of PK data to start. 
Specific details of the changes are provided below: 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Changes to treatment 
period dates and 
discharge time  
To enable discharge information to 
be captured 
Section 1.3 Schedule 
of Activities  
Part A: Single Ascending 
Dose Healthy 
Participants (Cohort 2). 
Addition of 48h Blood 
Split of cohort 1 and cohort 2 
activities into separate tables to 
accommodate the addition of PK 
sample to enable calculation of 


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Section # and Name 
Description of Change 
Brief Rationale 
PK sample and discharge 
activities moved to Day 3 
terminal half-life and enable 
discharge information to be 
captured 
Section 4.1 Overall 
design -  
Table 1. Changes to 
treatment period dates 
and discharge time 
To enable discharge information to 
be captured 
Section 4.3.1 
Starting Dose and 
Dose Escalation 
Updated text for the IV 
dose in rats 
Dose modification criteria updated 
to align with NOAEL 
Section 6.3. 
Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Updated text to define 
timing of unblinding 
Added text to clarify 
access to unblinded data 
To enable modelling of PK data to 
start after cohort 3 
To clarify which lines would have 
access to unblinded subject-level 
data after cohort 3 is complete 
Section 6.5.1 
Pharmacokinetic 
Criteria for Dose 
Modification 
Rat IV data used to 
calculate PK dose 
exposure 
Dose modification criteria updated 
to align with NOAEL 
Section 7.3 
Participant 
Discontinuation/Wit
hdrawal from the 
Study 
Day of discharge 
extended to day 3 
Updated discharge information  
Section 9.4.1.1 
Adverse Events and 
Serious Adverse 
Events 
Cohort 3 and 4 data will 
be pooled and reported 
together 
Addition of text to 
include the cohorts being 
reported 
As cohorts 3 and 4 are identical in 
every aspect expect the timing of 
bronchoscopy assessment, data 
from the two cohorts will be pooled 
and reported together  
Section 9.5.2 
Instream Analysis of 
PK Data 
Updated text to define 
timing of unblinding 
Added text to clarify 
access to unblinded data 
To enable modelling of PK data to 
start after cohort 3 
To clarify which lines would have 
access to unblinded subject-level 
data after cohort 3 is complete 
 


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Amendment [02]: 07-SEP-2020 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment  
This amendment is in response to questions raised by the Research Ethics Committee in 
the UK. The committee requested clarification on the withdrawal criteria for subjects 
who become COVID-19 positive, during the study. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.5 
Management of 
Participants who 
Develop COVID-19 
Symptoms During 
the Study 
Clarification on the 
management of the 
participants who become 
COVID-19 positive, 
during the study 
Clarification that participants that 
test positive for COVID-19 will 
receive no further doses of study 
treatment but continue with safety 
monitoring whilst in the unit 
 
 
Amendment [01]: 28-AUG-2020 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 


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Overall Rationale for the Amendment  
This is amendment is in response to questions raised in the MHRA’s Grounds for non-
acceptance letter which was received on the 20 August 2020 and includes justification for 
planned doses, addition of dose escalation stopping criteria, clarification to study 
stopping criteria, liver chemistry criteria, clarifications to contraceptive requirements and 
minor updates to references. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Addition of text around 
the dose modification and 
stopping criteria. 
To clarify the dose escalation 
process.  
Section 4.1 Overall 
Design  
Addition of text around 
the dose modification and 
stopping criteria. 
To cross reference the dose 
escalation stopping criteria and 
dose escalation  committee (DEC) 
structure. 
Section 4.3.1. 
Starting Dose and 
dose escalation and 
Table 3 
Addition of text and table 
on predicted target 
engagement for planned 
dose levels. 
To add further information on the 
predicted maximum target 
engagement for Part A dose levels. 
Section 4.3.2 Safety 
Margins 
Update to the table 
numbering in the 
protocol. 
Correction to table numbering as a 
new table was inserted into Section 
4.3.1. 
Section 4.3.3. 
Predicted Target 
Engagement at 
Steady State 
Addition of text and 
figure on predicted target 
engagement. 
To add further information on the 
predicted target engagement 
profiles for different repeat dose 
levels. 
Section 5.1.1 
Inclusion criteria: 
Parts A & B 
(Healthy 
participants) No.4  
Contraception changes to 
male contraception usage 
when having sexual 
intercourse with a woman 
of childbearing potential 
who is not currently 
pregnant. 
Clarification to contraception 
requirements for male participants 
and their female partner of 
childbearing potential. 
Section 5.1.2 
Inclusion criteria: 
Parts C (Participants 
with Asthma) No.8  
Contraception changes to 
male contraception usage 
when having sexual 
intercourse with a woman 
of childbearing potential 
who is not currently 
pregnant. 
Clarification to contraception 
requirements for male participants 
and female partner of childbearing 
potential.   


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5 Dose 
Modification  
Addition of references to 
dose modification and 
stopping criteria. 
To cross reference the dose 
escalation stopping criteria and 
DEC committee structure. 
Section 6 .5.1 
Pharmacokinetic 
Criteria for Dose 
Modification 
Update to 
Pharmacokinetic (PK) 
Criteria for Dose 
Modification. 
To clarify that if PK exposure limit 
is reached, there will be no further 
dosing of participants at that dose 
or any higher dose level. 
Section 6.5.2 Dose 
Escalation Stopping 
Criteria 
Addition of dose 
escalation Stopping 
Criteria. 
To outline specific criteria for 
stopping dose escalation.  
Section 7.2.1 Study 
Stopping Criteria 
Clarification for study 
stopping criteria. 
To clarify that dosing will be 
paused should two or more severe 
adverse events (AEs)  related to the 
study drug occur. 
Section 7.2.3 Liver 
Chemistry Stopping 
Criteria & Figure 1  
Addition of aspartate 
aminotransferase (AST)  
level to liver chemistry 
stopping criteria. 
Update to include AST in the 
figure. 
Section 10.1.5.1 
Dose Escalation 
Committee  
Clarification in Dose 
escalation committee. 
Cross reference update to the dose 
modification and escalation 
stopping criteria. 
Section 10.2 
Appendix 2: Clinical 
Laboratory Tests & 
Table 5 
Addition of AST to liver 
chemistry stopping 
criteria and update to 
table numbering. 
Footnotes updated to correctly 
cross reference liver chemistry 
stopping criteria & addition of AST 
to liver chemistry stopping criteria. 
Section 10.3.2 
Definition of SAE  
Addition of AST to liver 
chemistry stopping 
criteria. 
Addition of AST to liver chemistry 
criteria. 
Section 10.4.2 
Appendix: 4 
Contraceptive 
Guidance  
 
Edit to the Appendix 4 
title. 
Update to title to remove barrier. 
Section 10.4.2 
Contraception 
Guidance 
Update to the male 
contraception guidance. 
Added male contraception and 
female partner’s guidance.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.5 
Appendix 5 Liver 
Safety: Required 
Actions and Follow 
up Assessments 
Addition of AST to liver 
chemistry stopping 
criteria added to table. 
Addition of AST to Liver 
Chemistry stopping criteria. 
Section 10.7 
Appendix 7  
Update to the table 
numbering in the 
protocol. 
Correction to table numbering as a 
new table was inserted into Section 
10.7  
 


T M F -1 3 7 9 1 5 1 6  
C O N FI D E N TI A L  
 
 
 
2 1 3 4 9 7  
 
Pr ot o c ol A m d 0 4  
 
1 2 2  
 
1 1.  
R E F E R E N C E S  
Alta n -B o n n et N, Balla T. P h os p hati d yli n osit ol 4 -ki nases: h osta ges har nesse d t o b uil d 
pa n viral re plicati o n platf or ms. Tre n ds Bi oc he m Sci. 2 0 1 2; 3 7( 7): 2 9 3 -3 0 2.  
Britis h T h oraci c S ociet y/ S c ottis h I nt erc olle giat e 
G ui deli nes 
Net w or k ( B T S/ SI G N). 
SI G N 1 5 8, Britis h g ui deli ne o n t he ma na ge me nt of ast h ma. w w w. brit -t h oracic. or g. u k. 
2 0 1 9; 2; 1 -2 1 4.  
Casa n o va V, S o usa F H, Ste ve ns C, Barl o w P G. A nti viral t hera pe utic a p pr oac h es f or 
h u ma n r hi n o vir us i nfecti o ns. F ut ure Vir ol. 2 0 1 8; 1 3( 7): 5 0 5 -5 1 8.  
Dar p o B , Gar nett C, Be ns o n C T, Keir ns J, Leis h ma n D. Car diac safet y researc h 
c o ns orti u m: Ca n t he t h or o u g h Q T/ Q Tc st u d y b e re place d b y earl y Q T assess me nt i n r o uti ne 
cli nical p har mac ol o g y st u dies? Scie ntific u p date a n d a res earc h pr o p osal f or a p at h 
f or war d. A m H e art J. 2 0 1 4; 1 6 8: 2 6 2 -7 2.  
F D A  G ui da nce f or I n d ustr y: Esti mati n g t h e Ma xi m u m Safe Starti n g D ose i n I nitial Cli nical 
Trials f or T hera pe utics i n A d ult Healt h y V ol u nteers, 2 0 0 5  
Gastr o Pl us v 9. 6 User Ma n ual, Si m ulati o ns Pl us, I nc. 9. 6 ( 2 0 1 8).  
Gl o bal I nitiati ve f or Ast h ma ( GI N A).  Gl o bal Str ate g y f or Ast h ma M a na ge me nt a n d 
Pre ve nti o n. w w w. gi na ast h ma. or g. 2 0 2 0; 1; 1 -2 1 1.  
G S K 
D oc u me nt 
N u m b er 
2 0 1 1 N 1 2 4 2 6 5 _ 0 0, 
A si n gle -ce ntr e, d o u ble -bli n d, place b o 
c o ntr olle d t hree part st u d y t o e val uate t he safet y, t olera bilit y, p har mac o ki netics, a n d 
p har mac o d y n a m ics of si n gle a n d re peat d oses of ne b ulise d G S K 2 2 6 9 5 5 7 i n healt h y male 
s u bjects, 2 0 1 3 
G S K D oc u me nt N u m ber 2 0 1 3 N 1 8 3 5 8 6 _ 0 0, A Si n gle -ce ntr e, D o u ble -bli n d, Place b o 
C o ntr olle d T hree Part St u d y t o E val uate t he Safet y, T olera bilit y a n d P har mac o ki netics of 
Si n gle  a n d Re peat D os es of G S K 2 2 6 9 5 5 7 as a Dr y P o w der i n Healt h y S u bjects w h o S m o ke 
Ci garettes, 2 0 1 4  
G S K 
D oc u me nt 
N u m ber 2 0 1 9 N 4 1 9 5 0 1 _ 0 1: P h ysi ol o gicall y base d p har mac o ki neti c 
( P B P K) a n d P K P D m o delli n g pre dicti o ns t o u n dersta n d t he li kel y efficaci o us h u ma n 
cli nical d ose f or G S K 3 9 2 3 8 6 8, 2 0 1 9  
G S K D oc u me nt N u m ber 2 0 2 0 N 4 2 7 6 2 1 _ 0 0: G S K 3 9 2 3 8 6 8 I n v esti gat or’s Br oc h ure, 2 0 2 0.  
G S K d oc u me nt n u m b er 2 0 2 0 N 4 3 7 0 7 8 _ 0 1: G S K 3 9 2 3 8 6 8: A st u d y t o c haracterise t he i n -
vitr o perf or ma nce of G S K 3 9 2 3 8 6 8 5 0 mc g a n d 5 0 0 mc g 
M o n o d ose acr oss i n hal ati o n 
para meters re prese ntati ve of healt h y partici pa nts, usi n g t he Electr o nic L u n g a n d 
s u bse q ue nt L u n g De p ositi o n M o delli n g usi n g t he M ulti ple-Pat h Particle D osi metr y M o del, 
2 0 2 0  
C CI


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Hershenson M B. Review Article: Rhino-virus Induced Exacerbations of Asthma and 
COPD. Scientifica. 2013:1-12.  
Hsu N-Y, Ilnytska O, Belov G, Santiana M, Chen Y-H. Viral Reogranization of the 
Secretory Pathway Generates Distinct Organelles for RNA Replication. Cell. 
2010;141(5):799-811.  
Jacobs S E, Lamson D M, George K S, Walsh T J. Human Rhinoviruses. Clin Microbiol 
Review. 2013; 26(1); 135-162. 
Mello C, Aguayo E, Rodriguez M, Lee G, Jordan R et al.  Multiple classes of antiviral 
agents exhibit in vitro activity against human rhinovirus type C. Antimicrobial Agents and 
Chemotherapy. 2014;58(3):p1546-1555. 
Quanjer P H, Stanojevic S, Cole T J, Baur X, Hall G L et al.  Multi-ethnic reference values 
for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012; 40; 1324-1343. 
Roulin P S, Lötzerich M, Torta F, Tanner L B, van Kuppeveld F J. Rhinovirus Uses a 
Phosphatidylinositol 4-Phosphate/Cholesterol Counter-Current for the Formation of 
Replication Compartments at the ER-Golgi Interface. Cell Host & Microbe. 
2014;16(5):677-690.  
Turner R. Rhinovirus: More than Just a Common Cold Virus. J Infect Dis. 2007;195:765-
766.  

SAP_001.pdf: 
 
Protocol 
 
 
 
Study ID: 213497 
 
Official Title of Study: 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 
 
EudraCT: 2020-002203-19 
 
Date of Document: 30-Nov-2021 
 
 


C O N FI D E N TI A L  
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 4 9 7  
 
1  
Di visi o n  
: W orl d wi de De vel o p me nt  
I nf or m ati o n T y pe 
: Statistical A nal ysis Pla n ( S A P)  
Titl e P a g e  
Pr ot oc ol Title: A ra n d o mize d d o u ble -bli n d, place b o c o ntr olle d, si n gle asce n di n g a n d 
re peat d os e, First Ti me i n H u ma n st u d y i n healt h y partici pa nts a n d sta ble ast h matics t o 
assess safet y, t olera bilit y a n d p har mac o ki netics of G S K 3 9 2 3 8 6 8 i n halati o n p o w der  
 
Pr ot oc ol N u m ber:  2 1 3 4 9 7   
 
C o m p o u n d N u m ber:  G S K 3 9 2 3 8 6 8   
 
S h ort Title: Safet y, t olera bilit y a n d p har mac o ki netics of G S K 3 9 2 3 8 6 8 i n halati o n p o w der 
i n healt h y p artici pa nts a n d sta ble ast h matics. 
 
 
S p o ns or N a me: Gla x o S mit h Kli ne Researc h & De vel o p me nt Li mite d  
Re g ul at or y A ge nc y I de ntifier N u m ber(s)   
E u dr a C T  
2 0 2 0‐ 0 0 2 2 0 3‐ 1 9  
 
S A P  A ut h or(s):  
A ut h or  
 
Pri nci pal Statisticia n , Bi ostatistics  
 
Ass ociate Statisticia n, Bi ostatistics  
P P D
P P D


C O N FI D E N TI A L  
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 4 9 7  
 
2  
S A P  Te a m Re vie w C o nfir m ati o ns  ( E-m ail C o nfir m ati o n) : 
Re vie wer  
 
Scie ntist Ma na ger , Disc o ver y Me dici ne  
 
 Disc o ver y Me dici ne  
 
 Cli nical P har m ac ol o g y 
S A P Bi os t atistics Li ne A p pr o v al (P h ar m a T M F e Si g n at ure) :  
A p pr o ver  
 
, Bi ost atistics  
 
 
C o p yri g ht 2 0 2 1  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d . 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D


C O N FI D E N TI A L  
 
2 1 3 4 9 7  
 
3  
T A B L E O F C O N T E N T S  
P A G E  
1.  
I N T R O D U C TI O N ...................................................................................................... 5  
1. 1.  
O bj e cti v e s, E sti m a n d s a n d E n d p oi nt s  ........................................................... 5  
1. 1. 1.  
O bj e cti v e s a n d E n d p oi nt s  .............................................................. 5  
1. 1. 1. 1.  
P art s A a n d B ( H e alt h y p arti ci p a nt s)  ............................. 5  
1. 1. 1. 2.  
P art C ( P arti ci p a nt s wit h A st h m a)  ................................. 7  
1. 2.  
St u d y D e si g n  ................................................................................................ 8  
2.  
S U C C E S S C RI T E RI A  ............................................................................................ 1 1  
3.  
A N A L Y SI S S E T S  ................................................................................................... 1 2  
3. 1.  
D efi niti o n s f or P er Pr ot o c ol A n al y si s S et  ..................................................... 1 2  
4.  
S T A TI S TI C A L A N A L Y S E S  ..................................................................................... 1 3  
4. 1.  
G e n er al C o n si d er ati o n s  .............................................................................. 1 3  
4. 1. 1.  
G e n er al M et h o d ol o g y  .................................................................. 1 3  
4. 1. 2.  
B a s eli n e D efi niti o n  ....................................................................... 1 3  
4. 1. 3.  
M ulti c e ntr e St u di e s  ...................................................................... 1 3  
4. 1. 4.  
M o d el C h e c ki n g Di a g n o sti c s  ........................................................ 1 4  
4. 2.  
Pri m ar y E n d p oi nt s A n al y s e s  ....................................................................... 1 4  
4. 2. 1.  
D efi niti o n of e n d p oi nt s  ................................................................. 1 4  
4. 2. 2.  
M ai n a n al yti c al a p pr o a c h  ............................................................. 1 5  
4. 2. 2. 1.  
A d v er s e e v e nt s a n d s eri o u s a d v er s e e v e nt s ............... 1 5  
4. 2. 2. 2.  
L a b or at or y D at a, Vit al Si g n s, E C G s a n d 
S pir o m etr y  .................................................................. 1 6  
4. 3.  
S e c o n d ar y E n d p oi nt s A n al y s e s  .................................................................. 1 6  
4. 3. 1.  
D efi niti o n of e n d p oi nt( s)  ............................................................... 1 7  
4. 3. 2.  
M ai n a n al yti c al a p pr o a c h  ............................................................. 1 7  
4. 3. 2. 1.  
D o s e Pr o p orti o n alit y  ................................................... 1 8  
4. 3. 2. 2.  
A c c u m ul ati o n a n d St e a d y St at e A s s e s s m e nt .............. 1 9  
4. 3. 2. 3.  
P o p ul ati o n P K M o d el  .................................................. 1 9  
4. 5.  
Ot h er A n al y s e s  ........................................................................................... 2 2  
4. 5. 1.  
E xt e nt of E x p o s ur e  ...................................................................... 2 2  
4. 6.  
I nteri m A n al y s e s  ......................................................................................... 2 2  
4. 6. 1.  
D o s e E s c al ati o n C o m mitt e e ( D E C)  .............................................. 2 2  
4. 6. 2.  
I n str e a m A n al y si s of P K D at a ...................................................... 2 3  
4. 7.  
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  .......................... 2 3  
5.  
S A M P L E SI Z E D E T E R MI N A TI O N  ......................................................................... 2 4  
6.  
S U P P O R TI N G D O C U M E N T A TI O N  ....................................................................... 2 6  
6. 1.  
A p p e n di x 1 A b br e vi ati o n s a n d Tr a d e m ar k s  ................................................. 2 6  
6. 1. 1.  
Li st of A b br e vi ati o n s  .................................................................... 2 6  
6. 1. 2.  
Tr a d e m ar k s  ................................................................................. 2 6  
7.  
R E F E R E N C E S  ....................................................................................................... 2 7  
C CI


C O N FI D E N TI A L  
 
2 1 3 4 9 7  
 
4  
V er si o n hi st or y  
T his Statistical A nal ysis Pla n ( S A P) f or st u d y 2 1 3 4 9 7  is base d o n t he pr ot o c ol date d 2 4 -
Se p -2 0 2 1 .  
T a bl e 1  
S A P V er si o n Hi st or y S u m m ar y  
S A P 
Versi o n  
D oc u me nt 
D ate  
Pr ot oc ol 
Versi o n  
( D ate) o n 
w hic h S A P is 
B ase d  
C h a n ge  
R ati o n ale  
1  
- 
0 7 -Se p -2 0 2 0  
N ot A p plica ble  
Ori gi nal v ersi o n  
2  
 
2 4 -Se p -2 0 2 1  
-U p date d ‘ S A B A 
o nl y ’ treat me nt t o 
i ncl u de treat me nt 
wit h ‘i nter mitte nt 
I C S/ L A B A’ 
-U p date d access 
t o u n bli n de d data 
fr o m c o m plete 
c o h orts t o i ncl u de 
safet y e n d p oi nts 
 
-U p date d te xt to 
defi ne ti me of 
u n bli n di n g  
 
-C o h orts 3 a n d 4 
will be p o ole d 
a n d re p ort e d 
t o get her  
-P o p ulati o n treat me nt 
re q uire me nts u p dat e d i n 
li ne wit h u p date d 
treat me nt g ui deli nes.  
 
-T o  all o w better 
i nter pretati o n of b ot h 
safet y a n d P K dat a 
f oll o wi n g t he c o m pleti o n 
of eac h c o h ort, t o hel p t h e 
desi g n of f urt ur e st u dies.  
-T o e na ble m o d elli n g of 
P K data t o start after 
c o h ort 3. 
 
-As c o h orts 3 a n d 4 are 
i de ntical 
 
 
 
, data fr o m t he 
t w o c o h orts will be 
p o ole d a n d re p orte d 
to get her.  
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CONFIDENTIAL 
 
213497 
 
5 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 213497.  
Descriptive study population analyses such as summary of demography and baseline 
characteristics and additional detail with regards to data handling conventions and the 
specification of data displays (including COVID-19 reporting) will be provided in the 
Output and Programming Specification (OPS) document. 
1.1. 
Objectives, Estimands and Endpoints 
1.1.1. 
Objectives and Endpoints 
1.1.1.1. 
Parts A and B (Healthy participants) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of 
GSK3923868 following single and repeat 
inhaled administration in healthy 
participants. 
• 
Adverse events (AEs) and serious 
adverse events (SAEs). 
• 
Clinically significant laboratory values, 
vital signs,12-lead electrocardiogram 
(ECG) and spirometry measurements up 
to Day 2 of the final treatment period in 
Part A, and Day 18 in Part B. 
Secondary 
• 
To evaluate the plasma pharmacokinetics 
of GSK3923868 following single and 
repeat inhaled administration in healthy 
participants. 
Derived pharmacokinetic parameters as data 
permit, including (but not limited to): 
Single dose (Part A, Cohorts 1 & 2): 
• Area under the plasma GSK3923868 
concentration versus time curve from time 
zero to last quantifiable concentration 
(AUC(0-t)) and from time zero to infinity 
(AUC(0-∞)) (if determined). 
• Maximum observed GSK3923868 plasma 
concentration (Cmax). 
• Time to maximum observed plasma drug 
concentration (Tmax). 
Repeated dose (Part B, Cohorts 3 & 4):  
• AUC(0-) on Day 1 and Day 14 (=24h for 
once a day dosing regimen) (if 
determined). 
• Cmax and Tmax on Day 1 and Day 14. 


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1.1.1.2. 
Part C (Participants with Asthma) 
Objectives 
Endpoints 
Primary 
• To evaluate the safety and tolerability of 
GSK3923868 following repeat inhaled 
administration in participants with 
asthma. 
• 
AE and SAEs 
• 
Clinically significant laboratory values, vital 
signs, 12-lead ECG and spirometry 
measurements up to Day 8. 
Secondary 
To evaluate the plasma pharmacokinetics of 
GSK3923868 following repeat inhaled 
administration in participants with asthma. 
• 
AUC(0-) on Day 1 and Day 7 (=24h for 
once a day dosing regimen) (if 
determined). 
• 
Cmax and Tmax on Day 1 and Day 7. 


C O N FI D E N TI A L  
 
 
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8  
1. 2.  
St u d y D e si g n  
O ver vie w of St u d y Desi g n a n d Ke y Fe at ures  
 
 
 
Desi g n 
Fe at ures  
A ra n d o mize d d o u ble -bli n d, place b o c o ntr olle d, t hree-p art ( Parts A, B 
a n d C), First Ti me i n H u ma n ( F TI H) st u d y t o assess safet y, t olera bilit y 
a n d p har mac o ki netics of G S K 3 9 2 3 8 6 8 i n halati o n p o w der  
I n Part A, si n gl e asce n di n g d oses of G S K 3 9 2 3 8 6 8 will be assesse d i n 
t w o se q ue ntial cr oss o ver c o h orts ( C o h orts 1 a n d 2, 1 2 partici pa nts per 
c o h ort) of healt h y p artici pa nts, each wit h u p t o t hr ee treat me nt peri o ds.  
T here will be a mi ni m u m of 1 0 da ys bet wee n d oses, bef ore a f oll o w u p 
visit 7 -1 4 da ys p ost t he fi nal d ose.  
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Overview of Study Design and Key Features 
Part B will assess repeat doses of GSK3923868 for 14 days across two 
parallel cohorts (Cohorts 3 and 4) of 8 healthy participants (total 16 
participants in Part B).  
In Part C, further repeat dosing of GSK3923868 for 7 days will be 
assessed in a single parallel cohort (Cohort 5) of 16 participants with 
stable asthma. Part C will be randomized according to two strata:1) 
SABA and/or intermittent ICS/LABA users and 2) ICS or ICS/LABA 
users. 
A Dose Escalation Committee (DEC) will be responsible for the review 
of emerging safety, tolerability and plasma PK results to determine the 
progression of single ascending dose levels in each treatment period in 
Part A and the progression to repeat dose levels in Parts B and C.   
Study 
intervention 
The starting dose in Part A Cohort 1 Period 1 is 50 mcg.  
The planned doses for dose escalation in Part A after the first cohort 
with 50 mcg are 100, 250, 500, 1000, and 3000 mcg. The planned dose 
for Part B (Cohorts 3 and 4) and Part C is 3000 mcg. 
Part 
Screening 
Treatment Period 
Washout Period 
Follow-Up 
A 
Up to 30 
days 
before the 
first dose. 
Each cohort will be 
comprised of three 
treatment periods (3 days 
each) with a follow up 
phone call at 48 hours 
after each dose. 
Will be at least 10 
days between 
doses for each 
participant. 
Between 7 
to 14 days 
following 
the final 
dose. 
B 
Each participant will  
receive up to 14 days of 
treatment with additional 
observation up to 96 hours 
after their final dose. 
N/A 
C 
Each participant will 
receive up to 7 days of 
treatment. 
N/A 
The total duration of the study will be approximately 11 weeks in Part 
A, approximately 9 weeks in Part B and approximately 8 weeks in Part 
C. 
Study 
intervention 
Assignment 
In Part A (Cohorts 1 and 2), each cohort has a crossover design with 
four treatment sequences that participants will be randomized to. Of the 
four sequences, three include placebo for one of the treatment periods 
whilst the last contains active for all treatment periods. This gives a 3:1 
active:placebo ratio within each treatment period of the cohort (as 
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Overview of Study Design and Key Features 
 
Part B (Cohorts 3 and 4), follow a parallel group design where 
participants will be randomized in a 3:1 ratio (active:placebo) to receive 
study treatment. 
Part C (Cohort 5) also follows a parallel group design with participants 
randomized in a 3:1 ratio (active:placebo) to receive study treatment. In 
addition, Part C will be stratified to ensure 8 SABA and/or intermittent 
ICS/LABA participants (6 active and 2 placebo) and 8 ICS or 
ICS/LABA participants (6 active and 2 placebo) are randomized. 
Interim 
Analysis 
There are no formal interim analyses conducted as part of this study, 
however the  following in-stream analyses will be performed as 
described in the sections below. 
Dose 
Escalation 
Committee  
A review of preliminary safety, tolerability and plasma PK data will be 
conducted by the DEC prior to each dose level in Part A, before 
initiating repeat dosing in Part B, and before initiating repeat dosing 
asthmatics in Part C. 
 
Safety and tolerability data includes adverse event/serious adverse 
event (AE/SAE), clinical laboratory values, 12-lead electrocardiogram 
(ECG), vital signs and spirometry measurements. 
 
Additional details are available in the Dose Escalation Plan. 
Instream 
Analysis of 
PK Data  
Once each of Part A (Cohorts 1 and 2) and Part B (Cohorts 3 and 4) 
have completed, selected members of the GSK team will be formally 
unblinded to the treatment allocations of the completed participants for 
PK and safety data from these cohorts to enable the analysis and 
modelling of PK data to start. 
 
The aim of this analysis is to inform internal decision making around 
dose selection for future studies in the development plan of this 
compound. This analysis will not impact the conduct or the design of 
the current study and will be reported separately from this SAP. 
 


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2. 
SUCCESS CRITERIA 
Given this study is the FTIH for GSK3923868, no formal statistical hypotheses will be 
tested. The primary objective is to evaluate the safety and tolerability of GSK3923868 in 
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3. 
ANALYSIS SETS 
 
3.1. 
Definitions for Per Protocol Analysis Set 
This study does not have a per protocol analysis set. 
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 including 
those randomized in error. A participant who 
is recorded as a screen failure and was also 
randomized will be considered as 
randomized in error provided that they have 
not performed any study assessments.  
Study Population 
Safety 
All randomized participants who received at 
least 1 dose of study intervention. 
Participants will be analysed according to 
the treatment they received.  
Safety 
Pharmacokinetic 
(PK) 
All randomized participants in the Safety 
population who had at least 1 non-missing 
PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing 
values). 
• Participants will be analysed 
according to the treatment they 
received. 
PK 


C O N FI D E N TI A L  
 
 
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1 3  
4.  
S T A TI S TI C A L A N A L Y S E S  
4. 1.  
G e n er al C o n si d er ati o n s  
4. 1. 1.  
G e n er al M et h o d ol o g y  
T he Safet y  A n al ysis Set will be use d f or all o ut p uts e x ce pt f or p har mac o ki netic ( P K ) 
 
 e n d p oi nts w hic h will use t he P har mac o ki n etic A nal ysis 
Set.   
All c o h orts will be prese nte d se paratel y , e x ce pt C o h orts 3 a n d 4 w hic h will be c o m bi ne d, 
u nless ot her wise state d . I n a d diti o n, f or Part A, all o ut p uts  e x cl u di n g st u d y p o p ulati o n 
will be s u m marise d acc or di n g t o treat me nt a n d d ose le vel of G S K 3 9 2 3 8 6 8.  
I n t he cas e of wr o n g str atificati o n assi g n e d at t he ti me of ra n d o mizati o n, t he a nal yses will 
be perf or me d bas e d o n t he data c ollecte d i n t he eC R F, n ot t he a ssi g n e d strat u m at 
ra n d o mizati o n. 
C o nfi de nce i nter vals will use 9 5 % c o nfi d e nce le vels  f or b ot h s u m mar y statistics a n d 
statistical a nal ysis, u nless ot her wise state d.  
U nless ot her wise s pecifie d, c o nti n u o us data will be s u m marize d usi n g des cri pti ve 
statistics: n, mea n, sta n dar d de viati o n (st d), me dia n, mi ni m u m a n d ma xi m u m. 
Cate g orical data will be s u m mariz e d as t he n u m ber a n d perce nta ge of partici pa nts i n eac h 
cate g or y.  
4. 1. 2.  
B a s eli n e D efi niti o n  
F or all e n d p oi nts t he bas eli ne val ue will be t he lat est pre -d ose wit h a n o n -missi n g val ue, 
i ncl u di n g da y 1 pre -d ose a n d t h ose fr o m u nsc h e d ule d visits pri or t o t he first d ose of st u d y 
treat me nt. F or Part A, baseli ne will be defi ne d as t he latest pre -d os e as sess me nt at t he 
start of eac h treat me nt peri o d.   
Baseli ne Q Tc F will be calc ulate d as t he a v era ge of t he t hree pre -d ose m eas ure me nts o n 
Da y 1.  
U nless ot her wise state d, if baseli ne dat a is missi n g n o deri vati o n will be perf or me d a n d 
baseli ne will be set t o  missi n g.  
4. 1. 3.  
M ulti c e ntr e  St u di e s  
D ue t o t he s mall sa m ple siz e of t his first ti me i n h u ma n st u d y, if m ulti ple ce ntres are 
utilise d f or recr uit me nt p ur p oses, all data will be p o ole d a n d n o s u m maries will be 
pr o vi de d b y site  or c o u ntr y .  
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4.1.4. 
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 
‘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.  
 
4.2. 
Primary Endpoints Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified.  
Primary Endpoints: 
• Adverse events (AEs) and serious adverse events (SAEs). 
• Clinically significant laboratory values, vital signs, 12-lead electrocardiogram 
(ECG) and spirometry measurements up to Day 2 of the final treatment period in 
Part A, and Day 18 in Part B. 
• Clinically significant laboratory values, vital signs, 12-lead ECG and spirometry 
measurements up to Day 8 in Part C. 
4.2.1. 
Definition of endpoints 
Adverse events will be coded using the 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. 
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.  
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Clinically significant values are defined as: 
• Values in the potential clinical interest (PCI) ranges for laboratory values, vital 
signs and ECGs 
• Values that achieve the study stopping criteria (protocol section 7.2.5) for 
spirometry  
The same PCI ranges will be used for both healthy volunteers and stable asthmatics, with 
all ranges being defined in the OPS. 
4.2.2. 
Main analytical approach 
4.2.2.1. 
Adverse events and serious adverse events 
Adverse events analyses including the analysis of adverse events (AEs) and Serious AEs 
(SAEs) will be based on GSK Core Data Standards. All summaries will be tabulated by 
study intervention, cohort and dose, except for Cohorts 3 and 4. As cohorts 3 and 4 are 
identical in every aspect except the timing of bronchoscopy assessment, data from the 
two cohorts will be pooled and reported together. 
An overview summary of AEs, including counts and percentages of participants with any 
AE, AEs related to study intervention, moderate and severe AEs, moderate and severe 
AEs related to study intervention, AEs leading to permanent discontinuation of study 
intervention, study intervention related AEs leading to permanent discontinuation of 
study intervention, AE leading to dose reductions, AEs leading to dose delays, SAEs, 
SAEs related to study intervention, fatal SAEs, and fatal SAEs related to study 
intervention as well as bronchoscopy related AEs will be produced. 
The frequency and percentage of AEs will be summarized and displayed in two ways: 1) 
in descending order by preferred term (PT) only and 2) in descending order by system 
organ class (SOC) and PT.   
All SAEs will be tabulated based on the number and percentage of participants who 
experienced the event.  
Separate summaries will also be provided for study intervention-related AEs and SAEs, 
AEs leading to permanent discontinuation of study intervention and study intervention 
related AEs leading to permanent discontinuation of study intervention. These summary 
tables will be displayed by PT.   


C O N FI D E N TI A L  
 
 
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1 6  
4. 2. 2. 2.  
L a b or at or y D at a , Vit al Si g n s, E C G s a n d S pir o m etr y 
F or la b orat or y data, s e parate ta bles f or hae mat ol o g y, cli nical c he mistr y a n d uri nal ysis 
tests will be pr o d uce d. Li ver bi oc he mical para m eters  will be i ncl u de d wit h cli nical 
c he mistr y t ests. Vital si g ns data will i ncl u de se mi s u pi ne s yst olic a n d diast olic bl o o d 
press ure, p ulse rate, res pirat or y rat e a n d te m perat ure meas ure me nts.  
E C G data will i ncl u de  P R, Q R S, Q T a n d Q Tc F i nter vals.  
S pir o metr y dat a will i ncl u de F E V 1 a n d F V C meas ure me nts.  
F or hae mat ol o g y, cli nical c he mistr y, uri n al ysis , vital si g ns, E C G a n d s pir o metr y d ata t he 
f oll o wi n g i nf or mati o n will be s u m marise d: 
1.  Cli nicall y  si g nifica nt val ues at eac h visit 
2.  Ra w a n d c ha n ge  fr o m baseli ne val ues  at eac h visit  
N ote: T he first ta ble is t h e o nl y o n e i ncl u de d as p art of t he pri mar y e n d p oi nt. 
 
 
  
I n or der t o det ect p ote nti al br o nc h os pas ms, a n a d diti o nal ta ble f or s pir o metr y val u es will 
be pr o d uce d w hic h s u m marises t he c ha n ges bet w ee n dail y pre - a n d p ost -d ose F E V 1 a n d 
F V C val ues.  
F or E C Gs, a fi g ure pl otti n g t he b aseli ne Q Tc F  a n d t he w orst -cas e p ost -bas eli ne val ues 
will be pr o d uce d. T h e fi g ure will ha ve refere n ce li nes at 4 8 0 a n d 5 0 0 msec f or b ot h t he 
or di nate a n d t he a bscissa a x es. T here will be dia g o nal refere n ce li nes at e q ualit y (i.e. a 4 5 
de gree li ne), at e q u alit y pl us 3 0 msec, a n d at e q ualit y pl us 6 0 msec.  
4. 3.  
S e c o n d ar y E n d p oi nt s A n al y s e s  
All p har mac o ki netic a nal ys es will be p erf or me d o n t he P har mac o ki netic A nal ysis Set . 
F or P K e n d p oi nts, all a nal ysis will be perf or me d b y Part i.e. Part A ( C o h orts 1 a n d 2 
c o m bi ne d), Part B ( C o h orts 3 a n d 4 c o m bi ne d) a n d Part C ( C o h ort 5).  
Deri ve d p har mac o ki n etic para meters as dat a per mit, i ncl u di n g ( b ut n ot li mite d t o):  
Part A, C o h orts 1 & 2:  
•  Area u n d er t he plas ma G S K 3 9 2 3 8 6 8 c o nce ntr ati o n vers us ti me c ur ve fr o m ti me 
zero t o last q ua ntifia ble c o nce ntrati o n ( A U C( 0 -t)) a n d fr o m ti me zer o t o i nfi nit y 
( A U C( 0-∞)) (if d eter mi n e d).  
•  Ma xi m u m o bser ve d G S K 3 9 2 3 8 6 8 plas ma c o nce ntrati o n ( C ma x).  
•  Ti me t o ma xi m u m o bser ve d plas ma dr u g c o n ce ntrati o n ( T ma x).  
Part B, C o h orts 3 & 4:  
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• AUC(0- ) on Day 1 and Day 14 ( =24h for once a day dosing regimen) (if 
determined). 
• Cmax and Tmax on Day 1 and Day 14. 
Part C, Cohort 5: 
• AUC(0- ) on Day 1 and Day 7 ( =24h for once a day dosing regimen) (if 
determined). 
• Cmax and Tmax on Day 1 and Day 7. 
4.3.1. 
Definition of endpoint(s) 
If the AUC(0-) or AUC(0-Inf) is not calculatable due to non-quantifiable plasma 
GSK3923868 data, AUC(0-t’) may be calculated instead. t’ is the common timepoint for 
all subjects for the corresponding dose or cohort. 
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- ) 
Area under the concentration-time curve over the dosing interval. 
AUC(0-Inf) 
Area under the concentration-time curve extrapolated to infinity will be 
calculated as follows: AUC = AUC(0-t) + C(t)/λz.  
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data over the dosing interval. 
C  
Trough concentration 
Tmax 
Time to reach Cmax, determined directly from the concentration-time 
data. 
t½ 
Apparent terminal half-life will be calculated as:  
t½ = ln2 / λz 
(NOTE: λz is the terminal phase rate constant). 
NOTE: Additional parameters may be included as required. 
 
4.3.2. 
Main analytical approach 
Plasma GSK3923868 concentration-time data will be analysed 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 form and will be summarised 
descriptively. Analysis of dose proportionality (Part A), steady state assessment and dose 
accumulation (Parts B and C) will be conducted.  


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4.3.2.1. 
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. A minimum of 3 doses will be required to assess dose proportionality.  The 
assessment of dose proportionality will utilise Part A data only.  
Dose proportionality will be assessed using the following two methods: 
Pharmacokinetic Statistical Analyses for Dose Proportionality: Power Method 
Endpoint(s) 
• AUC(0-Inf) (if determined, otherwise use AUC(0-t)), 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-Inf) (if determined, otherwise use AUC(0-t’)), 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. 
• Separate lines will be fitted for each cohort by including terms for cohort and 
cohort*loge(dose). If the slopes are not significantly (p-value<0.05) different from each other, 
the interaction term will be removed and a single slope estimate obtained. If the slopes are 
significantly different from each other, a separate slope estimate and associated 90% 
confidence interval will be reported for each cohort. 
• 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 
• 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 


C O N FI D E N TI A L  
 
 
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1 9  
P h ar m a c o ki n etic St atisti cal A n al ys es f or D o s e Pr o p orti o n alit y: A N O V A M et h o d  
( d os e), a n d p oi nt esti m ates a n d ass oci ate d 9 0 % c o nfide nc e int erv als for t he r ati o 
t est/r efer e nc e. 
•  P oi nt esti m at es a nd 9 0 % c o nfi d enc e i nterv a ls f or A U C, C max will b e r e p orte d to 2 d eci mal 
pl ac es . Tr eat m e nt r ati os a nd 9 0 % CIs will b e pl otte d by d os e.  
•  Pl ots will als o be pr ovid e d sh o wi n g t h e a dj ust e d g eo m etric m e a n r ati o of t est t o r efer e nc e 
tr e at m e nt ( d ose) f or A U C( 0-∞)  or A U C( 0 -t’), a n d C m ax t o get h er wit h 9 0 % c o nfi d enc e 
i nt erv al. 
 
4. 3. 2. 2.  
A c c u m ul ati o n a n d St e a d y  St at e A s s e s s m e nt  
T he assess me nt of acc u m ulati o n  a n d stea d y state  will be perf or me d f oll o wi n g re p eate d 
d osi n g of G S K 3 9 2 3 8 6 8 i n Parts B a n d C o nl y.  
P h ar m a c o ki n etic St atisti cal A n al ys es  
E n d p oi nt( s)  
•  Acc u m ul ati on: A U C( 0 -), C (if d at a p er mit ), C max o n D ay 1 4 ( Part B), D ay 7 ( Part C) 
c o m p ar e d t o Day 1 
•  St e ady Stat e: C  fr o m D ay 1 t o D ay 1 4  ( P art B) or D ay 7 ( P art C)  
•  E ac h e n dp oi nt t o b e ass esse d s e p ar ately f oll o wi ng a log -tr a nsf or mati on. 
M o d el S p e cific ati o n  
•  A mix e d eff ect mo d el will b e fitt e d wit h d ay as a fix ed effect an d su bj ect as a r a n do m eff ect.  
•  T h e K e n w ar d & R og er ( K R) d e gr ees of fr e ed o m a p pr oac h will b e use d.  
•  D ay 1 4 will be c o m par e d to D ay 1 i n or d er to esti m at e th e accu m ul ati on r ati o(s) 
•  T h e accu m ul ati on r ati o(s) a n d 9 0 % c o nfi de nc e i nt erv al will b e c alc ul ate d by b ack -
tr a nsf or mi n g t h e differ e nc e b et w ee n th e le ast sq u are m e a ns f or t he t w o d ays a nd 
ass oci at ed 9 0 % c o nfi de nc e i nt erv al.  
M o d el R e s ult s Pr e se nt ati o n  
•  P oi nt esti m at es a nd c onfi d enc e i nterv als f or th e rati os will b e r e p orte d to 2 d eci mal pl ac es  
•  Sc att er pl ots of eac h e nd p oint ag ai nst d ay will be pr od uc e d. T he d at a p oints for e ach s u bject 
will b e j oi n e d wit h str aig ht lin es  
•  B ox pl ots of e ach e n d poi nt ag ai nst d ay will b e pr od uc ed. E ac h tr e at m ent will b e p ut o n a 
s e p ar ate p a ge.  
 
4. 3. 2. 3.  
P o p ul ati o n P K M o d el  
A p o p ulati o n P K dataset ma y b e ge nerate d t o s u p p ort s u bse q ue nt p o p ulati o n P K 
m o delli n g. P o p ulati o n P K dataset will i ncl u de P K data  
 fr o m all 
s u bjects i n t his st u d y ( Parts A, B a n d C).  T h e p o p ulati o n P K data file will be pr o d uce d 
b y or u n d er t he a us pices of Cli nical Statistics ( Pr o gra m mi n g).  
A p o p ulati o n P K m o del ( P O P P K) ma y be d e vel o pe d wit h all a vaila ble dat a as 
ap pr o priate a n d ma y be re p orte d se p aratel y.  
 
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2 0  
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2 1  
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4. 5.  
Ot h er  A n al y s e s  
T he ot her  a n al ys es will be base d o n t he Safet y  A nal ysis Set, u nless ot her wise s pecifie d.  
4. 5. 1.  
E xt e nt of E x p o s ur e  
N u m ber of da ys of e x p os ure t o st u d y dr u g will be calc ulate d base d o n t he f or m ula:   
D urati o n of E x p os ure i n Da ys = Treat me nt St o p Date –  ( Treat me nt Start Date) + 1 
F or Part A, e x p os ure t o st u d y dr u g will be calc ulat e d se paratel y f or eac h treat me nt 
peri o d /treat me nt r ecei v e d.  
S u bjects w h o were ra n d o mize d b ut di d n ot re p ort a treat me nt start d ate (i.e. were 
ra n d o mize d i n err or) will be  cate g orise d as  ha vi n g zer o da ys of e x p os ure.  
T he c u m ulati ve d ose will be base d o n t h e f or m ula:  
C u m ul ative D ose = S u m of ( N u m ber of D ays x T ot al D aily D ose)  
 
4. 6.  
I nt eri m A n al y se s  
4. 6. 1.  
D o s e E s c al ati o n C o m mitt e e ( D E C)  
A re vie w of preli mi nar y safet y, t olera bilit y a n d pl as ma P K data will be c o n d ucte d b y t he 
D E C pri or t o eac h d os e le vel i n Part A, bef or e i nitiati n g re p eat d osi n g i n Part B, a n d 
bef ore re peat d osi n g ast h matics i n Part C.  
Safet y a n d t olera bilit y data will be pr o vi de d b y t he site at t he e n d of eac h d osi n g sessi o n, 
al o n g wit h a n al ysis of t h e plas ma P K data w hic h will be perf or me d usi n g n o mi na l 
sa m pli n g ti mes. 
T o mi ni mize t he ris k of u n bli n di n g d uri n g D E C meeti n gs, i n di vi d ual P K data will be 
scra m ble d s uc h t hat t he bli n d is mai ntai ne d.  S u m mar y st atistics will als o be pr o vi de d f or 
plas ma P K para met ers ( C ma x a n d A U C).  T he data ma y be u n bli n de d s h o ul d a safet y 
c o ncer n arise d uri n g t h e bli n de d re vie w.  
A d diti o nal details are a v aila ble i n t he D ose Escal ati o n Pla n.  
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4.6.2. 
Instream Analysis of PK Data 
Once Cohort 3 has completed, selected members of the GSK sponsor staff team will be 
formally unblinded to the treatment allocations of participants who completed the study 
to enable the analysis and modelling of PK data to start. Once Cohort 4 has completed, 
the same sponsor staff will also be unblinded to the treatment allocations of the 
completed participants from Cohort 4 to incorporate their data into the ongoing PK 
analysis and modelling. Access to unblinded subject-level data will be restricted to 
members of the Statistics and Programming and Clinical Pharmacology Modelling and 
Simulation teams, DMPK Modelling and Computational Science.  
The aim of this analysis is to inform internal decision making around dose selection for 
future studies in the development plan of this compound. This analysis will not impact 
the conduct or the design of the current study and will be reported separately from this 
SAP. 
4.7. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 24-Sep-2021). 
 


C O N FI D E N TI A L  
 
 
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2 4  
5.  
S A M P L E SI Z E D E T E R MI N A TI O N  
N o f or mal statistical tec h ni q ues were us e d t o calc ulate t he sa m ple siz e f or t his st u d y.  
T he n u m ber of partici pa nts i ncl u de d is dee me d a n a de q uate n u m b er t o pr o vi de a n 
assess me nt of safet y a n d t olera bilit y a n d p h ar mac o ki netics meas ure me nts, a n d t here b y t o 
all o w pr o gressi o n t o lar ger cli nical st u dies.  
A mi ni m u m of 5 partici pa nts recei vi n g eac h  d os e of acti ve dr u g (eit her as a si n gle or 
re peat d os e) are re q uire d f or t he d ose es calati o n m eeti n gs. Wit h 5 partici pa nts, if t he tr ue 
a d verse o ut c o me rat e is 5 %, t he c ha n ce of n ot o bs er vi n g a n y a d v erse e ve nts at a gi v e n 
d ose is 7 7 %. If t he tr u e a d verse o utc o me rate is 2 0 %, t he c ha n ce of n ot o bs er vi n g a n y 
a d verse e ve nts at a gi v e n d ose le vel is 3 3 %.  
F or Part A, s ufficie nt healt h y a d ult partici pa nts will be scree n e d t o e ns ure a t otal of 1 2 
partici pa nts per c o h ort are ra n d o mize d wit h t he ai m t o ac hie ve a p pr o xi matel y 1 2 p er 
c o h ort c o m plete d.   
I n t otal f or Part A, 9 partici pa nts are pl a n ne d t o recei ve eac h d ose of acti ve dr u g i n eac h 
peri o d. If t he tr u e a d v ers e o utc o me rat e is 5 %, t he c ha nce of n ot o bser vi n g a n y a d verse 
e ve nts at a gi ve n d os e is 6 3 %. If t he t r ue a d verse o utc o me rate is 2 0 %, t he c ha nce of n ot 
o bser vi n g a n y a d v erse e v e nts at a gi ve n d ose le vel is 1 3 %.  
I n Part B, s ufficie nt healt h y a d ult partici pa nts will be scree ne d t o e ns ure 8 p artici pa nts 
are ra n d o mize d t o eac h of t he t w o c o h orts, wit h t he aim t o ac hie ve a p pr o xi matel y 8 
c o m plete d i n eac h c o h ort.   
F or Part C, s ufficie nt partici pa nts wit h ast h ma will be scree ne d t o e ns ure 1 6 partici pa nts 
are ra n d o mise d, wit h t he ai m t o ac hie ve 1 6 c o m pleters . Part C will be ra n d o mise d 
acc or di n g t o t w o strata, S A B A a n d/ or i nter mitte nt I C S/ L A B A users a n d I C S or I C S/ L A B A 
users.  
I n Parts B a n d C, 1 2 partici pa nts are pla n ne d t o recei v e eac h d ose of acti ve dr u g. T h e 
c orres p o n di n g pr o ba bilities f or 1 2 partici pa nts wit h tr ue e ve nt rates of 5 % a n d 2 0 % are 
5 4 % a n d 7 %, res p ecti vel y.   
T his le vel of pre dicti vit y is dee me d a de q u ate wit hi n t his p hase of de vel o p m e nt.  
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2 5  
F or Parts A, B a n d C if p artici pa nts pre mat urel y disc o nti n ue i n t he st u d y, t he y will be 
re place d at t he discreti o n of t he s p o ns or Me dical M o nit or i n c o ns ultati o n wit h t he 
Pri nci pal I n v esti gat or.   
 
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2 6  
6.  
S U P P O R TI N G D O C U M E N T A TI O N  
6. 1.  
A p p e n di x 1 A b br e vi ati o n s a n d Tr a d e m ar k s  
6. 1. 1.  
Li st of A b br e vi ati o n s  
A b br e vi ati o n  
D e s cri pti o n  
A E  
A d v er s e E v e nt  
CI  
C o nfi d e n c e I nt er v al  
C P M S  
Cli ni c al P h ar m a c ol o g y M o d elli n g & Si m ul ati o n  
C S  
Cli ni c al St ati sti c s  
C S R  
Cli ni c al St u d y R e p ort  
% C V  
C o effi ci e nt of V ari ati o n  
D E C  
D o s e E s c al ati o n C o m mitt e e  
D P  
D e ci m al Pl a c e s  
e C R F  
El e ctr o ni c C a s e R e c or d F or m  
F TI H  
Fir st Ti m e i n H u m a n  
G S K  
Gl a x o S mit h Kli n e  
I A 
I nt eri m A n al y si s 
M M R M  
Mi x e d M o d el R e p e at e d M e a s ur e s  
O P S  
O ut p ut a n d Pr o gr a m mi n g S p e cifi c ati o n  
P CI  
P ot e nti al Cli ni c al I m p ort a n c e  
P K  
P h ar m a c o ki n eti c  
P P  
P er Pr ot o c ol  
P T  
 Pr ef err e d T er m  
P o p P K  
P o p ul ati o n P K  
Q C  
Q u alit y C o ntr ol  
Q T c F  
Fr e d eri c a’ s Q T I nt er v al C orr e ct e d f or H e art R at e  
S A P  
St ati sti c al A n al y si s Pl a n  
S O C  
S y st e m Or g a n Cl a s s  
 
6. 1. 2.  
Tr a d e m ar k s  
Tr a d e m ark s of t h e Gl a x o S mit h Kli n e 
Gr o u p of C o m p a ni e s  
 
Tr a d e m ark s n ot o w n e d by t h e 
Gl a x o S mit h Kli n e Gr o u p of C o m p a ni e s  
N o n e  
 
N O N M E M  
 
 
S A S  
 
 
Wi n N o nli n  
 
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7. 
REFERENCES 
GSK Document Number 2011N124265_00, A single-centre, double-blind, placebo 
controlled three part study to evaluate the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single and repeat doses of nebulised GSK2269557 in healthy male 
subjects, 2013 
GSK Document Number 2013N183586_00, A Single-centre, Double-blind, Placebo 
Controlled Three Part Study to Evaluate the Safety, Tolerability and Pharmacokinetics of 
Single and Repeat Doses of GSK2269557 as a Dry Powder in Healthy Subjects who 
Smoke Cigarettes, 2014 
GSK Document Number 2020N430088_00, 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, 2020 
GSK Document Number TMF-13791516, 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, 2021