Clinical trial NCT05044325
Conditions: Heart Failure
Keywords: First Time in Human GSK3884464 Pharmacokinetics Pharmacodynamics Safety Tolerability
Sponsor: GlaxoSmithKline
Start date: 2021-09-20; Completion date: 2022-08-05
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This will be a FTIH study which aims to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat oral doses of GSK3884464 administered to healthy participants.

Detailed description:

Arms: arm 1: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: Placebo C1/ GSK3884464 3 milligrams (mg)/ GSK3884464 9mg across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 2: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: GSK3884464 1 mg/ Placebo C1/ GSK3884464 9mg across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 3: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: GSK3884464 1 mg/ GSK3884464 3 mg / Placebo C1 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 4: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: Placebo C2/ GSK3884464 110 mg/ Single Dose (SD) 6 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 5: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: GSK3884464 30 mg/ Placebo C2/ SD6 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 6: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: GSK3884464 30 mg/ GSK3884464 110 mg / Placebo C2 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 7: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: Placebo C3/ SD8/ SD9 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 8: Participants received GSK3884464 or placebo through oral administration in the treatment sequence: GSK3884464 70 mg/ SD8/ Placebo C3 across 3 treatment periods. There was a minimum of 7 days washout period between dosing in each session. arm 9: Participants received GSK3884464 15 mg through oral administration. arm 10: Participants received placebo through oral administration in Cohort 4.
Interventions: intervention 1: GSK3884464 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3884464 will be administered intervention 2: Placebo to match GSK3884464 will be administered.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
                                                      PROTOCOL 
 
 
Study ID: 213376 
 
Official Title of Study  A Two-Part First Time in Human (FTIH) Study to Evaluate 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Oral Doses 
of GSK3884464 in a Randomized, Double Blind, Placebo-Controlled, Dose Escalation Study in 
Healthy Participants 
 
NCT ID-NCT05044325     
 
Date of Document: 06-Apr-2022 
 
 


T M F - 1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
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 3 7 6
 
 
Pr ot A m e n d 4  
 
1  
TI T L E P A G E  
Pr ot oc ol Title: A T w o -P art First Ti me i n H u ma n ( F TI H) St u d y t o E v al uate Safet y, 
T olera bilit y, P har m ac o ki netics, a n d P har mac o d y n a mics of Si n gle a n d Re peat Oral D oses 
of G S K 3 8 8 4 4 6 4 i n a Ra n d o mize d, D o u ble Bli n d, Place b o -C o ntr olle d, D os e Escalati o n 
St u d y i n H ealt h y Partici p a nts  
Pr ot oc ol N u m ber : 2 1 3 3 7 6 / A me n d me nt 0 4  
C o m p o u n d 
N u m ber:  
G S K 3 8 8 4 4 6 4   
 
St u d y P h ase:  P hase 1  
 
S h ort Title : A F TI H st u d y t o e v al uate t he safet y, t olera bilit y, p har mac o ki n etics, a n d 
p har mac o d y n a mics of si n gle a n d re p eat d oses of G S K 3 8 8 4 4 6 4 i n healt h y partici pa nts  
 
S p o ns or N a me a n d Le g al Re gistere d A d dress:  
M D, P h D   
Gla x o S mit h Kli ne Researc h & D e vel o p me nt Li mite d  
9 8 0 Great W est R oa d  
Bre ntf or d  
Mi d dlese x, T W 8 9 G S  
U K  
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n  C a n be f o u n d i n t he St u d y Refere n ce 
Ma n ual  
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  2 0 2 1 -0 0 1 7 2 4 -1 7  
A p pr o v al D ate: 0 6  A pr 2 0 2 2  
 
 
C o p yri g ht 2 0 2 2  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


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
TMF Number 
Amendment 04 
06 Apr 2022 
TMF- 14577739 
Amendment 03 
17-FEB-2022 
TMF- 14464572 
Amendment 02 
04-JAN-2022 
TMF-14366164 
Amendment 01 
19-AUG-2021 
TMF-13947787 
Original Protocol 
09-JUN-2021 
TMF-13810865 
Amendment 04 06 Apr 2022 
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 because it impacts the safety of participants. 
Overall Rationale for the Amendment: This Protocol Amendment 04 is being 
implemented to update safety monitoring and to correct typographical errors. 
Where the Amendment Applies: 
This Protocol Amendment 04 applies to all countries and sites participating in the study. 
Table of Specific Changes: 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
3 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis: Overall 
Design, Disclosure Statement 
and Intervention Groups and 
Duration 
Previous: 
There will be three cohorts with 9 
participants in each cohort, each cohort 
will have 3 time periods. 
 
Revised: 
There will be up to three cohorts with 9 
participants in each cohort, each cohort 
will have up to 3 time periods. 
 
Previous: 
Part 2 will be a sequential design, 14-day 
(Cohorts 4 and 5) and 21-days (Cohort 6) 
repeat-dose (RD), dose escalation study 
in healthy participants. It will consist of 3 
ascending dose cohorts with 8 
participants per cohort. 
 
Revised: 
Part 2 will be a sequential design, 14-day 
(Cohorts 4 and 5) and up to 21-days 
(Cohort 6) repeat-dose (RD), dose 
escalation study in healthy participants 
(See Section 4.4). It will consist of up to 
3 dose cohorts with 8 participants per 
cohort. 
 
Previous: 
This is a First Time in Human Study. 
Sentinel dosing will be incorporated in 
each Part of the study and at each dose 
level. For Part 1, only 2 to 3 participants 
will be dosed at a time, and their LFTs 
will be monitored until Day 6 before the 
next participants in the cohort are dosed. 
Revised: 
This is a First Time in Human Study. 
Sentinel dosing will be incorporated in 
each Part of the study and at each dose 
level. For Part 1, up to 3 participants will 
be dosed at a time, and their LFTs will be 
monitored until Day 6 or until resolution 
(whichever is later) before the next 
participants in the cohort are dosed. For 
Part 2, up to 3 participants will be dosed 
at a time and will be monitored for a 
minimum of 5 days prior to dosing the 
rest of the cohort. 
 
Previous: 
Part 1 will consist of three cohorts. Each 
cohort will include 3 intervention periods. 
These will each be a single dose, 
The change was made to 
allow flexibility of up to 3 
cohorts in each Part and up 
to 3 dose levels in each 
cohort, and extension of 
duration of each cohort.  
 
 
 
This change was made to the 
dosing schedule to permit 
closer safety monitoring of 
LFTs for participants in Part 
2 of the study. 
 
 
 
 
The change was made to 
allow flexibility of up to 3 
participants in each Part (1 
and 2), up to 3 dose levels in 
each cohort, and in length of 
duration of Cohort 6. 
 
 
 
 
 
 
 
 
 
 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
4 
Section # and Name 
Description of Change 
Brief Rationale 
crossover design. 
Part 2 will consist of three cohorts. 
Cohorts 4 and 5 (14-day) and Cohort 6 
(21-day) will be a sequential group, 
repeat dose with one intervention period. 
 
Revised: 
Part 1 will consist of up to three cohorts. 
Each cohort could include up to 3 
intervention periods. These will each be a 
single dose, crossover design. 
Part 2 will consist of up to three cohorts. 
Cohorts 4 and 5 (14-day) and Cohort 6 
(up to 21-days) will be a sequential 
group, repeat dose with one intervention 
period (See Section 4.4). 
 
Previous: 
Part 1: Each of the 3 cohorts will be 
approximately 70 days. 
Part 2: Cohorts 4 and 5 will be 
approximately 61 days and Cohort 6 will 
be approximately 68 days. 
Revised: 
Part 1: Each of the 3 cohorts will be 
approximately 76 days. 
Part 2: Cohorts 4 and 5 will be 
approximately 72 days and Cohort 6 will 
be approximately 80 days. 
 
 
 
This change was made to the 
length of the study Parts as a 
result of the closer safety 
monitoring of LFTs for study 
participants.  
 
 
Update of length of study 
due to additional and 
updated safety measures. 
 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
5 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema  
 
 
 
 
 
 
 
 
Figure 1 Overall Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 Part 1 Design and 
Cohort Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Part 2 Design 
 
 
 
 
 
 
 
Previous: 
Within a cohort, participants will be 
randomized to one of 3 treatment 
sequences such that each participant 
receives 2 active doses and 1 placebo 
dose resulting in each active dose being 
administered to 6 participants and 
placebo to 3 participants. 
Revised: 
Within a cohort, participants will be 
randomized to one of 3 treatment 
sequences such that each participant 
receives up to 2 active doses and 1 
placebo dose resulting in each active dose 
being administered to up to 6 participants 
and placebo to up to 3 participants. 
Previous: 
Part 2, Cohorts 4 and 5 will be 14 days 
and Cohort 6 will be 21 days 
Revised: 
Part 2, Cohorts 4 and 5 will be 14 days 
and Cohort 6 will be up to 21 days 
Previous:  
Final Dose Escalation Meeting: Dose 
escalations will be determined by PK and 
full safety data 
Revised: 
Final Dose Escalation Meeting: Dose 
escalations will be determined by full 
safety data, PK data and PD data (if 
available). 
Previous: 
Dose escalations will be determined by 
PK and Safety data 
Revised: 
Dose escalations will be determined by 
Safety data, PK data and PD data (if 
available). 
Previous: 
Subsequent dose escalations will be 
determined based on safety and PK data 
Revised: 
Subsequent dose escalations will be 
determined based on safety, PK data and 
PD data (if available). 
This change was made to the 
length of the study Parts as a 
result of the closer safety 
monitoring of LFTs for study 
participants. 
 
 
 
 
 
Added in review of PD data 
for Dose escalation 
decisions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
6 
Section # and Name 
Description of Change 
Brief Rationale 
Figure 4 Part 2 Cohorts 4 and 
5 Dosing 
 
 
Figure 5 Part 2 Cohort 6 
Dosing 
 
Previous: 
Dose escalations will be determined by 
PK and Safety data 
Revised: 
Dose escalations will be determined by 
Safety data, PK data and PD data (if 
available) 
Previous: 
Cohorts 4 and 5 will be approximately 61 
days. 
 
Revised: 
Cohorts 4 and 5 will be approximately 72 
days. 
 
Previous: 
Cohort 6 will be approximately 68 days. 
 
Revised: 
Cohort 6 will be approximately 80 days. 
Study treatment may be less than 21 days. 
 
 
 
 
Update of length of study 
due to additional and 
updated safety measures. 
 
Section 1.3 Schedule of 
Activities 
Previous: 
The Ethics Committee (EC) will be 
informed of any safety issues that require 
alteration of the safety monitoring 
scheme or amendment of the informed 
consent form (ICF).  
Revised: 
The UK ethics board, the MHRA and 
investigator will be informed of any 
significant safety issues, including those 
that require amendment of the Patient 
Information Sheet and Consent Form 
(PICF). 
Clarification on who (and 
under what circumstance) to 
inform (UK ethics, MHRA 
and the investigator) when 
changes are required to the 
Patient Information Sheet 
and Consent Form (PICF). 
Language aligns with 
Section 8 Study Assessments 
and procedures. 
Section 1.3.1 Part 1: Single 
Dose Administration in 
Healthy Participants (Cohorts 
1, 2 and 3) 
 
Clinical laboratory assessments 
(heme/chem/ 
urinalysis-including liver 
chemistries) 
 
Plasma NT-proBNP 
Revised: Added X in SOA 
Gamma-glutamyl transferase (GGT) 
added in SOA to Days 4, 6, and Follow 
up  
Revised: Text Added 
*EW and Follow up Visit or until 
resolution (whichever is later). 
Previous: 
*Serum and renal chemistries only pre-
dose on D1.  
 
Revised: 
Daily serum chemistries D4 through D6 
Additional chemistry blood 
draws added in Part 1 to 
monitor for liver chemistry 
changes.  
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
7  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
a n d  E W  as re q uire d. F oll o w u p u ntil 
res ol uti o n as re q uire d, 
Pre vi o us:  
Pre -d ose a n d 2 4 hr o n D 2 a n d at f oll o w u p 
visit.  
Re vise d:  
Pre -d ose ,2 4 hr o n D 2 , Da y 6 pri or t o 
disc har ge , a n d at f oll o w u p visit.  
Secti o n 1. 3. 2: P art 2 ( C o h orts 
4 a n d 5): M ulti ple D ose 
A d mi nistrati o n t o Healt h y 
P artici pa nts f or 1 4 da ys of 
Treat me nt  
Cli nical la b orat or y assess me nts 
( he me/c he m/ 
uri nal ysis -i ncl u di n g li ver 
c he mistries)  
 
 
 
 
 
 
 
 
 
 
C ore Uri ne Safet y m o nit ori n g 
assess me nts  
 
 
 
 
 
 
 
C o nti n u o us car diac tele metr y  
 
 
 
 
 
 
 
 
 
 
E nter o -Trac ker  
or E nter o -T est ( bile sa m ple 
c ollecti o n  
E nter o -Trac ker  or E nter o -T est 
 
 
 
 
 
Re vise d: A d de d te xt  
* Ga m ma -G T o n da ys 7 -1 4, D 1 9, F oll o w 
u p a n d Earl y Wit h dra wal Visit or u ntil 
res ol uti o n ( w hic he ver is later). 
Pre vi o us:  
* D 1, D 4, D 1 1 a n d D 1 8  (ser u m a n d re nal 
c he mistries o nl y).  
Re vise d:  
Dail y ser u m c he mistries a n d uri nal ysis 
fr o m D 3 t hr o u g h 2 4 hrs after last da y of 
d osi n g , at D 1 9 a n d F oll o w u p Visit or 
u ntil res ol uti o n ( w hic he ver is l ater)  
Pre vi o us:  
* D 4 a n d D 1 1 o nl y.  
Re vise d  
* Dail y U A C R fr o m da y 4 t hr o u g h 2 4 hrs 
after last da y of d osi n g a n d D 1 9.   
A d diti o nal testi n g as re q uire d u ntil 
res ol uti o n. 
Pre vi o us :  
C o nti n u o us car diac m o nit ori n g s h o ul d be 
starte d a p pr o xi matel y 9 0 mi n b ef ore 
d osi n g o n D 1 t hr o u g h D 1 4 aft er t he 
H olter M o nit or is a p plie d .  
Re vise d:  
C o nti n u o us car diac m o nit ori n g s h o ul d be 
starte d a p pr o xi matel y 9 0 mi n b ef ore 
d osi n g o n D 1 t hr o u g h D 1 5  aft er  
 
is re m o ve d. 
Pre vi o us:  
O nl y i n eit her C o h ort 5 or 6 ( de pe n di n g 
A d diti o nal c he mistr y bl o o d 
dra ws a n d Uri ne Al b u mi n t o 
Creati ne rati o ( U A C R) a d de d 
i n P art 2 t o m o nit or f or li ver 
a n d re nal  c he mistr y c ha n ges.  
 
 
 
 
 
 
 
 
 
 
 
C orrecti o n of tele metr y 
n ote s. 
 
 
 
 
 
U p date d n otes t o i ncl u de 
C o h ort 4 as part of t he 
C CI
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
8  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
f o o d c ue 
 
o n P K fr o m C o h ort 1)  
Re vise d:  
O nl y i n eit her C o h ort 5 or 6 ( de pe n di n g 
o n P K fr o m P art 1, a n d C o h ort 4 ).  
decisi o n ma ki n g f or E nter o -
Trac ker ti mi n g.  
Secti o n 1. 3. 3: P art 2 ( C o h ort 
6): M ulti ple D ose 
A d mi nistrati o n t o Healt h y 
P artici pa nts f or 2 1 da ys of 
Treat me nt  
 
 
 
 
 
Cli nical la b orat or y assess me nts 
( he me/c he m/ 
uri nal ysis -i ncl u di n g li ver 
c he mistries)  
 
 
 
 
 
C ore Uri ne Safet y m o nit ori n g 
assess me nts  
 
 
 
C o nti n u o us car diac tele metr y  
 
 
 
 
 
E nter o -Trac ker  
or E nter o -T est ( bile sa m ple 
c ollecti o n  
E nter o -Trac ker  or E nter o -T est 
f o o d c ue 
Pre vi o us  
P art 2 ( C o h ort 6):  M ulti ple D ose 
A d mi nistrati o n t o Healt h y P artici pa nts f or 
2 1 da ys of Treat me nt  
Re vise d  
P art 2 ( C o h ort 6): M ulti ple D ose 
A d mi nistrati o n t o Healt h y P artici pa nts f or 
u p t o  2 1 da ys of Treat me nt . 
Re vise d:  
* Ga m ma -G T o n da y 7 -1 4 , D 2 1 , F oll o w 
u p  a n d Earl y Wit h dra wal  Visit or u ntil 
res ol uti o n ( w hic he ver is later). 
Pre vi o us:  
* D 1, D 4, D 1 1 a n d D 1 8  (ser u m a n d re nal 
c he mistries o nl y).  
Re vise d:  
* Dail y c he mistries a n d uri nal ysis fr o m 
D 3 t hr o u g h last da y of d osi n g, at  D 2 6  a n d  
F oll o w u p Visit or u ntil res ol uti o n 
( w hic he ver is later). 
Pre vi o us:  
* Da ys 4, 1 1 a n d 1 8 o nl y .  
Re vise d  
* Dail y U A C R fr o m da y 4 t hr o u g h 2 4 hrs 
after last da y of d osi n g a n d D 2 6 .  
A d diti o nal testi n g as re q uire d u ntil 
res ol uti o n. 
Pre vi o us :  
C o nti n u o us car diac m o nit ori n g s h o ul d be 
starte d a p pr o xi matel y 9 0 mi n b ef ore 
d osi n g o n D 1 t hr o u g h D 2 1  aft er t he 
H olter M o nit or is a p plie d .  
Re vise d:  
C o nti n u o us car diac m o nit ori n g s h o ul d be 
starte d a p pr o xi matel y 9 0 mi n b ef ore 
d osi n g o n D 1 t hr o u g h D 2 2  aft er  
 
 is re m o ve d. 
Pre vi o us:  
O nl y i n eit her C o h ort 5 or 6 ( de pe n di n g 
o n P K fr o m C o h ort 1)  
T he c ha n ge was ma de t o 
all o w fle xi bilit y of d osi n g i n 
C o h ort 6  
 
 
 
 
A d diti o nal c he mistr y bl o o d 
dra ws a n d Uri ne Al b u mi n t o 
Creati ne rati o ( U A C R) a d de d 
i n P art 2 t o m o nit or f or li ver 
a n d re nal c he mistr y c ha n ges  
 
 
 
 
 
 
 
 
C orrecti o n of tele metr y 
n otes.  
 
 
 
 
U p date d n otes t o i ncl u de 
C o h ort 4 as part of t he 
decisi o n ma ki n g f or E nter o -
Trac ker ti mi n g . 
C CI
C CI


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
9 
Section # and Name 
Description of Change 
Brief Rationale 
Revised: 
Only in either Cohort 5 or 6 (depending 
on PK from Part 1 and Cohort 4).  
Section 2.2 Background 
Previous: 
The preclinical findings to date 
(described in detail in the Investigator’s 
Brochure) suggest GSK3884464 acts 
through a novel mechanism of action for 
the treatment of HFrEF 
[GlaxoSmithKline Document Number 
RPS-CLIN-000167] 
Revised: 
The preclinical findings to date 
(described in detail in the Investigator’s 
Brochure) suggest GSK3884464 acts 
through a novel mechanism of action for 
the treatment of HFrEF 
[GlaxoSmithKline Document Number 
RPS-CLIN-000167] 
Updated IB number of IB 
Supplement. 
Section 2.3 Benefit/Risk 
Assessment 
Previous: 
Summaries of findings from these pre-
clinical studies can be found in the IB 
[GlaxoSmithKline Document Number 
RPS-CLIN-000167].  
Revised: 
Summaries of findings from these pre-
clinical studies can be found in the IB 
[GlaxoSmithKline Document Number 
RPS-CLIN-000167].  
Previous: 
IB [GlaxoSmithKline Document Number 
RPS-CLIN-000167]. 
Revised: 
IB [GlaxoSmithKline Document Number 
RPS-CLIN-000167031946]. 
Updated IB number of IB 
Supplement. 
Section 2.3.1 Risk 
Assessment Exclusion Criteria 
 
 
 
Study Stopping criteria  
Renal 
 
Previous: 
Screening urine albumin:creatinine ratio 
30 mg/gm (>3 mg/mmol). 
Revised: 
Screening urine albumin:creatinine ratio 
30 mg/gm (≥3 mg/mmol). 
Previous: 
Renal stopping criteria: Participants (all 
parts) 
Revised 
Renal stopping criteria: Individual (all 
Corrected symbol > to ≥. 
 
 
 
 
 
 
Section updated and renal 
stopping criteria was further 
defined to better monitor 
potential safety signals.  
 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
10 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Stopping criteria 
Hepatoxicity 
 
 
 
 
 
 
parts) 
Previous: 
New onset of any clinically significant 
and persistent (within 48 hrs) hematuria 
as confirmed by microscopy. 
Revised: 
New onset of any clinically significant 
and persistent (for 48 hrs) hematuria as 
confirmed by microscopy (in the absence 
of any other clinical cause). 
Previous: 
New onset of clinically significant and 
persistent (within 48 hrs) proteinuria 
(Spot Urine Albumin Creatinine ratio 
[ACR] ≥3mg/mmol) in the absence of 
another clinical explanation e.g. 
calculus/infection  
Revised: 
New onset of clinically significant and 
persistent (for 48 hours from the dosing 
day in the SAD part and at any point in 
the MAD) proteinuria (Spot Urine 
Albumin Creatinine ratio [ACR] 
≥30mg/mmol) in the absence of another 
clinical explanation e.g. 
calculus/infection  
Previous: 
Change in serum creatinine >26 μmol/L 
(0.3 mg/dl) from baseline or > 25 % from 
baseline. If change in serum creatinine 
measures >26 μmol/L (0.3 mg/dl) or > 25 
%, repeat within 24 hrs. If confirmed, the 
participant will be withdrawn. If a 
participant meets the withdrawal criteria 
for serum creatinine, then further 
investigations will be performed. 
Revised: 
If there is any increase in serum 
creatinine >26μmol/L (>0.3mg/dl), repeat 
within 24 hours. If confirmed, the 
participant will be withdrawn, and further 
investigations will be performed. 
Increase in serum creatinine (ΔsCr) of 
>25% from baseline on 2 consecutive 
assessments within 24 hours. If 
confirmed, the participant will be 
withdrawn, and further investigations will 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TMF-14577739 
CONFIDENTIAL 
213376 
 
Prot Amend 4 
 
11 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
be performed. 
Previous: 
The study will be temporarily halted if 2 
or more participants across all study parts 
develop any of the above withdrawal 
criteria when considered related to study 
treatment. 
Revised 
If 2 or more participants in a given dose 
cohort develop any of the above 
withdrawal criteria, when considered 
related to study drug, then that cohort will 
be temporarily halted. 
Previous: 
Liver enzymes and bilirubin assessments. 
Revised: 
Liver enzymes and bilirubin assessments 
D4 through D6 in SAD and daily (from 
day 3 through 24hrs after last day of 
dosing, and at D19) in the MAD part of 
the study.  
Revised: Added Text 
Careful LFT monitoring will be 
implemented in the Part 2 of the study to 
minimise the risk of exposing the 
participants to additional study drug in 
the case of an elevation of ALT/AST 
above the individual stopping criteria. 
Revised: Text added 
In the ongoing study 213376, three cases 
of transient LFT increase have been 
observed in the 110mg single dose level 
with no concurrent symptoms. 
Previous: 
Liver Stopping Criteria 
 
Revised: 
Individual Liver Stopping Criteria 
 
Clarified study stopping 
criteria based on study drug 
not placebo.  
 
 
 
 
 
Clarification of liver 
stopping criteria. 
 
 
 
 
Section updated and liver 
stopping criteria was further 
defined to better monitor 
potential safety signals.  
 
Section 4.1 Overall Design 
 
Previous: 
Each participant will participate in 3 
dosing periods and will receive 2 doses of 
GSK3884464 and 1 dose of placebo in a 
randomized fashion. 
Revised: 
Each participant will participate in up to 3 
dosing periods and will receive up to 2 
These changes were made to 
the dosing criteria to clarify 
that the dose may be adjusted 
between dosing periods and 
to describe how to proceed 
with dosing and the 
minimum number of 
participants required in case 
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Brief Rationale 
doses of GSK3884464 and 1 dose of 
placebo in a randomized fashion. 
Previous  
A minimum of 3 cohorts is anticipated. If 
a participant is withdrawn from the study, 
the participant may be replaced as 
necessary with another participant 
assigned to the same treatment sequence 
with respect to active and placebo doses 
to ensure that at least 4 participants 
receive each active dose and 1 participant 
receives placebo and must complete the 
safety and PK assessments through at 
least the 120hr post-dose (or 5 half-lives, 
whichever is longer). 
Revised: 
A minimum of 3 cohorts is anticipated. If 
a participant is withdrawn from the study, 
the participant may be replaced as 
necessary with another participant 
assigned to the same treatment sequence 
with respect to active and placebo doses 
to ensure that at least 3 participants 
receive each active dose and 1 participant 
receives placebo and must complete the 
safety and PK assessments through at 
least the 120hr post-dose (or 5 half-lives, 
whichever is longer). 
Previous: 
Part 2 will be a sequential design, 14-day 
(Cohorts 4 and 5) and a 21-day (Cohort 6) 
repeat-dose (RD), dose escalation study 
in healthy participants.  
Revised: 
Part 2 will be a sequential design, 14-day 
(Cohorts 4 and 5) and up to a 21-day 
(Cohort 6) repeat-dose (RD), dose 
escalation study in healthy participants 
(See Section 4.4). 
Previous: 
Participants will report to the Clinical 
Research Unit on Day –1 and will remain 
in the unit until completion of the 
assessments on Day 19 (Cohorts 4 and 5) 
or Day 26 (Cohort 6). Participants will be 
randomly assigned to receive 
GSK3884464 or placebo (approximately 
6 study intervention and 2 placebo). 
Plasma and urine PK, PD, and biomarker 
samples will be collected through the 19-
 
 
 
 
 
 
 
Update to language to permit 
at least 3 participants on 
active dose with safety and 
PK through 120 hours may 
be used dosing decisions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Update to language in Part 2 
to provide flexibility in 
Cohort 6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section # and Name 
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Brief Rationale 
day or 26-day in-patient stay. 
Revised: 
Participants will report to the Clinical 
Research Unit on Day –1 and will remain 
in the unit until completion of the 
assessments on Day 19 (Cohorts 4 and 5) 
or Day 26 at the latest (Cohort 6). 
Participants will be randomly assigned to 
receive GSK3884464 or placebo 
(approximately 6 study intervention and 2 
placebo). Plasma and urine PK, PD, and 
biomarker samples will be collected 
through the 19-day or up to 26-day in-
patient stay. 
Previous: 
Safety, tolerability, and PK data will be 
reviewed in a minimum of 4 participants 
receiving active treatment upon 
completion of assessments at the end of 
their cohort (before initiation of dosing in 
the next cohort). Participants will be 
replaced as required to maintain the 
minimum number on treatment. The dose 
of GSK3884464 may be adjusted (lower 
or higher) based on the data from Part 1 
and for cohorts going forward based upon 
the safety, tolerability, PK, and 
preliminary PD data from the previous 
cohort if available. See Section, 4.4 for 
information on the decision to proceed to 
the next dose level 
Revised: 
In both Part 1 and 2, the dose and/or 
frequency of GSK3884464 may be 
adjusted (lower or higher) based upon the 
safety, tolerability, PK, and PD data (if 
available) from previous Cohorts and 
dose levels. Safety, tolerability, and PK 
data will be reviewed in a minimum of 3 
participants receiving active treatment 
upon completion of assessments at the 
end of their cohort (before initiation of 
dosing in the next cohort); participants 
will be replaced as required to maintain 
the minimum number on treatment. This 
requirement will be superseded in case 
stopping criteria (see Section 7.1) are met 
and it is not deemed safe to proceed with 
dosing at a certain GSK3884464 dose 
level: in this scenario, the dose might be 
de-escalated and its level may be selected 
based on safety, tolerability, PK and PD 
 
 
 
 
 
 
 
 
 
 
This update permits change 
in dose levels based on 
active 3 participants and this 
change may be superseded 
by stopping criteria in 
Section 7.1 
 
 
 
 
 
 
 
 
 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
data (as available) in less than 3 
participants receiving active treatment.  
See Section, 4.4 for information on the 
decision to proceed to the next dose level 
Section 4.2 Scientific 
Rationale for Study Design 
Previous: 
As sufficient data from the Entero-
Tracker or Entero-Test string is expected 
following one dose of the study drug, this 
assessment will be restricted to only one 
cohort in Part 2 (anticipated to be the 
second or third dose level depending on 
PK results in Part 1) during a 
participants’ steady state. 
Revised: 
As sufficient data from the Entero-
Tracker or Entero-Test string is expected 
following one dose of the study drug, this 
assessment will be restricted to only one 
cohort in Part 2 (anticipated to be the 
second or third dose level depending on 
PK results in Part 1 and Cohort 4) during 
a participants’ steady state. 
 
Section 4.3.1 Prediction of 
Human PK and Safety Cover 
 
Previous: 
Methodological details of the dose 
prediction are described in 
GlaxoSmithKline Document Number 
RPS-CLIN-000167, 2021 
Revised: 
Methodological details of the dose 
prediction are described in 
GlaxoSmithKline Document Number 
RPS-CLIN-000167, 2022 
Previous: 
Dose escalation in each part of the study 
will be guided by the review of emerging 
PK, safety and tolerability data; the 
exposure increments will be 
approximately 2-3 fold. 
Revised: 
Dose escalation in each part of the study 
will be guided by the review of emerging 
PK, safety, tolerability data and PD data 
if available; the exposure increments will 
be approximately 2-3 fold. 
Updated IB number of IB 
Supplement  
 
 
 
 
 
 
 
 
 
Addition of PD data for 
review at Dose escalation 
meeting (if available) to help 
in dose selection.  
Section 4.3.2 Prediction of 
Dose Levels for Part 1 
Previous: 
The selection of the subsequent doses 
may deviate from those in the table, based 
on emerging available safety, tolerability, 
Addition of PD data for dose 
selection if it is available for 
Part 1. 


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Section # and Name 
Description of Change 
Brief Rationale 
and PK data from previous dose levels. 
Revised: 
The selection of the subsequent doses 
may deviate from those in the table, based 
on emerging available safety, tolerability, 
PK data and PD data if available from 
previous dose levels. 
Section 4.3.3 Prediction of 
Dose Levels for Part 2 
Previous: 
The decision to progress to Part 2 and the 
selection of the actual dose levels, of the 
repeat dose regimen and of the number of 
cohorts will be made by the DEC, based 
on safety, tolerability and PK data from 
Part 1 (Section 4.4, Section 10.1.5). The 
predicted doses to be explored in Part 2 
may be adjusted to the new start and 
maximum doses pending data obtained in 
Part 1. 
Revised: 
The decision to progress to Part 2 and the 
selection of the actual dose levels, of the 
repeat dose regimen and of the number of 
cohorts will be made by the DEC, based 
on all available safety, tolerability, PK 
and PD data from Part 1 (Section 4.4, 
Section 10.1.5). The predicted doses to be 
explored in Part 2 may be adjusted to the 
new starting and maximum doses pending 
data obtained in Part 1. 
Previous: 
Three dose levels are planned in Part 2; 
their expected steady-state Cmax and 
AUC will have been shown to be safe 
after a single dose in Part 1.   
Revised: 
Up to three dose levels are planned in 
Part 2; their expected steady-state Cmax 
and AUC will have been shown to be safe 
after a single dose in Part 1. 
Addition of PD data for dose 
selection if it is available for 
Part 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These changes were made to 
the dosing criteria to clarify 
dose may be adjusted 
between dosing periods.  
 
 
 
Section 4.4 Criteria for Dose 
Escalation and for Progressing 
Between Parts of the Study. 
Previous: 
The decision to proceed to the next dose 
level, to progress through each 
Part/Cohort, and to include an additional 
cohort/dose level (if necessary) will be 
made by the DEC. The anticipated mean 
plasma exposure (Cmax and AUC) for any 
dose level to be administered will not 
exceed the limiting exposure criteria 
based on the plasma NOAEL dose from 
the monkey 6-week GLP tox study 
These changes were made to 
the dosing criteria to clarify 
dose may be adjusted 
between dosing periods.  
This update permits change 
in dose levels based on 3 
active participants and this 
change may be superseded 
by stopping criteria in 
Section 7.1 Lastly this 
section has updated dose 


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Section # and Name 
Description of Change 
Brief Rationale 
(Section 4.3.1).  
Revised: 
The decision to proceed to the next dose 
level, to progress through each 
Part/Cohort, and to include an additional 
cohort/dose level (if necessary) will be 
made by the DEC. In addition, the DEC 
may review data from Cohort 5 and 
determine duration of treatment in Cohort 
6. The anticipated mean plasma exposure 
(Cmax and AUC) for any dose level to be 
administered will not exceed the limiting 
exposure criteria based on the plasma 
NOAEL dose from the monkey 6-week 
GLP tox study (Section 4.3.1).  
Previous: 
Each meeting will be scheduled to occur 
at the end of each cohort and / or 
treatment period on data obtained after 
each dose level. Dose escalation decisions 
will be based on data obtained from 4 or 
more participants on active treatment at 
the prior dose level. The review data set 
will consist at minimum AE listings, 
safety labs, electrocardiograms (ECG), 
vital signs (VS), and PK results derived 
from at least 24-hour plasma profiles. 
Pharmacodynamic (PD) data will be 
reviewed as available but will not be 
required for an escalation decision.  
Revised: 
Each meeting will be scheduled to occur 
at the end of each cohort and/or treatment 
period to review data obtained after each 
dose level. Dose escalation decisions will 
be based on data obtained from 3 or more 
participants on active treatment at the 
prior dose level, unless stopping criteria 
(see Section 7.1) are met at the prior dose 
level and the subsequent dose is de-
escalated. The review data set will consist 
at minimum AE listings, safety labs, 
electrocardiograms (ECG), vital signs 
(VS), and PK results derived from at least 
24-hour plasma profiles. 
Pharmacodynamic (PD) data will be 
reviewed as available for Part 1 and may 
be used with the rest of the data in dose 
selection to start and progress Part 2. PD 
data may not be required for an escalation 
decision 
escalation criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


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Section # and Name 
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Brief Rationale 
Previous: 
Progression to the next higher dose level 
will be halted if: 
Revised: 
Progression to the next higher dose level 
in a given cohort will be halted if: 
Previous: 
The dose escalation will stop, and no 
further participants will be dosed at that 
dose level or any higher level.  
Revised: 
The dose escalation will stop after 
completing the dose level, and no further 
participants will be dosed at that dose 
level or any higher level.  
Previous: 
At a minimum, Multiple Ascending Dose 
(MAD) Cohort dose levels will be 
defined based upon Dose Escalation 
Committee (DEC) review of the first five 
Single Ascending Dose (SAD) dose 
levels. Additional MAD cohorts will be 
based on DEC review of subsequent SAD 
dose levels and the previous MAD. 
Revised: 
At a minimum, Multiple Ascending Dose 
(MAD) Cohort dose levels will be 
defined based upon Dose Escalation 
Committee (DEC) review of up to the 
first five Single Ascending Dose (SAD) 
dose levels. Additional MAD cohorts will 
be based on DEC review of subsequent 
SAD dose levels and the previous MAD. 
Section 5.2 Exclusion Criteria 
Previous: 
Screening urine albumin:creatinine ratio 
>30 mg/gm (>3 mg/mmol). 
Revised: 
Screening urine albumin:creatinine ratio 
≥30 mg/gm (≥3 mg/mmol). 
 
Correction of typographical 
error. 
Section 6.3.2 Blinding 
Previous: 
In addition, the sponsor will be blinded to 
treatment allocations, except for roles 
required to be “unblind” in order to 
manage study conduct, oversight and 
safety. This will be documented and 
maintained in the electronic Trial Master 
Addition of GSK unblinded 
personnel.   


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Section # and Name 
Description of Change 
Brief Rationale 
File (eTMF). 
Revised: 
In addition, the sponsor will be blinded to 
treatment allocations, except for roles 
required to be “unblind” in order to 
manage study conduct, oversight and 
safety. Additional internal GSK safety 
representatives may be consulted and 
unblinded as deemed necessary by the 
DEC. This will be documented and 
maintained in the electronic Trial Master 
File (eTMF). 
Section 6.5 Dose Modification 
Previous: 
The dosing schedule may be modified to 
expand a dosing cohort to further evaluate 
safety, PK and/or PD at a given dose 
level or to add cohorts to evaluate 
additional dose regimens. 
Revised: 
The dosing schedule may be modified to 
expand a dosing cohort to further evaluate 
safety, PK and/or PD at a given dose 
level. 
This part of the sentence was 
removed to be in line with 
text in previous Sections 
detailed above. 
Section 7.1.1.3 Dose 
Expansion Criteria 
Previous: 
Four additional subjects on active and 2 
additional subjects on placebo will be 
recruited at the same dose level. Any 
cohort expansion will be contingent on 
approval of an amended protocol by the 
UK ethics board and the MHRA. 
Revised: 
Up to four additional participants on 
active and 2 additional participants on 
placebo may be recruited at the same 
dose level. Any further cohort expansion 
will be contingent on approval of an 
amended protocol by the UK ethics board 
and the MHRA. 
Clarification that less than 4 
additional participants may 
be recruited at a dose level. 
Section 7.1.5 Renal Section 
7.1.5 Renal Stopping Criteria 
Previous: 
New onset of any clinically significant 
and persistent (for 48 hours) hematuria as 
confirmed by microscopy (with no other 
identifiable clinical cause). 
Revised: 
New onset of any clinically significant 
and persistent (for 48 hours) hematuria as 
confirmed by microscopy (in the absence 
of any other clinical cause). 
Previous: 
Updated and further defined 
renal stopping criteria to 
better monitor any potential 
safety signals. 
 
 
 
 
 
 
 
 
Clarified renal monitoring 


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Section # and Name 
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Brief Rationale 
New onset of clinically significant and 
persistent (within 48 hours) proteinuria 
(Spot Urine ACR ratio 3 mg/mmol) in 
absence of another clinical explanation 
e.g. calculus/infection. 
Revised: 
New onset of clinically significant and 
persistent (for 48 hours from the dosing 
day in the SAD part and at any point in 
the MAD) proteinuria (Spot Urine 
Albumin Creatinine ratio [ACR] ≥30 
mg/mmol) in absence of another clinical 
explanation e.g. calculus/infection. 
Previous 
If there is any change in serum creatinine 
> 26µmol/L (0.3 mg/dl), repeat within 24 
hours. If confirmed, the participant will 
be withdrawn, and further investigations 
will be performed 
Revised:  
If there is any change in serum creatinine 
> 26µmol/L (>0.3 mg/dl), repeat within 
24 hours. If confirmed, the participant 
will be withdrawn, and further 
investigations will be performed 
Revised: Added text 
If 2 or more participants in a given dose 
cohort develop any of the above 
withdrawal criteria, when considered 
related to study drug, then that cohort will 
be temporarily halted. 
criteria for hematuria and 
increased ACR to greater 
than ≥ 30mg/mmol from≥ 
3mg/mmol to measure 
albuminuria (as required) not 
microalbuminuria. 
 
 
 
 
 
 
 
 
 
 
 
Updated renal stopping 
criteria. 
 
Section 8 Study Assessments 
And procedures 
Previous: 
The UK ethics board, the MHRA and 
investigator will be informed of any 
safety issues that require alteration of the 
safety monitoring scheme or amendment 
of the Patient Information Sheet and 
Consent Form (PICF). 
Revised: 
The UK ethics board, the MHRA and 
investigator will be informed of any 
significant safety issues, including those 
that require amendment of the Patient 
Information Sheet and Consent Form 
(PICF). 
Updated guidance on 
informing Ethics, Regulatory 
and the investigator of 
significant safety issues. 
Section 8.2.3.3 Continuous 
Cardiac Telemetry 
Revised: Added Text 
In addition, participants are permitted to 
be off telemetry during the 3D 
Updated guidance on 
removal of telemetry during 
an 3D echocardiogram. 


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Section # and Name 
Description of Change 
Brief Rationale 
echocardiogram procedure in Cohorts 4, 5 
and 6. 
Section 8.4.1 Plasma Sample 
Collection 
 
Previous: 
Intervention concentration information 
that may unblind the study will not be 
reported to investigative sites or blinded 
personnel until the study has been 
unblinded. 
Revised: 
Intervention concentration information 
that may unblind the study will not be 
reported to investigative sites or blinded 
personnel until the cohort/study Part has 
been unblinded. 
Language has been updated 
to provide flexibility in 
reporting data. 
Section 8.4.3 Bile Sample 
Collection 
Previous: 
Bile samples for analysis of metabolites 
will be collected via the Entero-Tracker 
or Entero-Test in either the second cohort 
(Day 14) or third cohort (Day 21) in Part 
2 (depending on PK results in Part 1). 
Revised: 
Bile samples for analysis of metabolites 
will be collected via the Entero-Tracker 
or Entero-Test in either the second cohort 
(Day 14) or third cohort (Day 21) in Part 
2 (depending on PK results in Part 1 and 
Cohort 4). 
Updated notes to include 
Cohort 4 as part of the 
decision making for Entero-
Tracker timing. 
Section 8.4.4 Sample Analysis 
 
Previous: 
Drug concentration information will not 
be reported to investigative sites or 
blinded personnel until the study has been 
unblinded. 
Revised: 
Drug concentration information will not 
be reported to investigative sites or 
blinded personnel until the cohort / study 
Part has been unblinded. 
Language has been updated 
to provide flexibility in 
reporting data. 
Section 8.4.6: Adverse Events 
of Special Interest  
 
Previous: 
No AE’s of special interest will be 
collected in this study. 
Revised: 
Adverse Events of Special Interest 
(AESI) are selected AEs that must be 
reported to the Sponsor’s Medical 
Monitor within 24 hours regardless of 
relationship to study treatment. 
Addition of language to 
define Adverse Events of 
Special Interest. 


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Section # and Name 
Description of Change 
Brief Rationale 
For this study the AESI represent 
moderate or severe increases in liver 
function analyses. 
 
Section 9.5 Interim analyses 
 
Previous: 
No formal interim analysis is planned. 
Safety and pharmacokinetic data will be 
reviewed by the DEC before dose 
escalation in each study Part, and 
between study Parts. 
Revised: 
Data may be analyzed at the end of each 
completed cohort/study Part. Safety and 
pharmacokinetic data (and PD data if 
available) will be reviewed by the DEC 
before dose escalation in each study Part, 
and between study Parts.  
Language has been updated 
to provide flexibility in 
reporting data. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests: 
Table 7 
Previous: 
Gamma-glutamyl transferase (GGT) 
removed from Other Assessments 
Revised 
Gamma-glutamyl transferase (GGT) 
moved from Other Safety Assessments 
 
Previous: 
If trace protein or blood in urine is 
detected, a repeat test will be performed 
within 48hrs, except if the repeat test is 
required at Screening the site should 
repeat as soon as possible within the 
screening period. 
Revised: 
If trace protein or blood in urine is 
detected, a repeat test will be performed 
within 24hrs, except if the repeat test is 
required at Screening the site should 
repeat as soon as possible within the 
screening period. 
 
Additional Gamma-glutamyl 
transferase (GGT) 
monitoring is now part of the 
safety update 
 
 
 
 
 
 
 
Updated trace protein or 
blood in urine test to shorter 
time period to repeat test. 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 2 
1. 
PROTOCOL SUMMARY ........................................................................................ 26 
1.1. 
Synopsis ..................................................................................................... 26 
1.2. 
Schema ...................................................................................................... 31 
1.3. 
Schedule of Activities .................................................................................. 33 
1.3.1. 
Part 1: Single Dose Administration in Healthy Participants 
(Cohorts 1, 2 and 3) ..................................................................... 34 
1.3.2. 
Part 2 (Cohorts 4 and 5): Multiple Dose Administration to 
Healthy Participants for 14 days of Treatment ............................. 45 
1.3.3. 
Part 2 (Cohort 6): Multiple Dose Administration to Healthy 
Participants for up to 21 days of Treatment .................................. 53 
2. 
INTRODUCTION .................................................................................................... 62 
2.1. 
Study Rationale .......................................................................................... 64 
2.2. 
Background ................................................................................................ 64 
2.3. 
Benefit/Risk Assessment ............................................................................ 65 
2.3.1. 
Risk Assessment ......................................................................... 66 
2.3.2. 
Benefit Assessment ..................................................................... 77 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 77 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 77 
4. 
STUDY DESIGN .................................................................................................... 80 
4.1. 
Overall Design ............................................................................................ 80 
4.2. 
Scientific Rationale for Study Design .......................................................... 81 
4.2.1. 
Participant Input into Design ........................................................ 82 
4.3. 
Justification for Dose .................................................................................. 82 
4.3.1. 
Prediction of Human PK and Safety Cover .................................. 82 
4.3.2. 
Prediction of Dose Levels for Part 1 ............................................. 83 
4.3.3. 
Prediction of Dose Levels for Part 2 ............................................. 84 
4.4. 
Criteria for Dose Escalation and for Progressing Between Parts of 
the Study .................................................................................................... 85 
4.5. 
End of Study Definition ............................................................................... 86 
5. 
STUDY POPULATION ........................................................................................... 87 
5.1. 
Inclusion Criteria ......................................................................................... 87 
5.2. 
Exclusion Criteria ........................................................................................ 89 
5.3. 
Lifestyle Considerations .............................................................................. 91 
5.3.1. 
Meals and Dietary Restrictions .................................................... 91 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 92 
5.3.3. 
Activity ......................................................................................... 92 
5.4. 
Screen Failures........................................................................................... 92 
6. 
STUDY INTERVENTION AND CONCOMITANT MEDICATION ............................. 93 
6.1. 
Study Intervention(s) Administered ............................................................. 93 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
2 3  
6. 2.  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  .............................................. 9 4  
6. 2. 1.  
Tr e at m e nt A s si g n m e nt  ................................................................. 9 5  
6. 3.  
M e a s ur e s t o Mi ni mi z e Bi a s: R a n d o mi z ati o n a n d Bli n di n g  ........................... 9 5  
6. 3. 1.  
R a n d o mi z ati o n  ............................................................................. 9 5  
6. 3. 2.  
B li n di n g ........................................................................................ 9 6  
6. 4.  
St u d y I nt er v e nti o n C o m pli a n c e  ................................................................... 9 7  
6. 5.  
D o s e M o difi c ati o n  ....................................................................................... 9 8  
6. 6.  
C o nti n u e d A c c e s s t o St u d y I nt er v e nti o n aft er t h e E n d of t h e St u d y  ............ 9 8  
6. 7.  
Tr e at m e nt of O v er d o s e  ............................................................................... 9 8  
6. 8.  
C o n c o mit a nt T h er a p y .................................................................................. 9 9  
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  ................................................................... 1 0 0  
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  ........................................................ 1 0 0  
7. 1. 1.  
Li v er C h e mi str y St o p pi n g Crit eri a  .............................................. 1 0 0  
7. 1. 1. 1.  
St u d y i nt er v e nti o n r e st art or r e c h all e n g e aft er 
li v er st o p pi n g crit eri a ar e m et .................................... 1 0 1  
7. 1. 1. 2.  
St u d y t e m p or ar y h alt crit eri a a n d p ot e nti al 
st u d y st o p pi n g crit eri a  ............................................... 1 0 1  
7. 1. 1. 3.  
D o s e e x p a n si o n crit eri a  ............................................ 1 0 1  
7. 1. 2.  
Q T c St o p pi n g Crit eri a  ................................................................ 1 0 1  
7. 1. 3.  
L eft V e ntri c ul ar ( L V) Ej e cti o n Fr a cti o n St o p pi n g Crit eri a  ............ 1 0 2  
7. 1. 4.  
C ar di a c Arr h yt h mi a St o p pi n g Crit eri a  ......................................... 1 0 2  
7. 1. 5.  
R e n al St o p pi n g Crit eri a  .............................................................. 1 0 3  
7. 1. 6.  
P h ar m a c o ki n eti c St o p pi n g Crit eri a  ............................................. 1 0 4  
7. 1. 7.  
A d diti o n al St o p pi n g Crit eri a  ....................................................... 1 0 4  
7. 1. 7. 1.  
N e ur o p s y c hi atri c I s s u e s  ........................................... 1 0 4  
7. 2.  
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  ............................. 1 0 6  
7. 3.  
L o st t o F oll o w U p  ...................................................................................... 1 0 6  
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  ................................................... 1 0 7  
8. 1.  
Effi c a c y A s s e s s m e nt s  ............................................................................... 1 0 8  
8. 2.  
S af et y A s s e s s m e nt s  ................................................................................. 1 0 8  
8. 2. 1.  
P h y si c al E x a mi n ati o n s  ............................................................... 1 0 8  
8. 2. 2.  
Vit al Si g n s  .................................................................................. 1 0 8  
8. 2. 3.  
C ar di a c A s s e s s m e nt s  ................................................................ 1 0 9  
8. 2. 3. 1.  
1 2 -l e a d s af et y E C G s ................................................ 1 0 9  
8. 2. 3. 3.  
C o nti n u o u s C ar di a c T el e m etr y  ................................. 1 0 9  
8. 2. 3. 5.  
E c h o c ar di o gr a m s  ..................................................... 1 1 0  
8. 2. 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  .................................... 1 1 0  
8. 2. 6.  
S ui ci d al I d e ati o n a n d B e h a vi or Ri s k M o nit ori n g  ......................... 1 1 1  
8. 2. 6. 1.  
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C -
S S R S)  ...................................................................... 1 1 1  
8. 2. 6. 2.  
Si x -It e m C o g niti v e I m p air m e nt T e st ( 6-CI T)  .............. 1 1 1  
8. 3.  
A d v er s e E v e nt 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  .................................................................................................. 1 1 1  
8. 3. 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 ................................................................................. 1 1 2  
C CI
C CI
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
2 4  
8. 3. 3.  
F oll o w -u p of A E s a n d S A E s  ....................................................... 1 1 2  
8. 3. 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  ........................... 1 1 3  
8. 3. 5.  
Pr e g n a n c y  ................................................................................. 1 1 3  
8. 3. 6.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  .............................................. 1 1 3  
8. 4.  
P h ar m a c o ki n eti c s  ..................................................................................... 1 1 4  
8. 4. 1.  
Pl a s m a S a m pl e C oll e cti o n  ......................................................... 1 1 4  
8. 4. 3.  
Bil e S a m pl e C oll e cti o n  ............................................................... 1 1 4  
8. 4. 4.  
S a m pl e A n al y si s  ........................................................................ 1 1 5  
8. 4. 5.  
Di s e a s e -R el at e d E v e nt s ( D R E) a n d/ or Di s e a s e -R el at e d 
O ut c o m e s ( D R O) N ot Q u alif yi n g a s S A E s  ................................. 1 1 5  
8. 4. 6.  
A d v er s e E v e nt s of S p e ci al I nt er e st  ............................................ 1 1 5  
8. 5.  
G e n eti c s  ................................................................................................... 1 1 5  
8. 6. 1.  
P h ar m a c o d y n a mi c s  ................................................................... 1 1 6  
8. 7.  
M e di c al R e s o ur c e Utili z ati o n a n d H e alt h E c o n o mi c  .................................. 1 1 7  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ...................................................................... 1 1 7  
9. 1.  
St ati sti c al H y p ot h e s e s ............................................................................... 1 1 7  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ...................................................................... 1 1 7  
9. 3.  
A n al y si s S et s  ............................................................................................ 1 1 8  
9. 4.  
St ati sti c al A n al y s e s  ................................................................................... 1 1 8  
9. 4. 1.  
G e n er al C o n si d er ati o n s  ............................................................. 1 1 8  
9. 4. 1. 1.  
Pri m ar y E n d p oi nt( s)  .................................................. 1 1 8  
9. 4. 1. 2.  
S e c o n d ar y E n d p oi nt( s)  ............................................. 1 1 9  
9. 5.  
I nt eri m A n al y s e s ....................................................................................... 1 2 0  
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  ............................................................................................. 1 2 1  
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  .......................................................................................... 1 2 1  
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  ...................................... 1 2 1  
1 0. 1. 2.  
Fi n a n ci al Di s cl o s ur e  ................................................................... 1 2 1  
1 0. 1. 3.  
I nf or m e d C o n s e nt Pr o c e s s ........................................................ 1 2 2  
1 0. 1. 4.  
D at a Pr ot e cti o n  .......................................................................... 1 2 2  
1 0. 1. 5.  
D o s e E s c al ati o n C o m mitt e e  ....................................................... 1 2 3  
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  ......................................... 1 2 3  
1 0. 1. 7.  
D at a Q u alit y A s s ur a n c e  ............................................................. 1 2 4  
1 0. 1. 8.  
S o ur c e D o c u m e nt s  .................................................................... 1 2 5  
1 0. 1. 9.  
St u d y a n d Sit e St art a n d Cl o s ur e  ............................................... 1 2 5  
1 0. 1. 1 0.  P u bli c ati o n P oli c y  ....................................................................... 1 2 6  
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  ....................................................... 1 2 7  
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  ..................................... 1 3 0  
1 0. 3. 1.  
D efi niti o n of A E  .......................................................................... 1 3 0  
1 0. 3. 2.  
D efi niti o n of S A E  ........................................................................ 1 3 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  ........................................... 1 3 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  .................................. 1 3 3  
1 0. 3. 5.  
R e p orti n g of S A E t o G S K  ........................................................... 1 3 6  
C CI
C CI
C CI
C CI
C CI


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 137 
10.4.1. 
Definitions: ................................................................................. 137 
10.4.2. 
Contraception Guidance: ........................................................... 138 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 139 
10.6. 
Appendix 6: Abbreviations and Trademarks .............................................. 141 
10.7. 
Appendix 7: Protocol Amendment History ................................................. 148 
11. REFERENCES ..................................................................................................... 165 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Two-Part First Time in Human (FTIH) Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Oral Doses 
of GSK3884464 in a Randomized, Double Blind, Placebo-Controlled, Dose Escalation 
Study in Healthy Participants 
Brief Title: A FTIH study to evaluate the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single and repeat doses of GSK3884464 in healthy participants  
Rationale: This study will be the first in human and the primary objective is to evaluate 
the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single 
and repeat doses of GSK3884464 administered to healthy participants. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
Primary 
• 
To characterize the safety and 
tolerability profile of GSK3884464 
in healthy participants. 
 
 
 
 
 
• 
To characterize the plasma PK of 
GSK3884464 in healthy 
participants. 
• 
Number and percentage of healthy 
participants with adverse events. 
 
• 
Clinically significant changes from 
baseline in laboratory values, vital signs, 
continuous telemetry, 12-lead 
electrocardiogram (ECG), and 
echocardiograms (in Part 2 only) up to 
and including the follow up visit (7-10 
days post final dose). 
• 
Plasma pharmacokinetic parameters 
following single oral doses including 
AUC(0-t), AUC(0-∞), Cmax, time to 
maximum observed plasma drug 
concentration (tmax), and terminal half-
life (t½). 
• 
Plasma pharmacokinetic parameters 
following repeat oral doses including 
AUC Cmax, trough plasma concentration 
(Cτ), time to maximum observed plasma 
drug concentration (tmax), terminal half-
life (t½), accumulation ratios based on 
AUCτ (RAUC), on Cmax (RCmax), and on Cτ 
(RCτ). 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
2 7  
O bjecti ves  
E n d p oi nts  
Sec o n d ar y  
Sec o n d ar y  
•  T o e val uate tar get e n ga ge me nt 
f oll o wi n g si n gle a n d re peat oral 
d oses  of G S K 3 8 8 4 4 6 4  i n healt h y 
partici pa nts .  
•  M a xi m u m c ha n ges  fr o m baseli ne  i n 
N Q O 1 m R N A i n w h ole bl o o d p ost 
treat me nt wit h G S K 3 8 8 4 4 6 4 i n all parts 
of t he st u d y .  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
2 8  
C CI


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Overall Design: This First Time in Human (FTIH) study 213376 will be a randomized, 
double-blind placebo-controlled study of the oral administration of GSK3884464 in 
healthy participants. As this will be the first time GSK3884464 will be given to humans, 
the study design may change based on emerging data as the study progresses. 
The study is planned to have two Parts and will be conducted at a single center.  
1. Part 1 will be a 3-period crossover design, single dose (SD), dose escalation 
study in healthy participants.  Participants will receive GSK3884464 or matching 
placebo as an oral dose.  There will be up to three cohorts with 9 participants in 
each cohort, each cohort will have up to 3 time periods.  
2. Part 2 will be a sequential design, 14-day (Cohorts 4 and 5) and up to 21-days 
(Cohort 6) repeat-dose (RD), dose escalation study in healthy participants (See 
Section 4.4). It will consist of up to 3 dose cohorts with 8 participants per cohort. 
Participants in each cohort will receive GSK3884464 or matching placebo; not all 
participants will receive placebo.   
Disclosure Statement: This is a First Time in Human Study. Sentinel dosing will be 
incorporated in each Part of the study and at each dose level. For Part 1, up to 3 
participants will be dosed at a time, and their LFTs will be monitored until Day 6 or until 
resolution (whichever is later) before the next participants in the cohort are dosed. For 
Part 2, up to 3 participants will be dosed at a time and will be monitored for a minimum 
of 5 days prior to dosing the rest of the cohort. 
The dose escalation committee will review data after each cohort and Part to assess 
safety. In addition, data from each Cohort will be evaluated to establish whether a switch 
to a gastro-resistant capsule will be used for the subsequent doses. Details of these 
criteria and switch are in Section 10.5. The participants, investigator, and study site staff 
will all be blinded. The sponsor will be blinded to treatment allocations, except for roles 
required to be “unblind” in order to manage study conduct, oversight and safety. GSK 
staff analyzing samples derived from this study will be unblinded. The schematics for 
each Part are provided in Section 1.2 and refer to Section 4.1 for Study Design. 
Number of Participants: 
A sufficient number of participants will be screened and randomly assigned to study drug 
(active or placebo) to achieve approximately 51 evaluable participants. It is estimated that 
Part 1 will have three cohorts for a total of 27 evaluable participants and Part 2 will have 
24 evaluable participants. Additional participants/cohorts may be enrolled to allow for 
evaluation of additional dosing regimens levels as required.  


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Intervention Groups and Duration: 
Screening 
All screening assessments listed in the Schedule of Activities (SoA) 
will be completed within 28 days prior to first dose. 
Intervention 
Period 
Part 1 will consist of up to three cohorts. Each cohort could include up 
to 3 intervention periods. These will each be a single dose, crossover 
design. 
Part 2 will consist of up to three cohorts. Cohorts 4 and 5 (14-day) and 
Cohort 6 (up to 21-days) will be a sequential group, repeat dose with 
one intervention period (See Section 4.4).  
Washout 
Period 
In Part 1, a washout period of a minimum of 7 days or 5 half-lives 
(whichever is the longer) between each dose for an individual 
participant. 
Follow-up 
Each cohort will have a follow up visit 7-10 days after the last study 
treatment. 
Total duration 
of study Parts 
(approximate) 
Part 1: Each of the 3 cohorts will be approximately 76 days. 
Part 2: Cohorts 4 and 5 will be approximately 72 days and Cohort 6 
 will be approximately 80 days. 
Dose Escalation Committee: A Dose Escalation Committee (DEC) will be used to 
ensure data integrity in dose selection decisions by performing clinical data review and 
appropriate quality control of data prior to making dose selection decisions for this study. 
The Committee will review emerging data and recommend changes to the study, and 
review safety parameters during the study. The details and composition of the DEC will 
be included in the Dose Escalation Plan (DEP), to be completed prior to commencement 
of study enrolment. 


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1.2. 
Schema 
Figure 1 
Overall Study Design 
 
 
Figure 2 
Part 1 Design and Cohort Dosing 
Initial dosing for each dose level will be staggered so that 2 participants will be dosed as 
sentinel participants, one with study drug and one with placebo (see Section 4.1). Within 
a cohort, participants will be randomized to one of 3 treatment sequences such that each 
participant receives up to 2 active doses and 1 placebo dose resulting in each active dose 
being administered to up to 6 participants and placebo to up to 3 participants.   
Starting dose (Dose 1) = 1 mg 
Subsequent dose escalations will be determined based on safety, PK data and PD data (if 
available). 
Maximum predicted dose = 550 mg  


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Washout = minimum 7 days or 5 half-lives, whichever is longer 
See Section 1.3.1, Section 4.1 and refer to SRM 
Figure 3 
Part 2 Design  
 
Figure 4 
Part 2 Cohorts 4 and 5 Dosing 
 
Figure 5 
Part 2 Cohort 6 Dosing 
Initial dosing for each dose level will be staggered so that 2 participants will be dosed as 
sentinel participants, one with study drug and one with placebo. See Section 1.3.2 and 
Section 4.1. 
 


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1.3. 
Schedule of Activities 
The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic and biomarkers, may be altered during the course of the study based 
on emerging data or in-stream analyses (e.g., to obtain data closer to the time of peak 
plasma concentrations) to better characterize safety, PK, or PD. 
Any changes in the timing or addition of time points for any planned study assessments 
will be documented and approved by the relevant study team member and then archived 
in the sponsor and site study files but will not constitute a protocol amendment.  
The UK ethics board, the MHRA and investigator will be informed of any significant 
safety issues, including those that require amendment of the Patient Information Sheet 
and Consent Form (PICF). The changes will be approved by the IRB/IEC before 
implementation as required. Allowed time windows will be specified in the Study 
Reference Manual (SRM).  
 


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1.3.1. 
Part 1: Single Dose Administration in Healthy Participants (Cohorts 1, 2 and 3) 
 
 
Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
X 
X 
As needed for additional safety 
evaluation between each study 
treatment (minimum 10 days). 
COVID-19 Testing1 
X 
 
 
  
  
  
 
X 
 
X* 
Screening: in accordance with site 
procedures. 
Day 1 to 5: Ad hoc testing based on 
clinical presentations and site 
procedures.  
D6: Sample collected upon discharge. 
*Early withdrawal only 
Admission to the Clinical Unit 
 
X 
 
 
 
 
 
 
 
 
 
Inpatient Stay in the Clinical Unit 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 


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Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Recheck clinical status before 
randomization and/or 1st dose of study 
intervention. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Study intervention 
 
 
X 
 
 
 
 
 
 
 
 
Full physical examination including 
height 
X 
 
 
 
 
 
 
 
 
X* 
Height is collected at Screening only.  
Refer to Section 8.2.1 
*Early withdrawal only 
Weight 
X 
 
 
 
 
 
 
X 
 
 
Weight must be collected in the 
morning after urination, before drinking 
or eating. 
Brief physical 
 
X 
 
X 
 
 
 
X 
 
X 
Refer to Section 8.2.1 


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Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
Medical/Medication/Drug/Alcohol/
CV disease history  
X 
X 
 
 
 
 
 
 
 
 
Review and update on D-1. Refer to 
Section 5.3.2 
Refer to SRM for testing 
FSH test 
X 
 
 
 
 
 
 
 
 
 
If indicated in women, Refer to Section 
10.4.1 
Urine Drug and Alcohol Breath 
Test 
X 
X 
 
 
 
 
 
 
 
 
 
Gamma-glutamyl transferase 
(GGT) 
X 
 
 
 
 
X 
 
X 
 
X* 
*EW and Follow up Visit or until 
resolution (whichever is later). 
HIV, Hepatitis B and Hepatitis C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
Smokelyzer test 
X 
X 
 
 
 
 
 
 
 
 
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
3 7  
 
 
Tre at m e nt P eri o d   
St u d y P eri o d ( D a y s)  
W a s h 2 -
o ut  
 
N ot e s  
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s b ef ore 
D a y 1)  
-1  
1  
2  
3  
4  
5  
6  
 
F oll o w -U p  
( 7-1 0 d ays 
p ost l ast  
d os e) 1 
/ E arl y 
wit h dra w al  
 
Cli nic al l a b or at ory ass ess m e nts 
( h e ma /c h e m/ uri n alysis-i ncl u di n g 
liv er c h e mistri es)  
X  
X  
X  
X  
X  
X * 
X * 
X * 
 
X * 
R ef er t o S ecti o n 1 0. 2  
*D aily  s er u m c h e mistri es D 4 t hr o u g h 
D 6  a n d E W as r e q uir e d . F oll o w u p u ntil 
r es ol uti o n as r e q uir e d.  
F or uri n al ysis, first v oi d, w h e n p ossi bl e. 
F asti n g H b A 1c  
X  
 
 
 
 
 
 
 
 
 
 
C CI


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Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
Vital signs and Temperature 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs to include HR, BP, and 
respiration rate.  
BP and HR will be assessed in a semi-
supine position. 
Triplicate readings to be conducted for 
all BP readings.  
Vital Signs to be conducted on D -1 and 
pre-dose on D1 and then at the 
subsequent time points post-
dose:15min, 1hr, 2hr, 4hr, 12hr, 24hr, 
48hr, 72hr, 96hr, 120hr (morning of 
D6).  
(Refer to Section 8.2.2). 
Daily temperature. 


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Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
ECGs scheduled at the same time as a 
PK draw should be performed before 
PK draw.  
Single 12-Lead ECGs to be conducted 
in a semi-supine position daily and on 
Day 1 predose and then at the 
subsequent time points post-dose: 15 
min, 1 hr, 2hr, 4hr, 12hr, 24hr, 48hr, 
72hr, 96hr, 120hr (morning of D6)  
(Refer to Section 8.2.3.1). 
Timings will be reviewed as cohorts 
progress and may be adjusted to 
ensure appropriate measurements 
relative to peak concentrations for 
subsequent cohorts. 
If any abnormal ECG reading is 
recorded, refer to Section 7.1.2 for 
appropriate action. 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 0  
 
 
Tre at m e nt P eri o d   
St u d y P eri o d ( D a y s)  
W a s h 2 -
o ut  
 
N ot e s  
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s b ef ore 
D a y 1)  
-1  
1  
2  
3  
4  
5  
6  
 
F oll o w -U p  
( 7-1 0 d ays 
p ost l ast  
d os e) 1 
/ E arl y 
wit h dra w al  
 
C CI


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Treatment Period  
Study Period (Days) 
Wash2-
out 
 
Notes 
Procedure 
Screening  
(up to 28 
days before 
Day 1) 
-1 
1 
2 
3 
4 
5 
6 
 
Follow-Up 
(7-10 days 
post last 
dose)1 
/Early 
withdrawal 
 
Continuous cardiac telemetry 
 
 
X 
X 
X 
 
 
 
 
 
Continuous cardiac monitoring should 
be started approximately 90min before 
dosing on D1. Full disclosures will be 
reviewed in detail in real-time.  
Remove D3 approximately 60hrs after 
dosing. 
3D Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 2  
 
 
Tre at m e nt P eri o d   
St u d y P eri o d ( D a y s)  
W a s h 2 -
o ut  
 
N ot e s  
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s b ef ore 
D a y 1)  
-1  
1  
2  
3  
4  
5  
6  
 
F oll o w -U p  
( 7-1 0 d ays 
p ost l ast  
d os e) 1 
/ E arl y 
wit h dra w al  
 
Pl as m a hs Tr o p o ni n  
 
 
X  
X  
 
 
 
 
 
X  
Pr e -d os e a n d 2 4 hr o n D 2 a n d at f oll o w 
u p visit.  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 3  
 
 
Tre at m e nt P eri o d   
St u d y P eri o d ( D a y s)  
W a s h 2 -
o ut  
 
N ot e s  
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s b ef ore 
D a y 1)  
-1  
1  
2  
3  
4  
5  
6  
 
F oll o w -U p  
( 7-1 0 d ays 
p ost l ast  
d os e) 1 
/ E arl y 
wit h dra w al  
 
Pl as m a N T -pr o B N P  
 
 
X  
X  
 
 
 
X  
 
X  
Pr e -d os e, 2 4 hr o n D 2,  D ay 6 pri or t o 
disc h ar g e, a n d at f oll o w u p visit . 
P D W h ol e Bl o o d P A X g e n e 
s a m pl es (i ncl u di n g N Q O 1 m R N A)  
 
 
X  
X  
 
 
 
 
 
 
F or N Q O 1 (
 
a n alys es:  
Pr e -d os e a n d 2 hr, 6 hr,  1 2 hr, 2 4 hr ( D 2) 
p ost -d os e.   
R ef er t o S R M.  
M e als  
 
X  
X  
X  
X  
X  
X  
X  
 
 
N o br e akf ast o n D 1.  
F or p artici p a nts t aki n g t h e st u dy 
i nt erv e nti o n i n g astr o-r esist a nt c a ps ul e 
f or m, f asti n g m ust b e f or 2 hr p ost-d os e.  
A E  r evi e w 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
S A E r evi e w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
C o nc o mit a nt m e dic ati o n r evi e w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 6. 8  
C CI
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 4  
 
 
Tre at m e nt P eri o d   
St u d y P eri o d ( D a y s)  
W a s h 2 -
o ut  
 
N ot e s  
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s b ef ore 
D a y 1)  
-1  
1  
2  
3  
4  
5  
6  
 
F oll o w -U p  
( 7-1 0 d ays 
p ost l ast  
d os e) 1 
/ E arl y 
wit h dra w al  
 
Disc h ar g e fr o m t h e cli nic al u nit  
 
 
 
 
 
 
 
X  
 
 
F oll o wi n g c o m pl eti o n of all 
ass ess m e nts.  
1.  
F oll o w -U p visit: If a partici pa nt meets t he criteria of a partici pa nt wit h k n o w n C O VI D -1 9 p ositi ve c o ntacts i n t he past 1 4 da ys or  is deter mi ne d t o ha v e a hi g h 
cli nical i n de x of s us pici o n f or C O VI D -1 9 or  has a p ositi ve la b orat or y c o nfir mati o n of C O VI D -1 9 i nfecti o n t he foll o w -u p visit ma y be deferre d be y o n d 1 4 da ys 
after t he last d ose a n d sc he d ul e d/resc he d ule d at a ti me p oi nt as dee me d a p pr o priate b y t he I n vesti gat or.  
2.  
W as h o ut p eri o d is defi ne d as a mi ni m u m 7 da ys or 5 half -li ves, w hic he ver is l o n ger. Eac h pat ie nt will d o t hree was h o uts. 
C CI


TMF-14577739 
CONFIDENTIAL 
213376 
 
 
Prot Amend 4 
 
45 
1.3.2. 
Part 2 (Cohorts 4 and 5): Multiple Dose Administration to Healthy Participants for 14 days of Treatment  
 
Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
19 
 
 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
X 
X 
 
COVID-19 Testing1 
X 
 
  
 
 
 
 
X* 
 
 
Screening: in accordance with site procedures.  
Days -1 to 18: Ad hoc testing based on clinical 
presentations and site procedures.  
*D19 only: Sample collected upon discharge. 
Admission to Clinical Unit 
 
X 
 
 
 
 
 
 
 
 
 
Inpatient stay at Clinical Unit 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Recheck clinical status before randomization and/or 1st dose of 
study intervention. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
including height 
X 
 
 
 
 
 
 
 
 
X 
Height is collected at Screening only. Refer to Section 8.2.1 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
 
 
 
Weight must be collected in the morning after urination, before 
drinking or eating. 


TMF-14577739 
CONFIDENTIAL 
213376 
 
 
Prot Amend 4 
 
46 
 
Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
19 
 
 
 
Brief physical 
 
X 
X 
X* 
 
 
X 
X* 
X 
 
Refer to Section 8.2.1 
*D2 and D15 only. 
Medical/Medication/Drug/Alcoh
ol/CV disease history 
X 
X 
 
 
 
 
 
 
 
 
Review and update on D -1.  
Refer to Section 5.3.2. 
Refer to SRM for testing. 
FSH test 
X 
 
 
 
 
 
 
 
 
 
If indicated in women, Refer to Section 10.4.1. 
Urine Drug & Alcohol Breath 
Test 
X 
X 
 
 
 
 
 
 
 
 
Refer to Section 10.2. 
Gamma-glutamyl transferase 
(GGT) 
X 
 
 
 
X 
X 
X 
X* 
X 
X 
*Gamma-GT on days 7-14, D19, Follow up and Early Withdrawal 
Visit or until resolution (whichever is later). 
HIV, Hepatitis B and Hepatitis 
C screening 
X 
 
 
 
 
 
 
 
 
 
 
Fasting HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
Fasting Serum Insulin  
 
 
X 
X* 
 
X* 
X 
 
 
 
*D4 and D11 only 
Adrenocorticotropic hormone 
(ACTH) and Cortisol 
 
X* 
X* 
 
 
 
X* 
X* 
 
X 
*Collect midnight D-1 and D14 and at 8am before dosing on D1 
and 8am on D15.  
Samples should be collected at same time of day (i.e. no more 
than ±1hr of the collection time).  
If labs are abnormal, follow up should also be included after at 
least 7 days off treatment,  


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 7  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
Earl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g 
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
1 9  
 
 
 
Al d ost er o n e  
 
X  
X  
X*  
 
X*  
 
 
X  
X  
* D 4 a n d D 1 1  o nly  
C oll ect all s a m pl es at first A M dr a w. 
S m ok elyz er t est  
X  
X  
 
 
 
 
 
 
 
 
 
C CI


TMF-14577739 
CONFIDENTIAL 
213376 
 
 
Prot Amend 4 
 
48 
 
Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
19 
 
 
 
Vital signs and Temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs to include HR, BP, and respiration rate.  
BP and HR will be assessed in a semi-supine position. 
Triplicate readings to be conducted for all BP readings. 
Vital Signs to be conducted on Day -1 and pre-dose every day. 
In addition, the following timepoints should be obtained on Days 
1 and 14 post-dose: 15 min, 1hr, 2hr, 4hr, 12hr, 24hr, 48hr, 72hr, 
96hr, 120hr. 
(Refer to Section 8.2.2). 
Daily temperature. 
Columbia Suicide Severity 
Rating Scale (C-SSRS) 
 
X 
 
 
X 
 
X 
 
X 
X 
Refer to SRM 
Cognitive Assessment (6-CIT) 
 
X 
 
 
X 
 
X 
 
X 
X 
Refer to SRM 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECGs scheduled at the same time as a PK draw should be 
performed before PK draw.  
Single 12-Lead ECGs to be conducted on Day -1 and pre-dose 
every day.  
In addition, the following timepoints should be obtained on; D1 
post-dose: 15 min, 1hr, 2hr, 4hr, 12hr. 
Days 2-13 daily. 
D14 post-dose: 15 min, 1hr, 2hr, 4hr, 12hr, 24hr, 48hr, 72hr, 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
4 9  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
Earl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g 
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
1 9  
 
 
 
9 6 hr, 1 2 0 hr . 
R ef er t o S ecti o n 8. 2. 3. 1 . 
Ti mi n gs will b e r evi e w e d as c o h orts pr o gr ess a n d m ay b e 
a dj ust e d t o e ns ur e a p pr o pri at e m e as ur e m e nts r el ativ e t o p e ak 
c o nc e ntr ati o ns f or s u bs e q u e nt c o h orts.  
If a ny a b n or m al E C G r e a di n g is r ec or d e d, r ef er t o S ecti o n 7. 1. 2 
for a p pr o pri at e acti o n.  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 0  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
Earl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g 
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
1 9  
 
 
 
 
3 D Ec h oc ar di o gr a m  
X  
 
 
 
 
 
X*  
 
 
 
* M ay b e p erf or m e d wit hi n 2 4 hrs pr e- or p ost -d osi n g.  
E nt er o -Tr ack er  
or E nt er o -T est ( bil e s a m pl e 
c oll ecti o n 
 
 
 
 
 
 
X  
 
 
 
O nly i n eit h er C o h ort  5 or 6 ( d e p e n di n g o n P K fr o m P art 1  a n d 
C o h ort 4 ).  
E nt er o -Tr ack er c a ps ul e t o b e s w all o w e d ~ 2 hr aft er d osi n g  
D et ails ar e i n t h e S R M.  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 1  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
Earl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g 
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
1 9  
 
 
 
E nt er o -Tr ack er  or E nt er o -T est  
f o o d c u e 
 
 
 
 
 
 
X  
 
 
 
O nly i n eit h er C o h ort 5 or 6  ( d e p e n di n g o n P K fr o m P art 1 a n d 
C o h ort 4 ).  
F o o d c u e will b e giv e n ~ 6 hr p ost -d os e.  
D et ails ar e i n t h e S R M . 
Pl as m a hs Tr o p o ni n  
 
 
X  
 
X  
 
X  
 
X  
X * 
Pr e -d os e s a m pl es  
* C oll ect w h e n d ecisi o n t o wit h dr a w al is m a d e. 
Pl as m a N T -pr o B N P  
 
 
X  
 
X  
 
X  
 
X  
X * 
Pr e -d os e s a m pl es  
 
* C oll ect w h e n d ecisi o n t o wit h dr a w al is m a d e. 
P D 3 W h ol e Bl o o d P A X g e n e 
s a m pl es (i ncl u di n g N Q O 1 
m R N A)  
 
 
X  
 
X  
 
X  
 
 
 
F or N Q O 1 (
a n alys es:   
Pr e -d os e a n d 6 hr, a n d 1 2 hr p ost -d os e.  
R ef er t o S R M  
P D 3 s er u m s a m pl es 
 
 
X  
 
X  
 
X  
 
 
 
F or oxi d ativ e str ess bi o m ark ers .  
Pr e -d os e s a m pl es. R ef er t o S R M  
C CI
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 2  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
Earl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g 
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
1 9  
 
 
 
M e als  
 
X  
X  
X  
X  
X  
X  
X  
 
 
N o br e akf ast o n D 1 a n d D 1 4, s eri al  P K d ays.  
F or p artici p a nts t aki n g t h e st u dy i nt erv e nti o n i n g astr o -r esist a nt 
c a ps ul e f or m, f asti n g m ust b e f or 2 hr p ost-d os e.  
St u dy i nt erv e nti o n  
 
 
X  
X  
X  
X  
X  
 
 
 
 
A E r evi e w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
S A E r evi e w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
C o nc o mit a nt m e dic ati o n r evi e w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 6. 8  
Disc h ar g e fr o m t h e cli nic al u nit  
 
 
 
 
 
 
 
X*  
 
 
* Disc h ar g e o n D 1 9 f oll o wi n g c o m pl eti o n of all ass ess m e nts. 
1.  F oll o w -U p visit: If a partici pa nt meets t he criteria of a partici pa nt wit h k n o w n C O VI D -1 9 p ositi ve c o ntacts i n t he past 1 4 da ys, or is deter mi ne d t o ha ve a 
hi g h cli nical i n de x of s us pici o n f or C O VI D -1 9, or has a p ositi ve la b orat or y c o nfir mati o n of C O VI D -1 9 i nfecti o n t he f oll o w -u p visit ma y be deferre d be y o n d 
1 4 da ys after t he last d ose  a n d sc he d ule d/resc he d ule d at a ti me p oi nt as dee me d a p pr o priate b y t he I n vesti gat or  
3.  P D = P har mac o d y na mic  
C CI
C CI


TMF-14577739 
CONFIDENTIAL 
213376 
 
 
Prot Amend 4 
 
53 
1.3.3. 
Part 2 (Cohort 6): Multiple Dose Administration to Healthy Participants for up to 21 days of Treatment  
 
Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
20 
Day 
21 
Days 
22-26 
 
 
 
Outpatient Visit 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
COVID-19 Testing1 
X 
 
 
 
 
 
 
 
 
X* 
 
 
Screening: in accordance with site procedures.  
D1 through D25: Ad hoc testing based on 
clinical presentations and site procedures.  
*D26 only: Sample collected upon discharge. 
Admission to Clinical Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
. 
Inpatient stay at Clinical Unit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Recheck clinical status before randomization 
and/or 1st dose of study intervention. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
including height 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height is collected at Screening only. Refer to 
Section 8.2.1 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
  
X 
 
 
 
Weight must be collected in the morning after 
urination, before drinking or eating. 


TMF-14577739 
CONFIDENTIAL 
213376 
 
 
Prot Amend 4 
 
54 
 
Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
20 
Day 
21 
Days 
22-26 
 
 
 
Brief physical 
 
X 
 
X* 
 
 
X 
X* 
 
X* 
X 
 
*D2, D15 and D22 only.  
Refer to Section 8.2.1  
Medical/Medication/Drug/Alcohol/
CV disease history 
X 
X 
 
 
 
 
 
 
 
 
 
 
Review and update on Day -1.  
Refer to Section 5.3.2. 
Refer to SRM for testing. 
FSH test 
X 
 
 
 
 
 
 
 
 
 
 
 
If indicated for women. Refer to Section 10.4.1 
Urine Drug & Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Refer to Section 10.2. 
Gamma-glutamyl transferase 
(GGT) 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
X* 
*Gamma-GT on days 7-14, D21, Follow up, 
and Early Withdrawal Visit or until resolution 
(whichever is later).. 
HIV, Hepatitis B and Hepatitis C 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adrenocorticotropic hormone 
(ACTH) and Cortisol 
 
X* 
X* 
 
 
 
 
 
X* 
X* 
X 
 
*Collect midnight D-1 and D21 and at 8am 
before dosing on D1 and 8am on D22. 
Samples should be collected at same time of 
day (i.e. no more than ±1hr of the collection 
time).  
If labs are abnormal, follow up should also be 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 5  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
i ncl u d e d aft er at l e ast 7 d ays off tr e at m e nt, 
Al d ost er o n e  
 
X  
X  
X*  
 
X*  
 
X*  
 
 
X  
X  
* D 4, D 1 1, a n d D 1 8 o nly 
C oll ect all s a m pl es at first A M dr a w.  
F asti n g S er u m I ns uli n  
 
 
X  
X*  
 
X*  
 
X*  
X  
 
 
 
* D 4, D 1 1 a n d D 1 8 o nly 
S m ok elyz er t est  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 6  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
Vit al si g ns a n d T e m p er at ur e  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vit al si g ns t o i ncl u d e H R, B P, a n d r es pir ati o n 
r at e.  
B P a n d H R will b e ass ess e d i n a s e mi -s u pi n e 
p ositi o n.  
Tri plic at e r e a di n gs t o b e c o n d uct e d f or all B P 
r e a di n gs. 
Vit al Si g ns t o b e c o n d uct e d o n D -1 a n d pr e -
d os e ev ery d ay.  
I n a d diti o n, t h e f oll o wi n g ti m e p oi nts s h o ul d b e 
o bt ai n e d o n D 1 a n d D 2 1 p ost -d os e: 1 5 mi n, 
1 hr, 2 hr, 4 hr, 1 2 hr, 2 4 hr, 4 8 hr, 7 2hr, 9 6 hr, 
1 2 0 hr.  
( R ef er t o S ecti o n 8. 2. 2 ). 
C ol u m bi a S uici d e S ev erity R ati n g 
Sc al e ( C - S S R S))  
 
X  
 
 
X  
 
X  
 
X  
 
X  
X  
R ef er t o S R M  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 7  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
C o g nitiv e Ass ess m e nt ( 6 -CI T)  
 
X  
 
 
X  
 
X  
 
X  
 
X  
X  
R ef er t o S R M  
1 2 -l e a d E C G 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E C Gs sc h e d ul e d at t h e s a m e ti m e as a P K 
dr a w s h o ul d b e p erf or m e d b ef or e P K  dr a w.   
Si n gl e 1 2 -L e a d E C Gs t o b e c o n d uct e d o n D ay -
1 a n d pr e -d os e ev ery d ay.  
I n a d diti o n, t h e f oll o wi n g ti m e p oi nts s h o ul d b e 
o bt ai n e d o n D 1 p ost -d os e:  1 5 mi n,  1 hr, 2 hr, 
4 hr, 1 2 hr.  
D ays 2 -2 0 d aily.  
D 2 1 p ost -d os e:  1 5 mi n, 1 hr, 2 hr, 4 hr, 1 2 hr, 
2 4 hr, 4 8 hr, 7 2 hr, 9 6 hr, 1 2 0 hr.  
R ef er t o S ecti o n 8. 2. 3. 1 .  
Ti mi n gs will b e r evi e w e d as c o h orts pr o gr ess 
a n d m ay b e a dj ust e d t o e ns ur e a p pr o pri at e 
m e as ur e m e nts r el ativ e t o p e ak c o nc e ntr ati o ns 
f or s u bs e q u e nt c o h orts.  
If a ny a b n or m al E C G r e a di n g is r ec or d e d, r ef er 
t o S ecti o n 7. 1. 2  f or a p pr o pri at e acti o n. 
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
5 8  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
3 D Ec h oc ar di o gr a m  
X  
 
 
 
 
 
X*  
 
X*  
 
 
 
* M ay b e p erf or m e d wit hi n 2 4 hrs pre - or p ost -
d osi n g.  
C CI
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Screening and 
Baseline Period 
Treatment Period Study Period (Days) 
Follow 
Up (7-
10 days 
post 
last 
dose)1 
Early 
With-
drawal  
Notes  
Procedure 
Screening 
(up to 28 
days 
before Day 
1) 
Day 
 -1 
Day 
1 
Days  
2-6 
Day 
7 
Days 
8-13 
Day 
14 
Days 
15-
20 
Day 
21 
Days 
22-26 
 
 
 
D1: pre-dose, post dose: 30min, 1hr, 1.5hr, 2hr, 
3hr, 4hr, 6hr, 8hr, 12hr; 18hr, 24hr.  
D7: collect at the following timepoints: pre-
dose, 6hr and 12hr 
*Draw only on D4, D11 and D18 and collect 
only pre-dose samples.  
D21 through D26: pre-dose, post dose: 30min, 
1hr, 1.5hr, 2hr, 3hr, 4hr, 6hr, 8hr, 12hr; 18hr, 
24hr, 36hr, 48hr, 72hr, 96hr, 120hr 
The PK sampling time points stated may be 
modified depending on emerging PK 
information as appropriate.  
**Metabolite plasma samples only on D1, D21 
and D22 (to collect 24 hr sample only) with 
same timepoints as described for PK plasma 
sample above (See Section 8.4.1and SRM). 
Entero-Tracker or Entero-Tes (bile 
sample collection 
 
 
 
 
 
 
 
 
X 
 
 
 
Only in either Cohort 5 or 6 (depending on PK 
from Part 1 and Cohort 4).  
Entero-Tracker capsule to be swallowed ~2hr 
after dosing  
Details are in the SRM. 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
6 0  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
E nt er o -Tr ack er  or E nt er o -T est 
f o o d c u e 
 
 
 
 
 
 
 
 
X  
 
 
 
O nly i n eit h er C o h ort 5 or 6 ( d e p e n di n g o n P K 
fr o m P art 1 a n d C o h ort 4 ).  
F o o d c u e will b e giv e n ~ 6 hr p ost -d os e.  
Pl as m a hs Tr o p o ni n  
 
 
X  
 
X  
 
 
 
X  
 
X  
X*  
Pr e -d os e s a m pl es.  
* C oll ect w h e n d ecisi o n t o wit h dr a w al is m a d e. 
Pl as m a N T -pr o B N P  
 
 
X  
 
X  
 
 
 
X  
 
X  
X*  
Pr e -d os e s a m pl es.  
* C oll ect w h e n d ecisi o n t o wit h dr a w al is m a d e. 
P D 3 W h ol e Bl o o d P A Xg e n e 
s a m pl es (i ncl u di n g N Q O 1 m R N A)  
 
 
X  
 
X  
 
 
 
X  
 
 
 
F or N Q O 1 ( a n d ot h er g e n e ex pr essi o n) 
a n alys es:   
Pr e -d os e a n d 6 hr, 1 2 hr p ost -d os e.  R ef er t o 
S R M.  
P D 3 s er u m s a m pl es 
 
 
X  
 
X  
 
 
 
X  
 
 
 
F or oxi d ativ e str ess bi o m ark ers . 
Pr e -d os e s a m pl es. R ef er t o S R M  
M e als  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
N o br e akf ast o n D 1 a n d D 2 1, s eri al P K d ays.  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
 
Pr ot A m e n d 4  
 
6 1  
 
S cr e e ni n g a n d 
B a s eli n e P eri o d  
Tre at m e nt P eri o d St u d y P eri o d  ( D a y s) 
F oll o w 
U p  ( 7-
1 0 d ays 
p ost 
l ast 
d os e) 1 
E arl y  
Wit h -
dra w al   
N ot e s   
Pr o c e d ure  
S cr e e ni n g  
( u p t o 2 8 
d a y s 
b ef ore D a y 
1)  
D a y  
 -1  
D a y 
1  
D a y s  
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y  
1 4  
D a y s 
1 5 -
2 0  
D a y 
2 1  
D a y s  
2 2 -2 6  
 
 
 
F or p artici p a nts t aki n g t h e st u dy i nt erv e nti o n i n 
g astr o -r esist a nt c a ps ul e f or m, f asti n g m ust b e 
f or 2 hr p ost-d os e.  
St u dy i nt erv e nti o n  
 
 
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
A E r evi e w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
S A E r evi e w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 8. 3  
C o nc o mit a nt m e dic ati o n r evi e w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
R ef er t o S ecti o n 6. 8  
Disc h ar g e fr o m t h e cli nic al u nit  
 
 
 
 
 
 
 
 
 
X*  
 
 
* Disc h ar g e o n D 2 6 f oll o wi n g c o m pl eti o n of all 
ass ess m e nts  
1.  F oll o w -U p visit: If a partici pa nt meets t he criteria of a partici pa nt wit h k n o w n C O VI D -1 9 p ositi ve c o ntacts i n t he past 1 4 da ys, or is deter mi ne d t o ha ve a 
hi g h cli nical i n de x of s us pici o n f or C O VI D -1 9, or has a p ositi ve la b orat or y c o nfir mati o n of C O VI D -1 9  i nfecti o n t he foll o w -u p visit ma y be deferre d be y o n d 
1 4 da ys after t he last d ose a n d sc he d ule d/resc he d ule d at a ti me p oi nt as dee me d a p pr o priate b y t he I n vesti gat or  
 
3.  P D = P har mac o d y na mic  
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2. 
INTRODUCTION 
GSK3884464 is a selective oral KEAP1 blocker/NRF2 activator that is being investigated 
as a once daily, first in class treatment for heart failure. GSK3884464 fully restored 
cardiac function without altering heart rate or blood pressure in a preclinical model of 
non-ischemic heart failure (HF), and also improved oxidation impaired contractility in 
human iPSC cardiomyocytes (iPSC-CMs). These findings suggest KEAP1 
blockade/NRF2 activation may represent a novel mechanism for the treatment of heart 
failure. 
There are currently an estimated 40 million heart failure (HF) patients worldwide, half of 
whom have heart failure with reduced ejection fraction (HFrEF). In the US alone the 
number of HF patients is projected to exceed 8 million by 2030 [Shah, 2017]. HF has a 
complex etiology driven by a spectrum of cardiac stressors of which the most common 
are hypertension, ischemic injury, vascular disease, or genetic predispositions to cardiac 
dysfunction. The progression of HF is characterized by structural and molecular 
remodeling of the heart, which may include ventricular hypertrophy, dilation, deranged 
myocardial metabolism, oxidant stress, inflammation, fibrosis and cell death [Shimizu, 
2016]. The net effect of this maladaptive remodeling is reduced cardiac performance 
which progresses inexorably to pump failure [Drazner, 2011]. The current standard of 
care, including renin-angiotensin-aldosterone system inhibitors, neprilysin inhibitors, β-
blockers, and cardiac resynchronization therapy all report decreased left ventricular (LV) 
dilation and end systolic dimensions with significant improvements in contractile 
function. However, despite the benefits of current therapies the 5-year HF mortality rate 
remains over 75%, with a mean survival of 2.1 years, in patients hospitalized for HF 
[Shah, 2017]   
GSK3884464 is an orally active, non-covalent KEAP1-NRF2 competitive inhibitor that 
selectively targets the Kelch domain of KEAP1. The compound blocks the incorporation 
of NRF2 into the KEAP1 E3-ligase ubiquitin complex and thereby impairs the 
constitutive proteasomal degradation of NRF2. The net effect is the liberation and nuclear 
translocation of NRF2 and subsequent activation of NRF2 regulated gene transcription. 
KEAP1 is a ubiquitously expressed cytosolic redox sensor and substrate adapter protein 
for the Cullin-3 E3 ubiquitin ligase complex. The canonical regulation of KEAP1 is 
through its redox sensing domain (BTB domain), where reactive oxygen species modify 
cysteine residues resulting in a destabilized KEAP1 E3 ligase complex and subsequent 
liberation of substrate transacting proteins such as NRF2 (Figure 6).  


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
6 3  
Fi g ur e 6  
N R F 2 i s r e g ul at e d b y K E A P 1  
N R F 2 i s r e g ul at e d b y K E A P 1, a u bi q uit o u sl y e x pre s s e d c yt o s oli c re d o x s e n s or a n d s u b strat e a d a pt er pr ot ei n 
f or t h e C ulli n-3, E 3 u bi q uiti n li g a s e c o m pl e x. W h e n o xi d a nt stre s s i s l o w, K E A P1 k e e p s N R F 2 c o m pl e x e d wit h 
C ulli n -3, E 3 u bi q uiti n li g a s e t o i n d u c e pr ot e a s o m al d e gra d ati o n a n d pre v e nt N R F 2 n u cl e ar a c c u m ul ati o n. W h e n 
o xi d a nt stre s s i s hi g h, E 3 li g a se i s di sr u pt e d a n d N R F 2 i s n ot d e gra d e d a n d c a n tra n sl o c at e i nt o t h e n u cl e u s. 
T he m ost well c haracterize d s u bstrate a n d pat h wa y of K E A P 1 relat es t o t he tra nscri pti o n 
fact or N R F 2, w here re d o x stress res ults i n N R F 2 n uclear tra nsl ocati o n a n d N R F 2 
me diate d tra nscri pti o nal acti vati o n of p hase II x e n o bi otic meta b olis m ge nes [Di n k o va - 
K ost o va , 2 0 1 7]. H o we ver, G S K 3 8 8 4 4 6 4 d oes n ot f u ncti o n t hr o u g h t h e re d o x se nsi n g 
mec ha nis m b ut i nstea d selecti vel y bi n d s t o t he K E A P 1-kelc h d o mai n w hi c h has bee n 
s h o w n t o res ult i n re d o x i n de pe n de nt li berati o n of N R F 2 acti vit y. I m p orta ntl y, 
G S K 3 8 8 4 4 6 4 is mec ha nisticall y disti nct a n d p har mac ol o gi call y differe ntiate d fr o m 
c o vale nt, n o n -sel ecti ve c o m petit or assets t hat tar get t he B T B d o mai n of K E A P 1. I n 
a d diti o n, t he c he mical a n d p h ysic o c he mical pr o p erties of G S K 3 8 8 4 4 6 4 are fa v ora bl e f or 
t he de vel o p me nt of a m e dici ne.  
G S K 3 8 8 4 4 6 4 has de m o nstrate d p ote nt disr u pti o n of t he K E A P 1 -N R F 2 pr otei n -pr otei n 
i nteracti o n i n bi oc he mical assays a n d p ote nt acti vati o n of t he N R F 2 pat h wa y i n m ulti ple 
h u ma n cell t y p es. I n a d diti o n, G S K 3 8 8 4 4 6 4 has de m o nstrate d r o b ust tar get e n ga ge me nt 
i n m ulti ple r o de nt a n d n o n-r o de nt s peci es f oll o wi n g re peat oral d osi n g, 
I n a series of precli nical r o de nt heart fail ure relate d st u dies, K E A P 1  bl oc kers a n d N R F 2 
acti vat ors ha v e s h o w n be nefit.  F urt her m ore, G S K 3 8 8 4 4 6 4 has de m o nstrate d t he ca pacit y 
t o pr otect t he via bilit y a n d c o ntractile f u n cti o n of h u ma n i n d uce d pl uri p ote nt ste m cell-
deri ve d car di o m y oc yte s (i P S C-C M s) e x p ose d t o a se ver e o xi dati o n a n d c yt ot o xicit y 
c halle n ge, w hi c h ma y be rele va nt c o nsi d eri n g t hat h u ma n H F patie nts c arr y a si g nifica nt 
o xi da nt b ur de n. I n a d diti o n, i n a m o use H F m o del of se vere he m o d y na mic stress, 
a d mi nistrati o n of G S K 3 8 8 4 4 6 4 a n d ot her K E A P 1  bl oc ker / N R F 2 acti vat or were s h o w n t o 
n or malize left ve ntric ular ( L V) eje cti o n fracti o n assesse d b y tra nst h oracic 
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echocardiography. Importantly, the ejection fraction increase did not appear to occur by 
changing afterload (i.e. lowering blood pressure) or heart rate, the mechanisms by which 
many established HF therapies (i.e. Angiotensin-converting enzyme inhibitor (ACE) 
inhibitors/Angiotensin II receptor blockers (ARBs)/β-blockers) improve cardiac function. 
The findings in the mouse HF model have been highly reproducible, and the magnitude 
of benefit is exceptional in the context of non-hemodynamic mechanisms.  
There are other aspects of the KEAP1-NRF2 protein that may provide a beneficial effect 
on metabolic disease. In addition to the cardioprotection demonstrated with GSK3884464 
and other similar KEAP1 blockers/NRF2 activators, which suggests a novel mechanism 
for treating heart failure with reduced ejection fraction, the KEAP1/NRF2 pathway has 
also been reported to play a role in metabolic homeostasis. Pharmacological activation of 
NRF2 by the covalent NRF2 activators TBE-31 or Sulforaphane in mice with diet-
induced type 2 diabetes mellitus (T2DM) resulted in improved glucose disposal [Sharma, 
2018, Axelsson, 2017], while treatment with Sulforaphane reduced fasting blood glucose 
and glycated hemoglobin (HbA1c) in obese patients with T2DM [Axelsson, 2017]. 
Additionally, pharmacological activation of NRF2 with TBE-31 in mice with diet-
induced obesity and insulin resistance reversed insulin resistance, suppressed hepatic 
steatosis and ameliorated both nonalcoholic steatohepatitis (NASH) and liver fibrosis 
[Sharma, 2018]. These preclinical findings support potential utilization in additional 
patient populations (i.e. diabetes, NASH, obesity, etc.), including patients with HF with 
preserved ejection fraction (HFpEF) where insulin sensitivity (signalling for glucose/fat 
utilization) contributes to the underlying pathophysiology. Other exploratory biomarkers 
are being collected to inform these alternative indications. 
2.1. 
Study Rationale 
This will be a first in human study and the main objective is to evaluate the safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and repeat 
oral doses of GSK3884464 administered to healthy participants. 
2.2. 
Background 
Despite the relatively large number of approved therapies on the market for HFrEF, 
significant unmet need still exists for these patients as the 5-year mortality remains 
around 50%. Therefore, there is a significant need for novel therapies to treat HFrEF. The 
current SoC for HFrEF generally provides benefit by affecting loading conditions or 
supraphysiologically increasing cardiomyocyte cytosolic calcium levels, creating the 
potential for hypotension and proarrhythmogenesis, respectively, which limits dose and 
therapeutic potential. Novel investigative drugs that target other mechanisms that do not 
affect blood pressure or heart rate, such as GSK3884464, have the potential to fill this 
large unmet need for HFrEF patients.  
GSK3884464 protects the viability and contractile function of human iPSC-CMs exposed 
to severe oxidative stress (relevant as HFrEF patients demonstrate a significant oxidant 
burden) and normalizes LV ejection fraction in a murine model of non-ischemic heart 
failure. The preclinical findings to date (described in detail in the Investigator’s 
Brochure) suggest GSK3884464 acts through a novel mechanism of action for the 
treatment of HFrEF [GlaxoSmithKline Document Number RPS-CLIN-000167] 


TMF-14577739 
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65 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK3884464 is provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
There is no expected benefit to participants taking part in this study.  
To date, GSK3884464 has not been administered to human participants; therefore, no 
clinical data are available. This is the first single and multiple dose study proposed in 
human participants with GSK3884464. 
The risk assessment of GSK3884464 is based on the pre-clinical studies conducted to 
date and data in the published literature. Summaries of findings from these pre-clinical 
studies can be found in the IB [GlaxoSmithKline Document Number RPS-CLIN-
000167]. - 
Details of these risks and the proposed strategy to mitigate/monitor these risks are 
detailed in Section 2.3.1. In this study, safety will be monitored closely both by 
subjective reporting and by objective means, i.e. serial assessments of vital signs, clinical 
laboratory information and cardiac monitoring. This study will be run in a clinical unit 
with immediate access to hospital facilities for the treatment of medical emergencies.  
In light of the coronavirus 2019 (COVID-19) pandemic, all participants will be screened 
for COVID-19 prior to, during, and at the end of the study period(s). 
More detailed information about the known and expected benefits and risks and 
reasonable expected adverse events for GSK3884464 may be found in the IB 
[GlaxoSmithKline Document Number RPS-CLIN-000167]. 
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
6 6  
2. 3. 1.  
Ri s k A s s e s s m e nt  
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  
St u d y I nt er v e nti o n  
R e n al  
I n r ats giv e n ≥0. 3 m g/k g/ d ay, d ose- a nd ti me -
d e pe n de nt i ncr e ase d ki dn ey w ei g ht, t ub ul ar 
d e ge n er ati o n/r eg en er atio n a n d m on on ucl ear c ell 
i nfl a m m ati o n w ere o bs erv ed.  T he eff ects 
c o ntri b ute d t o th e m oribu n d c o n diti on i n fe m al e 
r ats giv e n 1 m g/kg/ d ay for 10 d ays. F oll o wi n g a 4 
w e ek off -tr e at m ent perio d, eff ects w er e l ar g ely 
r ev ersibl e. 
w er e i ncr eas e d 
o n D ay 7 of dosi n g w he n me as ur ed i n a n 
aff ecte d r at giv en 0. 3 m g/kg/ d ay. Si mil ar ki d n ey 
w ei g ht a n d  microsc o pic fi ndi n gs w er e o bs erv ed 
i n mic e b ut w er e of mi ni m al s ev erity, not 
c o nsi d er ed a dv ers e, b ut persist e d foll o wi n g a 4 
w e ek off -pr e tr e at m e nt p eriod. I n m o nk eys, 
eff ects w er e li mit e d to i ncr eas e d kid n ey wei g ht at 
all d os es.   
T h e r at is co nsi der e d t o  be s e nsitiv e to r e nal 
eff ects v ers us ot h er s p eci es (i ncl u di n g h u m an) 
d u e t o sp eci es diff er enc es in p har mac ol o gy.  
T h er e is ap pr oxi m ately 0.0 1 - f ol d, 0. 1 9- f ol d, a nd 
2. 7 - f old m ar gi ns fr o m t he pr e dict e d h u m an 
ex p osur e ( A U C) at th e hi g h est pr op os ed r e pe at 
d o s e of 2 1 0 mg/ d ay t o t h e N O A E L i n r ats, mic e, 
T h e f oll o wi n g i n cl usi o n a n d e x cl usi o n crit eri a 
h a v e be e n i ncl u d e d t o f urt h er miti g at e t his 
ri s k: 
I n cl u si o n crit eria: 
Uri n ary a n alysis at scr e e ning t o b e fr e e of blo o d 
a n d pr ot ein. If t r ac e pr otei n or bl o o d is f ou nd, a 
r e p e at t est will b e p erf or med wit hi n 2 4 hrs, or as 
s o o n as p ossi bl e wit hin scr ee ni n g p eriod.   If 
tr ac e bl oo d or pr otei n is still s e e n o n r ep eat 
a n alysis, th e p ati ent is i neli gi bl e. 
E x cl usi o n criteri a:  
•  Hist ory of c urre nt o r past sig nific a nt r e nal 
dis e as es t o b e excl u d e d, e.g. Ac ut e Ki d n ey 
I nj ury, p ar e nc hy mal ki d n ey dis e as e. N ot to 
excl u d e p ast hist ory of r en al c alc uli . 
•  Scr e e ni ng esti m at e d gl o m erul ar filtr ati o n rat e 
( e G F R) ( C K D-E PI)  9 0 ml/ mi n/ 1. 7 3 m 2. 
•  Scr e e ni ng urine al bu mi n:cr eati ni n e r ati o 3 0  
m g/ g m  (≥3 m g/ m m ol) . 
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Summary of Data/Rationale for Risk 
Mitigation Strategy 
and monkeys, respectively. 
Monitoring (all Parts): 
• Monitoring serum potassium. 
• Serum renal function and urinary analysis 
monitoring (first void if possible). 
• Urine albumin:creatinine ratio (first void if 
possible). 
• Urine glucose by dipstick, if dipstick is 
positive then send for laboratory urine 
glucose with contemporaneous serum 
glucose. 
• By observing the PK safety margin for renal 
findings by targeting up to the total plasma 
AUC and Cmax to be below the monkey 
plasma NOAEL (AUC0-24h of 316000 ng.h/mL 
and a mean plasma Cmax of 48300 ng/mL). 
• Monitor for clinical symptoms of polyuria and 
polydipsia; if symptoms are suggestive, then 
exclude endocrine causes and quantify urine 
output (Refer to SRM). 
Renal stopping criteria: Individual (all parts) 
• Relevant renal safety data from the current 
and any previous cohort will be considered 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
as part of dose escalation decisions. 
• New onset of any clinically significant and 
persistent (for 48 hrs) hematuria as 
confirmed by microscopy (in the absence of 
any other clinical cause). 
• New onset of clinically significant and 
persistent (for 48 hours from the dosing day 
in the SAD part and at any point in the MAD) 
proteinuria (Spot Urine Albumin Creatinine 
ratio [ACR] ≥30mg/mmol) in the absence of 
another clinical explanation e.g. 
calculus/infection  
• If there is any increase in serum creatinine 
>26 μmol/L (>0.3mg/dl) repeat within 24 
hours. If confirmed, the participant will be 
withdrawn. and further investigations will be 
performed. 
• Increase in serum creatinine (ΔsCr) of >25% 
from baseline on 2 consecutive assessments 
within 24 hours. If confirmed, the participant 
will be withdrawn, and further investigations 
will be performed. 
• Reduction in eGFR from baseline > 25 % 
from baseline. If reduction in eGFR is > 25 
%, repeat within 24 hrs. If confirmed, the 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
6 9  
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  
p articip a nt will b e wit hdr a w n. If a p articipa nt 
m e ets t h e wit hdr a w al crit eria f or e G F R, t h e n 
f urt h er i nvesti g ati o ns will be p erf or me d 
St u d y St o p pi n g crit eria  
If 2 or m or e particip a nts i n a giv e n d os e c o hort 
d ev el op a ny of t he a b ov e wit h dr a w al crit eria , 
w h e n co nsi d ere d r el at e d t o st u dy  dr u g , t h en th at 
c o h ort will b e t e m por arily h alt e d. 
H e p atot oxicity  
I n r ats, d ose-d e pe nd e nt advers e effects i n t he 
liv er (i ncr e as es liv er w ei g ht a n d/or h ep atoc ell ul ar 
hy p ertr op hy, ser u m liv er e nzy m es a n d t otal 
biliru bi n, h e p at oc ell ul ar cyt o pl as mic r ar ef acti on, 
a n d mix ed c ell i nfl a m m atio n) w er e o bserv e d, 
w hic h occ urre d at d oses b el o w esti m at e d 
effic aci o us cli nic al exp os ur es b ut wer e l ar gely 
r ev ersibl e.  T he r at is co nsid er e d t o b e se nsitiv e 
t o a dv ers e liv er eff ects v ersus oth er s peci es 
(incl u di n g h u m a n) d ue t o speci es differ e nces i n 
p h ar mac ol ogy.  
T h e f oll o wi n g e xcl u si o n crit eri a ha v e b e e n 
i n cl u d e d t o f urt h er miti g ate t hi s ris k: 
•  
C urr e nt or c hro nic history of liv er dis e as e or 
k n o w n h e patic or bili ary a b nor maliti es.  
•  
Al a ni n e tr a nsa mi n as e ( A L T)  U L N.  
•  
Biliru bi n  U L N . 
•  
P ositiv e H ep atitis C a n d /or H e p atitis B 
a nti bo dy test r esult.  
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
In mice, hepatocellular hypertrophy was 
observed at ≥5 mg/kg/day and was associated 
with increased liver weight.  Following an off-
treatment period, similar effects were observed 
but were lesser in severity.   
 
In monkeys, increased liver weight, decreased 
total cholesterol and bilirubin were observed at 
≥ 5mg/kg/day. At ≥ 25mg/kg/day, decreased 
ALP was observed. 
There is approximately 0.01- fold, 0.19- fold, and 
2.7- fold margins from the predicted human 
exposure (AUC) at the highest proposed repeat 
dose of 210 mg/day to the NOAEL in rats, mice, 
and monkeys, respectively. 
 
In the ongoing study 213376, three cases of 
transient LFT increase have been observed in 
the 110mg single dose level with no concurrent 
symptoms. 
• 
Regular alcohol consumption within 
recommended limit within the past six 
months prior to the study. 
Monitoring: 
• 
Liver enzymes and bilirubin assessments 
daily D4 through D6 in SAD and from day 3 
through 24hrs after last day of dosing, and 
at D19) in the MAD part of the study  
• 
Bile samples for analysis of GSK3884464 
and any metabolites in one of the cohorts 
only (Entero-Tracker). 
• 
Careful LFT monitoring will be implemented 
in the Part 2 of the study to minimise the 
risk of exposing the participants to 
additional study drug in the case of an 
elevation of ALT/AST above the individual 
stopping criteria. 
 
Individual Liver stopping criteria: 
• ALT ≥ 3xULN.  
Relevant liver safety data from the current and 
any previous cohort will be considered as part of 
dose escalation decisions.  
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
7 1  
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  
GI effects  
I n mic e a n d r ats, dos e-d ep en d ent, r eversibl e 
hy p er pl asia/ hyp erk er atosis a n d/or mix e d  c ell 
i nfl a m m ati o n i n t he eso p hag us, sto m ac h 
( n o n gl an dul ar a nd gla n dul ar), a n d (i n mic e o nly) 
t o n gu e wer e obs erv e d.  In mic e, t h ese eff ects 
c o ntri b ute d t o m or bidity. T he r o d ent GI eff ects 
w er e r ev ersibl e foll o wi n g a n off -tr e at m e nt p erio d. 
W hil e t h e r od ent gastr oi ntesti n al eff ects occ urre d 
b el o w esti m at e d efficaci o us ex p osur es, th e 
w ei g ht of evi de nce s u p p orts t h at t hes e eff ects 
ar e p har mac ol ogic ally m e diat e d, r o de nt -s pecific, 
a n d n ot r el ev a nt to h u m a n.  
 
I n m o nkey, decr e ase d b o dy w ei g ht, e m esis an d 
r e d uc ed e ati n g/s aliv ati on wer e o bserv e d at 1 0 0, 
≥ 3 0 a n d ≥ 10 m g/kg/ d ay, res p ectiv ely, i n th e 
a bs enc e of microsc o pic fin di n gs.  
 
T h er e is ap pr oxi m ately 0.0 1 - f ol d, 0. 1 9- f ol d, a nd 
2. 7 - f old m ar gi ns fr o m t he pr e dict e d h u m an 
ex p osur e ( A U C) at th e hi g h est pr op os ed r e pe a t 
d os e of 2 1 0  mg/ d ay t o t h e N O A E L i n r ats, mic e, 
a n d m onk eys, r es p ectiv ely.  
T h e f oll o wi n g e xcl u si o n crit eri a ha v e b e e n 
i n cl u d e d t o r e d u ce t hi s ri sk f urt h er: 
•  
Hist ory or pr es enc e of si g nific a nt 
g astr oi ntesti nal dis or ders ( G E R D, n aus e a, 
v o miti n g or dysp ha gi a). 
P articip a nt m o nitorin g will be d on e usi n g  a d aily 
 I n th e ev e nt of 
cli nic ally si g nific a nt t oxicity, t h e p articip ant will b e 
wit h dr a w n, a n d s u pp ortiv e th er a py pr ovi d ed 
acc or di n g t o st a nd ar d m edic al pr actic e.  
R el ev a nt GI s af ety d ata fr o m t h e c urrent an d a ny 
pr evi o us co h ort will b e c o nsi d er e d as p art of 
d os e esc al atio n d ecisi o ns wit h a n o pti o n to  
s witc h t o g astr o-r esist ant c aps ul es if th e 
i nci d e nc e of GI sy m pto ms exc e e ds t h e pl ac e b o 
ar m / hist oric al plac e bo eff ects.   
 
N R F -2 activ ati o n -de pe n de nt t u m o ur pr o gr essi on 
a n d/or i ncr e ase d tu m o ur che m or esist a nce 
( b as e d o n d ata i n liter at ur e) 
A p ote ntial cl ass risk exists f or N R F 2 activ at ors, 
wit h r es p ect t o pr ovi di ng a gr o wt h a dva nta ge t o 
est a blis he d ca nc ers/a n d or c h e m or esist anc e i n 
p ati ents.  
 
H o w ev er, anti oxi da nts a nd N R F 2 activ at ors h av e 
b e en avail a bl e as di et ary s up pl e m e nts or 
P articip a nts will b e exp ose d t o stu dy m edic ati o n 
f or a s h ort dur ati on i n th e curre nt st u dy 
( maxi mu m 2 1  d ays d osi ng).  
T h e f oll o wi n g e xcl u si o n crit eri a ha v e b e e n 
i n cl u d e d t o r e d u ce t hi s ri sk f urt h er: 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
medicinal products for decades. For instance, 
the NRF2 activator Tecfidera (dimethyl fumarate) 
has been administered to at least 300,000 
multiple sclerosis patients since launch. 
Currently, no excess malignancies are reported 
in the literature or in the Tecfidera prescribing 
information. 
Data from genotoxicity assessments suggest that 
GSK3884464 does not present a genotoxic 
hazard to humans. 
• Lymphoma, leukaemia, or any malignancy 
within the past 5 years except for basal cell 
or squamous epithelial carcinomas of the 
skin that have been resected with no 
evidence of metastatic disease for 3 years. 
• Breast cancer within the past 10 years. 
 
Reproductive toxicity 
Animal reproductive studies have not been 
conducted with GSK3884464.  
The following inclusion criteria have been 
included to reduce this risk further: 
• 
Male or females of non-childbearing 
potential (Section 5.1 and Section 10.4).  
For male subjects that are with female partners 
of childbearing potential, contraception must be 
used (Appendix 4). 
Potential effects on CNS 
KEAP1/NRF2 are ubiquitously expressed in 
human organs; including high amounts in the 
brain.  
Animal studies showed that GSK3884464 
concentration was low in the brain, with tissue to 
plasma ratios of 0.061 and 0.026 for brain in rats 
and monkeys respectively.  
In vitro CNS multielectrode array toxicity assay 
showed no substantial effect with GSK3884464 
• 
Participants with a history or current 
evidence of depression, bipolar disorder, 
suicidal ideation and behavior, or a lifetime 
history of suicide attempt will be excluded. 
Participants will be closely monitored. 
• 
Sentinel dosing approach will be utilized.  
• 
In line with FDA guidance, assessment of 
suicidal ideation and behaviour occurrence 
will be conducted in participants who receive 
repeated doses. 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
7 3  
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  
o n C N S activity u p t o 1 0 µ M.  
N o b eh avi our al si g ns wer e n ot e d d urin g 6 -w e ek 
st u di es i n r ats at dos e u p to 3 0 m g/kg a n d 
m o nk eys at dos e u p to 5 0 m g/k g, an d n o effect s 
w er e o bserv e d i n t he I R WI N t est at dos es u p to 
3 0 m g/kg.  
•  
Ass ess m e nts of co g nitive saf ety will b e 
p erf or m e d in particip a nts wit h r e pe ate d 
d os es.  
•  
St o ppi n g crit eria b ase d o n ass ess m e nts of 
s uici d al i d e ati o n a nd b e havi o ur, an d 
c o g nitiv e saf ety. 
St u d y Pr o c e d ure s   
Bil e S a m pli ng ( E nter o -Tr ack er  or  E nt er o -T est ) 
 
T h e use of t he E nt er o -T est h as b e en a ppr ov ed 
by t he E uro p ea n r eg ul at ory a ut h oriti es (I S O 9 00 1 
a n d C E M ark C ertific ati on; E ur o pe a n U ni o n 
M e dic al D evic es Dir ectiv e ( M D D)).   
•  Str e aks of bl oo d o n t h e string d ue to l oc al 
irrit ati o n h ave b e e n i nfr e qu ently n ot e d.  
•  R ar ely, a p ati ent will b e u n abl e t o s w all o w 
t h e ca ps ul e b eca use of g aggi n g or will 
v o mit aft er d oi ng s o.   
•  G a g gin g u p on r etri ev al of the strin g ca n 
occ ur. 
•  O n a f e w occasi o ns, a n e ntir e stri n g h as 
b e en s w all o w ed wit h out ill eff ects a n d 
p ass es o ut fr o m t he b o dy i n t h e f a eces.  
•  T h e strin g will b e s ecur ely ta p ed i n pl ac e (to 
t h e ch e ek of e ac h p articipant) d uring t he 
c oll ecti o n ti me t o mi ni miz e risk of 
s w all o wi n g t he e ntir e stri n g.   
•  A ny p articip a nt i nc ap a ble of s w all o wi n g th e 
stri n g will b e all o we d to c o nti n u e i n t he 
st u dy wit ho ut 
c oll ecti o n.  
•  P articip a nts u nd er goi n g bil e s a m pli n g 
s h o ul d n ot b e ex pos ed t o m a g netic 
r es o n anc e i m a gin g ( M RI) f or at l e ast 7 2 hrs 
p ost s w all o wi ng of t he c a psul e devic e –  
s uc h ti me will all o w th e stai nl ess-st e el b all 
t o b e exp ell e d int o t h e st ool.  
 
Ot h er  
C O VI D -1 9  
P articip ati on wit hi n a cli nic setti n g m ay i ncr e ase 
t h e risk of c o ntr acti n g C O VI D-1 9.  
T h e f oll o wi n g i n cl usi o n crit eri a h av e be e n 
i n cl u d e d t o r e d u ce t hi s ri sk f urt h er: 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Exposure to other participants and staff may 
increase the risk of exposure. 
 
18 to 50 years of age inclusive. 
COVID-19 screening prior to study and testing 
during the study.  
Monitoring for clinical presentation of COVID-19 
signs/symptoms.  
Conduct study at a site(s) which have the 
appropriate mitigation strategies in place.  
The following exclusion criteria have been 
included to reduce this risk further: 
• Participants with signs and symptoms 
suggestive of COVID-19 within 14 days of 
admission.  
• Participants with known COVID-19 positive 
contacts in the past 14 days. 
Immunocompromization potential 
In placebo-controlled trials, 6% of patients taking 
Tecfidera (dimethyl fumarate, DMF), a non-
specific NRF2 activator, experienced lymphocyte 
counts of <0.5x109/L (lower limit of normal 
0.91x109/L). No difference in infection rates was 
seen between patients taking Tecfidera and 
those taking placebo (Tecfidera, 2020 
Prescribing Information, Revised 2020). 
GSK3884464 
In mice, rats and monkeys, dose-dependent 
decreased thymic weight and cellularity were 
observed, reversible in rats and were considered 
The following criteria have been included to 
reduce this risk further: 
• 
Clinical laboratory hematological 
assessments conducted at screening and at 
baseline. 
• 
Participants monitored throughout the study 
dosing cohorts.  
The following exclusion criteria have been 
included to reduce this risk further: 
• 
History or presence of significant 
hematological disorder capable of 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
7 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  
s ec o nd ary t o str ess. In r o dents, d ecr e ase d 
ly mp h ocyt e co unt an d m ar gi n al z o ne 
ly mp h ocyt es a nd/ or i ncr ease d a bs ol ut e platel et 
c o u nt w er e obs erv ed at n on-t ol er at e d d os es 
a n d/or attribut a bl e to str ess.   A d ditio n ally, 
i m m u n o p h en otypi n g of m onk ey bl oo d foll o wi n g 6 
w e eks of d osi ng did n ot de m o nstr at e a ny effects.  
c o nstit uti n g a risk w h e n t akin g th e stu dy 
tr e at m e nt; or i nt erf ering wit h t h e 
i nt er pr etati o n of d ata. 
•  
A ny cli nic ally r el ev a nt a b nor mality o n th e 
scr e e ni n g l a bor at ory ex a mi n ati on a n d at any  
ti m e d urin g t h e st udy p er M e dic al M o nitor 
r evi e w. 
C ar di ov asc ul ar Eff ects  
I n t oxicol o gy stu di es, w hic h w er e c o nd ucte d for 
u p to six w e eks with d aily or al d osi ng a n d i n 
si n gl e dos e saf ety p har macol o gy stu di es, t her e 
h av e b ee n n o c ardi ov asc ular eff ects o bserv e d i n 
a ni mals giv en G S K 3 88 4 46 4.  S pecific ally, t her e 
w er e n o or g an w ei ght, m acrosc o pic or 
microsc o pic eff ects obs erv ed i n h e art a n d/ or t he 
v asc ul at ure, nor w er e th er e a ny 
el ectr oc ar di ogr a phy eff ects o bs erv ed. In vitr o, 
eff ects w er e li mit e d to p arti al  h E R G i n hibiti o n at 
c o nc entr ati ons f ar exc e edi ng t he esti m ate d 
cli nic al ex p osur e r a ng e. 
I n pr ecli nic al effic acy st u dies, u pr eg ul atio n of 
i n t he my oc ar di u m w as se e n 
as e arly as d ay t hr ee aft er th e i niti ati o n of 
tr e at m e nt.  N o effect on myoc ar di al fu ncti on w as 
n ot e d i n h e althy r od e nts, a nd i m pr ov e m e nts i n 
ej ecti o n fr acti on (r e m o d elli ng) w er e not e d aft er 
a p pr oxi m ately t w o w eeks of tr e at m ent i n a 
m o us e m o del of pr ess ure -ov erlo a d h e art f ail ur e.  
T h e f oll o wi n g e xcl u si o n crit eri a ha v e b e e n 
i n cl ud e d t o r e d u ce t hi s ri sk f urt h er:  
•  
Cli nic ally si g nific a nt hi g h bl oo d pr essur e 
a n d/or hist ory of hyp erte nsio n as d et er mi n e d 
by t he i nv estig ator.  
•  
S er u m tr o po ni n I or tr op oni n -T gr e at er th an 
t h e u p per li mit of nor mal. 
•  
Q Tc F 4 5 0 ms ec;   
•  
Scr e e ni ng 1 2 -l e a d E C G with a ny of t h e 
f oll o wi n g: 
•  
S ec o nd - or third - d egr e e atri ov e ntric ul ar 
bl ock ( A V B).  
o  T w o or m or e si gnific a nt p ath ol o gi cal Q-
w av es ( d efin e d as Q -w ave  4 0 ms ec or 
d e pth gr eat er t h an 0.4 -0.5 m V) i n a 
p atter n c onsist e nt wit h a prior 
my oc ar di al i nf arcti on.  
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 
o Ventricular pre-excitation. 
o Bradycardia as defined by sinus rate ≤ 
30 beats per minute (BPM)  
o Complete left bundle branch block 
(LBBB) 
o History of QTc prolongation, 
symptomatic cardiac arrhythmias or 
cardiac arrest. 
• 
Screening Holter (24 hours) with any of the 
following: 
o Sinus bradycardia ≤ 30 BPM  
o Non-sustained ventricular tachycardia 
(NSVT) or more than 30 Ventricular 
Premature Depolarisations (VPD) during 
an hour.  
o Atrial arrhythmia  100 BPM for 3 
seconds or longer or more than 40 Atrial 
Premature Depolarisation (APD) during 
an hour.  
During the trial period, telemetry and ECG 
monitoring will be performed.  Additionally, 
regular measurements of high-sensitivity 
troponin and NT-pro BNP will be reviewed during 
the study. 
 


TMF-14577739 
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Prot Amend 4 
 
77 
2.3.2. 
Benefit Assessment 
No clinical benefit is expected for participants in this FTIH study. 
This study will provide initial safety, tolerability, pharmacokinetic, and 
pharmacodynamic data to better inform dose selection and safety monitoring in the 
subsequent studies in the clinical development program. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to the participants in this study, the 
potential risks identified in association with study intervention and procedures are 
considered minimal and justified. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Primary 
• 
To characterize the safety and 
tolerability profile of GSK3884464 in 
healthy participants. 
 
 
 
 
 
 
• 
To characterize the plasma PK of 
GSK3884464 in healthy participants 
(single and repeat dosing).  
 
• 
Number and percentage of healthy 
participants (single and repeat doses) 
with adverse events. 
 
• 
Clinically significant changes from 
baseline in laboratory values, vital signs, 
continuous telemetry, 12-lead 
electrocardiogram (ECG), and 
echocardiograms (in Part 2 only) up to 
and including the follow up visit (7-10 
days post final dose). 
 
• 
Plasma pharmacokinetic parameters 
following single oral doses including 
AUC(0-t), AUC(0-∞), Cmax, time to 
maximum observed plasma drug 
concentration (tmax), and terminal half-
life (t½). 
• 
Plasma pharmacokinetic parameters 
following repeat oral doses including 
AUC, Cmax, trough plasma 
concentration (Cτ), time to maximum 
observed plasma drug concentration 
(tmax), terminal half-life (t½), 
accumulation ratios based on AUCτ 
(RAUC), on Cmax (RCmax), and on Cτ 
(RCτ). 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
7 8  
O bjecti ves  
E n d p oi nts  
Sec o n d ar y  
Sec o n d ar y  
•  T o e val uate tar get e n ga ge me nt 
f oll o wi n g si n gle a n d re peat oral d oses 
i n healt h y p artici pa nts.  
•  Ma xi m u m c ha n ges fr o m baseli ne i n 
N Q O 1 m R N A i n w h ole bl o o d p ost 
treat me nt wit h G S K 3 8 8 4 4 6 4 i n all parts 
of t he st u d y.  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
7 9  
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This First Time in Human (FTIH) study 213376 will be a randomized, double-blind, 
placebo-controlled study of the oral administration of GSK3884464 in healthy 
participants. As this will be the first time GSK3884464 is given to humans, the study 
design may change based on emerging data as the study progresses. 
The study is planned to have two Parts (Parts 1, and 2) and will be conducted at one 
center.  
1. 
Part 1 will be a 3-period crossover design, single dose (SD), dose escalation study 
with 3 participants per sequence in healthy participants. Each participant will participate 
in up to 3 dosing periods and will receive up to 2 doses of GSK3884464 and 1 dose of 
placebo in a randomized fashion. There will be a minimum of 7 days (or 5 half-lives, 
whichever is longer) washout period between dosing in each session.  
Approximately 9 participants will be enrolled in each cohort. Participants will be 
admitted to the Clinical Research Unit on Day –1 and will remain in the unit until 
completion of the assessments on Day 6 as outlined in the SoA. Participants will be 
discharged from the clinical unit for the washout period between dosing sessions and will 
return approximately 7-10 days after their last dosing session for a follow-up visit. 
Participants will be randomized to treatment sequences such that in each period up to 6 
participants will receive active dose and up to 3 participants will receive placebo. Up to 2 
to 3 participants will be dosed at a time, and their LFTs will be closely monitored before 
the next participants receive study treatment.  A minimum of 3 cohorts is anticipated. If a 
participant is withdrawn from the study, the participant may be replaced as necessary 
with another participant assigned to the same treatment sequence with respect to active 
and placebo doses to ensure that at least 3 participants receive each active dose and 1 
participant receives placebo, and must complete the safety and PK assessments through at 
least the 120hr post-dose (or 5 half-lives, whichever is longer). Additional participants 
may be dosed at a given level if additional data are necessary to establish safety, 
tolerability, or PK parameters prior to dose escalation. 
2. Part 2 will be a sequential design, 14-day (Cohorts 4 and 5) and up to a 21-day 
(Cohort 6) repeat-dose (RD), dose escalation study in healthy participants (See Section 
4.4). Each cohort will consist of approximately 8 participants. Participants in each cohort 
will receive GSK3884464 or matching placebo according to a randomization schedule 
prepared prior to the start of the study. The study will be conducted sequentially starting 
with Dose 1. Participants will receive repeat daily doses of the study intervention or 
placebo based on PK data obtained in Part 1 and ongoing PK data in Part 2. 
Participants will report to the Clinical Research Unit on Day –1 and will remain in the 
unit until completion of the assessments on Day 19 (Cohorts 4 and 5) or Day 26 at the 
latest (Cohort 6). Participants will be randomly assigned to receive GSK3884464 or 
placebo (approximately 6 study intervention and 2 placebo). Plasma and urine PK, PD, 
and biomarker samples will be collected through the 19-day or up to 26-day in-patient 
stay. All participants will return to the Clinical Research Unit for a follow up visit 
approximately 7-10 days after their last dose of study treatment.  


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
8 1  
I n b ot h Part 1 a n d 2, t he d ose a n d/ or freq ue n c y of G S K 3 8 8 4 4 6 4 ma y b e a dj uste d (l o wer 
or hi g her) bas e d u p o n t he safet y, t olera bilit y, P K, a n d P D data (as a vaila ble) fr o m 
pre vi o us C o h orts a n d d ose le vels.  Safet y, t olera bilit y, a n d P K dat a will be re vie we d i n a 
mi ni m u m of 3 partici pa nts recei vi n g acti ve treat m e nt u p o n c o m pleti o n of assess me nts at 
t he e n d of t heir c o h ort (b ef ore i nitia tio n of d osi n g i n t he ne xt c o h ort ); partici pa nts will be 
re place d as r e q uire d t o m ai ntai n t he mi ni m u m n u m ber o n treat me nt. T his r e q uire me nt 
will be s u perse de d i n c as e st o p pi n g criteria (see Secti o n 7. 1 ) are met a n d it is n ot dee me d 
safe t o pr ocee d wit h d osi n g at a certai n G S K 3 8 8 4 4 6 4 d ose le vel: i n t his sce nari o, t he 
d ose mi g ht be de -escalat e d a n d its le vel ma y be s electe d base d o n safet y, t olera bilit y, P K 
a n d P D data (if a vaila ble ) i n less t ha n 3 partic i pa nts recei vi n g acti ve treat m e nt.  See 
Secti o n s 4. 4  f or i nf or mati o n o n t he decisi o n t o pr ocee d t o t he n e xt d ose le vel 
Discl os ure St ate me nt : T his is a First Ti me i n H u ma n St u d y. E ac h acti ve d ose le vel will 
be a d mi nistere d i nitiall y t o a s maller gr o u p of se nti nel partici pa nts ( 1 o n acti ve a n d 1 o n 
place b o) t o e v al uate safet y at eac h d os e le vel.  I n P art 1, se nti nel partici pa nts will be 
f oll o we d cli nically f or 6 da ys  ( pre dict e d half-life f or G S K 3 8 8 4 4 6 4 is a p pr o xi matel y 
1 2 hrs) t o all o w f or a de q u ate o bser vati o n of safet y . I n Part 2, se nti nel partici pa nts will be 
f oll o we d cli nicall y f or 1 4 da ys  t o all o w f or a d e q uate o bser vati o n of safet y t o m o nit or f or 
e mer ge n ce of a d vers e e v e nts . If n o ac ut e safet y iss ues are o bs er ve d i n t his s maller gr o u p 
of se nti nel partici pa nts (i ncl u di n g re vie w of t h e safet y l a b orat or y res ults), t he n t he 
re mai ni n g p artici pa nts will recei ve t he s a me d ose pri or t o d ose escalati o n (Sec ti o n 4. 4 ). 
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 he st u d y d esi g n is bas e d o n well -esta blis he d a n d p u blis he d met h o ds t o e val uate t he first 
si n gle a n d re peat d ose a d mi nistrati o n of e x peri me ntal dr u gs, i ncl u di n g t he use of 
se nti nels. T his st u d y is pl ace b o -c o ntr olle d  t o all o w f or a vali d e v al uati o n of a d verse 
e ve nts attri b uta ble t o treat me nt vers us t h ose i n de pe n de nt of treat me nt.   
Partici pa nts i n Part 2 will be e nr olle d i nt o t he st u d y wit h a B MI ra n ge fr o m 2 2 -3 0 . T his 
selecte d ra n ge will bias t o war ds hea vier pa rtici pa nts w h o are m or e li kel y t o ha ve i ns uli n 
resista nce t o det er mi ne if G S K 3 8 8 4 4 6 4 has a n i m pact o n fasti n g gl uc ose a n d ins uli n 
le vels. 
T his F TI H st u d y will i ncl u de e val uati o n of P D mar kers t o assess tar get e n ga ge me nt  (i.e. 
N Q O 1 m R N A  i n w h ole bl o o d). A d diti o nal e x pl orat or y bi o mar kers of o xi dati ve stress , 
i nfla m mati o n, a n d re nal t o xicit y ma y be assesse d t o u n dersta n d effects of G S K 3 8 8 4 4 6 4 
i n healt h y p artici pa nts. 
I n or der t o c h aracteriz e p ote ntial biliar y eli mi nati o n pat h wa ys, t his st u d y will als o 
e m pl o y t he E nter o -Trac k er or  E nter o -Test f or sa m pli n g of 
 t o c o n d uct 
q ualitati ve assess me nt of dr u g met a b olites i n t hi s matri x. T he E nter o-T rac ker or  E nter o -
Test is a rece nt re pla ce m e nt de vice f or a si milar de vice, E nter o-Test, a n F D A 5 1 0 k 
e x e m pt de vice w hic h has bee n s h o w n t o be a n eas y -t o-us e a n d mi ni mall y -i n vasi ve 
met h o d f or sa m pli n g bile fr o m t he d u o de n u m [G ui ne y , 2 0 1 1 ]. 
I nf or mati o n o n t he biliar y dis p ositi o n of dr u g-relate d material deri v e d i n t he c urre nt st u d y 
ma y a v oi d t he nee d f or i n vasi ve met h o ds of bile c ollecti o n i n f ut ur e st u dies. As s ufficie nt 
data fr o m t he E nter o -Trac ker or  E nter o -T est stri n g is e x pecte d f oll o wi n g o ne d ose of t he 
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
8 2  
st u d y dr u g, t his assess me nt will be restricte d t o o nl y o ne c o h ort i n Part 2 (a ntici pate d t o 
be t he sec o n d or t hir d d ose le vel de pe n di n g o n P K res ults i n Part 1 a n d C o h ort 4 ) d uri n g a 
partici pa nts’ stea d y stat e. T he E nter o -Trac ker or  E nter o -Test bile sa m ple c ollecte d fr o m 
place b o -d os e d s u bjects will be c o nsi dere d as t he c o ntr ol.  
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 partici p a nt i n p ut i nt o t he st u d y desi g n  of t he Pr ot oc ol .  
4. 3.  
J u stifi c ati o n f or D o s e  
4. 3. 1.  
Pr e di cti o n of H u m a n P K a n d S af et y C o v er  
P har mac o ki netics of G S K 3 8 8 4 4 6 4 i n h u ma n was pre dicte d b y all o metric s cali n g of data 
fr o m rat, d o g, a n d m o n ke y [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 2 0 N 4 5 9 1 0 3 _ 0 1 , 
2 0 2 1 ]. E x vi v o tar get e n ga ge me nt, i n ter ms of N Q O 1 m R N A i n d ucti o n i n h u ma n bl o o d, 
was m o delle d as a f u ncti o n of dr u g c o nce ntrati o n a n d ti me. T he i n vi v o ti me c o urse of 
N Q O 1 m R N A le vel after a si n gle d os e a n d d uri n g re peat e d d osi n g were t he n si m ulate d 
acc or di n g t o t he pre dicte d P K pr ofiles. 
 
 
. Met h o d ol o gic al details of t he d ose pre dicti o n are des cri be d i n Gla x o S mit h Kli ne 
D oc u me nt N u m ber R P S -C LI N -0 0 0 1 6 7 , 2 0 2 2  [Gla x o S mit h Kli ne D oc u me nt N u m ber 
2 0 2 1 N 4 6 7 0 3 6 _ 0 0 , 2 0 2 1 ]. 
T he starti n g d os e f or Part 1 will be 1 m g. T his d os e is pre dicte d t o pr o d u ce a p pr o xi matel y 
1 5 % N Q O 1 m R N A i n d u cti o n at pea k w hic h is  c o nsi dere d as t he mi ni mal a ntici pate d 
bi ol o gical  effect le vel ( M A B E L). T he pre dicte d t h era pe utic d os e is u p t o a p pr o xi matel y 
1 0 0 m g/ da y. D os e escalati o n i n eac h part of t h e st u d y will be g ui de d b y t he re vie w of 
e mer gi n g P K, safet y, t olera bilit y data a n d P D data if a vaila ble; t he e x p os ure i ncre me nts 
will  be a p pr o xi matel y  2 -3 f ol d. T o acc o u nt f or t he hi g h u ncertai nt y i n t hera pe utic d ose 
pre dicti o n a n d t he li kel y i ncreas e d varia bilit y (i n d osi n g a d h ere n ce, P K, P D, safet y a n d 
C CI
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tolerability) in future large outpatient trials in diverse populations, the planned top dose 
will aim to achieve exposure close to parity with exposure at the NOAEL dose in the 
most relevant toxicology species to adequately assess the safety and tolerability to protect 
patients in future trials. 
Among the toxicology species, the plasma exposure at the NOAEL is in the order of 
monkey > mouse > rat. Because the dose limiting gastrointestinal toxicity in the mouse 
and renal toxicity in the rat are considered rodent-specific, the monkey is considered as 
the most sensitive relevant species.  
The predicted human PK and exposure margin to the NOAEL in the monkey at the 
proposed doses for each part of the study are shown in the following sections (Section 
4.3.2 and Section 4.3.3 for Part 1 and 2 respectively). For all Parts of the study, the mean 
plasma drug exposure at the top dose, predicted by emerging PK data, will not exceed the 
corresponding steady-state value at the NOAEL of 50 mg/kg/day in the six-week 
toxicology study in the monkey (Day 42 AUC = 316000 ng.h/mL and Cmax = 48300 
ng/mL). 
4.3.2. 
Prediction of Dose Levels for Part 1 
The predicted exposure and the safety cover of the doses planned for Part 1 are shown in 
Table 1. The starting dose will be 1 mg (expected MABEL). The selection of the 
subsequent doses may deviate from those in the table, based on emerging available 
safety, tolerability, PK data and PD data if available from previous dose levels.  
The decision on progression to the next dose level will be made by the Dose Escalation 
Committee (DEC); (see Section 4.4 and Section 10.1.5). The top dose will be aimed to 
cover the exposure that is anticipated to be produced during repeat (due to accumulation) 
in subsequent parts of the study. 
In the event the observed exposure at the starting dose (1 mg) is lower than the 
corresponding predicted exposure, the next dose will target the exposure at the MABEL. 
In this case the escalation increment can be greater than 3-fold. In the event the observed 
exposure at the starting dose (1 mg) is substantially higher than the corresponding 
predicted exposure, the next dose will be revised to produce a 2-3-fold increment in 
exposure, consistent and no greater than the currently planned increments, if the dose 
escalation stopping criteria are not met. 


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Table 1 
Projected plasma GSK3884464 exposure and safety cover following 
single oral doses of GSK3884464. 
Dose Level  
Dose [mg] 
Predicted plasma exposures1 
Fold safety cover2 
Cmax [ng/mL] 
AUC [ng/mL × h] 
Cmax[ng/mL] 
 AUC [ng/mL × 
h] 
1 
1 
84.337 
557.14 
572.7 
567.2 
2 
3 
253.01 
1671.4 
190.9 
189.1 
3 
9 
759.03 
5014.3 
63.6 
63.0 
4 
20 
1686.6 
11143 
28.6 
28.4 
5 
40 
3373.2 
22286 
14.3 
14.2 
6 
80 
6746.4 
44572 
7.2 
7.1 
7 
160 
13493 
89144 
3.6 
3.5 
8 
300 
25299 
167142 
1.9 
1.9 
9 
550 
46382 
306427 
1.0 
1.0 
1. Total plasma exposure predicted via allometry (Cmax is maximum concentration achieved after single dose, and 
AUC is area under concentration extrapolated to infinity). 
2. Ratio of steady-state plasma drug exposure at the 6-week monkey toxicity study NOAEL dose of 50 mg/kg/day 
(Day 42 AUC and Cmax of 316000 ng.h/mL and 48300 ng/mL, respectively) to predicted plasma AUC and Cmax in 
human after a single dose. 
 
4.3.3. 
Prediction of Dose Levels for Part 2  
The decision to progress to Part 2 and the selection of the actual dose levels, of the repeat 
dose regimen and of the number of cohorts will be made by the DEC, based on all 
available safety, tolerability, PK and available PD data from Part 1 (Section 4.4, Section 
10.1.5). The predicted doses to be explored in Part 2 may be adjusted to the new starting 
and maximum doses pending data obtained in Part 1. 
A once daily (QD) regimen is currently planned for repeat dosing; twice-daily (BID) 
dosing might be considered depending on PK data from Part 1, if QD dosing is predicted 
to produce high fluctuations in PK (Cmax/Cτ > 5-fold).  
Up to three dose levels are planned in Part 2; their expected steady-state Cmax and AUC 
will have been shown to be safe after a single dose in Part 1. The exposure at the top dose 
will not exceed the monkey NOAEL. The predicted exposure and related safety cover for 
the planned QD doses are shown in Table 2.  
The possibility to include additional cohort(s), to investigate higher dosing levels (with 
exposure capped at monkey NOAEL), might be considered in the event that no safety 
signals are observed in the three planned cohorts. In the event the observed exposure at 
the starting dose (1 mg) is substantially higher than the corresponding predicted 
exposure, the next dose will be revised to produce a 2-3-fold increment in exposure, 


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consistent and no greater than the currently planned increments, if the dose escalation 
stopping criteria are not met. 
Table 2 
Projected plasma GSK3884464 exposure and safety cover following 
multiple oral doses of GSK3884464. 
Dose Level  
Dose 
[mg/day] 
Predicted plasma exposures1 
Fold safety cover2 
Cmax,SS 
[ng/mL] 
AUCτ [ng/mL × h] 
Cmax,SS 
[ng/mL] 
 AUCτ [ng/mL × 
h] 
1 
20 
1858.7 
11143 
26.0 
28.4 
2 
70 
6505.5 
39001 
7.4 
8.1 
3 
210 
19516 
117002 
2.5 
2.7 
1. 
Total plasma exposure predicted via allometry (Cmax_SS is maximum concentration at steady state, and AUCτ is 
area under concentration over dosing Interval=24 hours). 
2. 
Ratio of steady-state plasma drug exposure at the 6-week monkey toxicity study NOAEL dose of 50 mg/kg/day 
(Day 42 AUC and Cmax of 316000 ng.h/mL and 48300 ng/mL, respectively) to predicted plasma AUC and Cmax 
in human.  
4.4. 
Criteria for Dose Escalation and for Progressing Between Parts 
of the Study 
The decision to proceed to the next dose level, to progress through each Part/Cohort, and 
to include an additional cohort/dose level (if necessary) will be made by the DEC. In 
addition, the DEC may review data from Cohort 5 and determine duration of treatment in 
Cohort 6 The anticipated mean plasma exposure (Cmax and AUC) for any dose level to be 
administered will not exceed the limiting exposure criteria based on the plasma NOAEL 
dose from the monkey 6-week GLP tox study (Section 4.3.1).  
GSK will conduct regular dose escalation meetings throughout the course of Part 1 and 
Part 2. Each meeting will be scheduled to occur at the end of each cohort and / or 
treatment period to review data obtained after each dose level. Dose escalation decisions 
will be based on data obtained from 3 or more participants on active treatment at the prior 
dose level, unless stopping criteria (see Section 7.1) are met at the prior dose level and 
the subsequent dose is de-escalated. The review data set will consist at minimum AE 
listings, safety labs, electrocardiograms (ECG), vital signs (VS), and PK results derived 
from at least 24-hour plasma profiles. Pharmacodynamic (PD) data will be reviewed as 
available for Part 1 and may be used with the rest of the data in dose selection to start and 
progress Part 2.  PD data may not be required for an escalation decision. Flagged vital 
signs, cardiac monitoring (telemetry), ECG and laboratory findings will also be reviewed. 
The decision to switch to the gastro resistant capsules will be made by the DEC after 
review of the AE listings and will be based on clinical judgement. 
Progression to the next higher dose level in a given cohort will be halted if: 
• 
Two or more participants in the same cohort experience severe non-serious adverse 
reactions (i.e. severe non-serious adverse events considered as at least possibly 
related to the administration of GSK3884464), independent of within or not within 


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the same system-organ-class; and independent of whether it is related to study 
intervention or not. 
• 
Any participant experiences a serious adverse reaction (i.e. a serious adverse event 
considered at least possibly related to the administration of GSK3884464). 
• 
Three or more participants in a cohort experience the same adverse event of 
moderate severity that can be reasonably attributed to dosing with GSK3884464. 
The dose escalation will stop after completing the dose level, and no further participants 
will be dosed at that dose level or any higher level. Lower doses and progression to Part 2 
may occur. If after consultation the Sponsor deems that dosing can resume at that level or 
higher, the Sponsor will submit an application for a substantial amendment to the 
Regulatory Agency. 
The decision to progress from Part 1 to Part 2 of the will be made by the DEC in 
consultation with the Nephrology and other safety panels, if required. The final dose-
escalation decision and rationale for each cohort will be discussed with the investigator(s) 
during teleconferences(s) and documented in writing, with copies maintained at each 
study site and in the study master file. 
Progression to the next part of the study will be halted if: 
• 
Stopping criteria will be mean exposure exceeding or predicted to exceed the 
exposure observed at plasma NOAEL in the 6-week GLP monkey toxicity study (50 
mg/kg/day), corresponding to Day 42 monkey plasma AUC of 316000ng.mL×h and 
Cmax of 48300 ng/mL.  
• 
Three or more participants in the same part experience severe non-serious adverse 
reactions (i.e. severe non-serious adverse events considered as at least possibly 
related to the administration of GSK3884464), independent of within or not within 
the same system-organ-class; or four or more participants in the same part 
experience the same adverse event of moderate severity that can be reasonably 
attributed to dosing with GSK3884464. 
• 
Any participant experiences a serious adverse reaction (i.e. a serious adverse event 
considered at least possibly related to the administration of GSK3884464). 
The dose levels in Part 2 will only be started after the same or higher dose cohorts are 
complete in Part 1 with no dose escalation stopping criteria having been met, therefore, 
Part 2 may start before the completion of Part 1. At a minimum, Multiple Ascending 
Dose (MAD) Cohort dose levels will be defined based upon Dose Escalation Committee 
(DEC) review of up to the first five Single Ascending Dose (SAD) dose levels. 
Additional MAD cohorts will be based on DEC review of subsequent SAD dose levels 
and the previous MAD.  Lastly, the maximum dose for Part 2 cannot exceed the 
maximum dose in Part 1.  
4.5. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases in the particular part of the study they participated in, including the last scheduled 
procedure shown in the Schedule of Activities (see Section 1.3.1). 


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The end of the study is defined as the date of the last visit of the last participant in the 
study or if the Sponsor decides not to move to the next cohort. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
1. Healthy as determined by the experienced investigator or medically qualified 
designee based on a medical evaluation including medical history, physical 
examination, laboratory tests, and cardiac monitoring/assessment. 
NOTE: A participant with a clinical abnormality, clinical history or laboratory 
parameter(s), which is/are not specifically listed in the inclusion or exclusion 
criteria, that are outside the reference range for the population being studied may 
be included only if the investigator and the Medical Monitor (as required) agree 
and document that the finding is unlikely to introduce additional risks and will 
not interfere with the study procedures. 
Screened participants with laboratory values outside of the normal range may be 
repeated once for inclusion into the study at the discretion of the Investigator. 
 
WEIGHT 
2. Part 1: Body weight  50kg, body mass index (BMI) 18 and  30 kg/m2 
(inclusive).  
Part 2: Body weight  50kg, BMI  22 and  30 kg/m2 (inclusive).   
 
AGE 
3. 18 to 50 years of age inclusive at the time of signing the informed consent. 
 
RELEVANT HABITS 
4. Non-smokers only (defined as a non-smoker during the last 3 months prior to 
screening). 


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SEX 
5. Male or females of non-childbearing potential.  
Contraceptive use by men and male participants’ childbearing potential partners or 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. Participants with same sex 
partners (abstinence from penile-vaginal intercourse) are eligible. 
a. Male Participants: 
No reproductive exposure precautions (i.e., condom or other contraceptive) are required 
for male participants with a female of nonreproductive potential or male partner, when 
this is their preferred and usual lifestyle.  Male participants with a female partner of 
reproductive potential are eligible to participate if they agree to the following during the 
dosing period and for at least 60 hrs after last dose plus: 
• Refrain from donating sperm. 
PLUS either: 
• Are currently abstinent from intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR 
• Have had a vasectomy with documentation of azoospermia. The documentation 
on male sterility can come from the site personnel’s review of subject’s medical 
records, medical examination and/or semen analysis, or medical history interview. 
OR 
• Must agree to use contraception/barrier as detailed below:  
o Agree to use a male condom; 
o Additionally, female partner to use a highly effective contraceptive 
method with a failure rate of <1% per year as described in Appendix 4 
when having sexual intercourse with a woman of childbearing potential 
who is not currently pregnant. 
o Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
b. Female Participants:  
• A female participant is eligible to participate if she is a woman of nonchildbearing 
potential (WONCBP), as defined in Appendix 4. 
 
INFORMED CONSENT 
6. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the consent 
form and in this protocol. 


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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
• 
History or presence of significant cardiovascular, respiratory, hepatic, renal, 
gastrointestinal (Gastroesophageal reflux disease (GERD), nausea, vomiting or 
dysphagia), endocrine, hematological or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting 
a risk when taking the study treatment; or interfering with the interpretation of data. 
• History of current or past significant renal diseases (e.g. Acute Kidney Injury, 
parenchymal kidney disease).  
• 
Clinically significant high blood pressure and/or history of hypertension as 
determined by the investigator. 
• 
Serum troponin I or troponin-T greater than the upper limit of normal (ULN). 
• 
Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
• 
Breast cancer within the past 10 years. 
• 
QTcF >450 msec;   
• 
Screening 12-lead ECG with any of the following: 
• 
Second- or third- degree atrioventricular block (AVB). 
• 
Two or more significant pathological Q-waves (defined as Q-wave > 40 
msec or depth greater than 0.4-0.5 mV) in a pattern consistent with a prior 
myocardial infarction. 
• 
Ventricular pre-excitation. 
• 
Bradycardia as defined by sinus rate ≤ 35 beats per minute (BPM)  
• 
Complete left bundle branch block (LBBB) 
• History of QTc prolongation, symptomatic cardiac arrhythmias or cardiac arrest. 
• 
Screening Holter (24 hours) with any of the following: 
• 
Sinus bradycardia ≤ 30 BPM  
• 
Non-sustained ventricular tachycardia (NSVT) or more than 30 
Ventricular Premature Depolarisations (VPD) during an hour.  
• 
Atrial arrhythmia > 100 BPM for 3 seconds or longer or more than 40 
Atrial Premature Depolarisation (APD) during an hour.  
• 
Any clinically relevant abnormality on the screening medical assessments. 
• 
Alanine transaminase (ALT) > ULN.  


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• 
Bilirubin > ULN.  
• Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
 
PRIOR/CONCOMITANT THERAPY 
• 
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a 
potential enzyme inducer [eg. Rifampin, St John’s Wort extract]) or 5 half-lives 
(whichever is longer) prior to the first dose of study medication, unless in the opinion 
of the Investigator and GSK Medical Monitor the medication will not interfere with 
the study procedures or compromise subject safety. By exception, all participants may 
take Paracetamol (≤ 2 grams/day) up to 48 hours prior to the first dose of study drug.   
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
• 
Participation in the study would result in loss of blood or blood products in excess of 
500 mL within a 56-day period. 
• 
Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day. 
• Current enrollment or past participation in a clinical trial within the last 30 days 
before signing of the consent in this or any other clinical study involving an 
investigational drug or any other type of medical research. 
 
DIAGNOSTIC ASSESSMENTS  
• 
A positive laboratory confirmation of COVID-19 infection, or high clinical index of 
suspicion for COVID-19. 
NOTE: High clinical index of suspicion:  Participants with signs/symptoms suggestive 
of COVID-19 (i.e. fever, cough, etc) w/in 14 days and /or with known COVID-19 
positive contacts in the past 14 days. 
• 
Participants with an HbA1c > 48 mmol/mol at screening. 
• 
Presence of Hepatitis B surface antigen at screening.  
• 
Positive Hepatitis C antibody test result at screening. 
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved 
disease can be enrolled only if a confirmatory negative Hepatitis C RNA test is 
obtained. 
• 
Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment. 
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DIAGNOSTIC ASSESSMENTS  
are not required to also undergo Hepatitis C RNA testing. 
• 
Positive pre-study drug/alcohol screen. 
• 
Positive human immunodeficiency virus (HIV) antibody test. 
• 
Estimated glomerular filtration rate (eGFR)  90 ml/minute/1.73m2 calculated by the 
CKD-EPI equation as below:  
eGFR = 141 x min (SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if 
female] x 1.159 [if Black] 
• Screening urine albumin:creatinine ratio ≥30 mg/gm (≥3 mg/mmol) 
• 
Regular use of known drugs of abuse. 
 
OTHER EXCLUSIONS 
• 
Regular alcohol consumption within six months prior to the study defined as:  
• 
An average weekly intake of ≥14 units for males ≥14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 
ml) of wine or 1 (25 ml) measure of spirits.  
• 
Smokelyzer test levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 3 
months prior to screening. 
• 
Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study. 
• Subjects with a history or current evidence of depression, bipolar disorder, suicidal 
ideation and behavior, or a lifetime history of suicide attempt will be excluded. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the start of study drug dosing until after the final dose. 
• 
Participants taking study intervention in gastro-resistant capsule form will be fasted 
for at least 2 hrs post dose. Participants must fast from all food and drink (except 
water) for at least 8 hours prior to any fasting clinical laboratory evaluations.  
• 
Participants will not receive breakfast on days when serial planned PK samples are 
collected. 


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5.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 
• 
During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample.  
• 
Participants will refrain from smoking or using tobacco or nicotine-containing 
products from at least 3 months prior to the Screening Visit through the last blood 
sample collected. 
5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during the study (e.g., watching television, reading). 
All participants must be resting in a semi-supine position for 10 minutes prior to and 5 
minutes after each ECG/VS/and PK draw while on the continuous cardiac monitoring. 
Participants must be in a semi-supine resting position that must be maintained 60 minutes 
prior to dosing. 
It is recommended that participants should self-quarantine when outside of the clinical 
unit from the time of COVID-19 testing on first admission through the follow up visit 
and should be encouraged to wear a mask or facial covering when moving between home 
and the clinic. Participants should monitor body temperature daily while not in the 
clinical unit and report an elevation above 100.4F (38 C). In addition, participants should 
report a lack of smell to the clinical site staff. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened and retested, but only after consultation and agreement with the GSK 
Medical Monitor. 


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6. 
STUDY INTERVENTION AND CONCOMITANT MEDICATION  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
ARM Name 
Experimental 
Control 
Experimental 
Control 
Intervention 
Name 
GSK3884464 
Placebo 
GSK3884464 
Placebo 
Type  
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation  
Solution 
Solution 
Capsule 
Capsule 
Unit Dose 
Strength(s)  
0.1 mg/mL 
Volume to match 
Study Drug 
Flexible dosing 
from 3mg – 100 
mg per capsule. 
Excipient fill weight 
and capsule count 
to match Study 
Drug. 
Dosage Level(s) 
1 – 3 mg 
To match study 
drug 
Up to 550 mg QD 
using multiple 
capsules 
To match study 
drug 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental  
Placebo 
Experimental  
Placebo 
IMP and NIMP 
IMP 
NIMP 
IMP 
NIMP 
Sourcing 
 
Pharmaceutical 
ingredient 
provided 
centrally by the 
Sponsor with 
solution 
prepared by 
CUC, 
Cambridge, UK 
Solution 
prepared by 
CUC, 
Cambridge, UK 
Pharmaceutical 
ingredient 
provided centrally 
by the Sponsor 
with capsules 
prepared by 
CUC, Cambridge, 
UK  
Capsules provided 
centrally by 
prepared by CUC, 
Cambridge, UK  


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ARM Name 
Experimental 
Control 
Experimental 
Control 
Packaging and 
Labelling 
 
Solutions will 
be prepared in 
amber type-1 
glass bottles 
with child 
resistant 
closures and 
labelled as 
required per 
country 
requirement. 
Solutions will be 
prepared in 
amber type-1 
glass bottles 
with child 
resistant 
closures and 
labelled as 
required per 
country 
requirement 
Capsules are 
packaged in 
round, opaque 
white, high 
density 
polyethylene 
(HDPE) bottles 
with child 
resistant closures 
and labelled as 
required per 
country 
requirement. 
Capsules are 
packaged in round, 
opaque white, high 
density 
polyethylene 
(HDPE) bottles with 
child resistant 
closures and 
labelled as required 
per country 
requirement. 
 
The active pharmaceutical ingredient 
(API) will be weighed into hydroxypropyl 
methylcellulose (HPMC) capsules for 
oral administration. If deemed 
necessary as the study progresses, 
gastro-resistant capsules (composed of 
hydroxypropyl methylcellulose acetate 
succinate (HPMC-AS) may be 
substituted.  
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. 
• The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
• Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM).  
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 


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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 Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions will be provided to the investigator. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact. 
6.2.1. 
Treatment Assignment 
Subjects will be assigned to treatments in accordance with the randomization schedule 
generated by Clinical Statistics (GSK), prior to the start of the study, using validated 
software. 
Doses of GSK3884464 will be compounded at CUC Pharmacy United Kingdom. For 
doses ≥3 mg, the active pharmaceutical ingredient (API) will be weighed into 
Hydroxypropyl methylcellulose (HPMC) capsules for oral administration. If deemed 
necessary as the study progresses, gastro-resistant capsules (composed of HPMC/ 
Hydroxypropyl methylcellulose Acetate Succinate (HPMC-AS) may be substituted.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
Participants will be randomised to a treatment or treatment sequence at the start of each 
Part/Cohort in accordance with the randomisation schedule generated by Clinical 
Statistics, GSK. 
Part 1: Each cohort will have approximately 9 participants and will be randomized to 
one of 3 treatment sequences, with 3 participants per sequence, (See Table 3, Table 4 and 
Table 5) in a 1:1:1 ratio. Within each period, allocation to GSK3884464 and placebo will 
be 2:1. Within each sequence, an increasing dose of GSK3884464 will be administered in 
each period. 
Table 3 
Part 1, Cohort 1 
Sequence 
Period 1 
Period 2 
Period 3 
1.1 
Placebo 
SD2 
SD3 
1.2 
SD1 
Placebo 
SD3 
1.3 
SD1 
SD2 
Placebo 


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Table 4 
Part 1, Cohort 2 
Sequence 
Period 1 
Period 2 
Period 3 
1.4 
Placebo 
SD5 
SD6 
1.5 
SD4 
Placebo 
SD6 
1.6 
SD4 
SD5 
Placebo 
Table 5 
Part 1, Cohort 3 
Sequence 
Period 1 
Period 2 
Period 3 
1.7 
Placebo 
SD8 
SD9 
1.8 
SD7 
Placebo 
SD9 
1.9 
SD7 
SD8 
Placebo 
Part 2: Each dose cohort will have approximately 8 participants and will be randomized 
to receive either GSK3884464 or placebo in sequential design using a 3:1 allocation ratio 
as illustrated in Table 6.  
Table 6 
Part 2 
Dose Cohort 
Regimen 
Cohort 2.1 
RD1 or Placebo 
Cohort 2.2 
RD2 or Placebo 
Cohort 2.3 
RD3 or Placebo 
6.3.2. 
Blinding 
This will be a double-blind study, which means that the participant, investigator and trial 
staff at the study site (apart from unblinded administrator(s) and pharmacy staff) will be 
blinded to the trial treatment allocated to each individual participant. 
In addition, the sponsor will be blinded to treatment allocations, except for roles required 
to be “unblind” in order to manage study conduct, oversight and safety. Additional 
internal GSK safety representatives may be consulted and unblinded as deemed necessary 
by the DEC. This will be documented and maintained in the electronic Trial Master File 
(eTMF). 
In the case of emergency unblinding, the following will apply:  


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• 
The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
investigator.  
• 
Investigators have direct access to the participant’s individual study treatment.  
• 
It is preferred (but not required) that the investigator first contact the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.  
• 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study.  
The date and reason for the unblinding must be fully documented in the case report form 
(CRF). 
A participant will be withdrawn if the participant’s study drug code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
6.4. 
Study Intervention Compliance 
• 
When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• 
When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents. The 
dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site staff will examine each participant’s 
mouth to ensure that the study intervention was ingested. 
• 
A record of the quantity of GSK3884464 or placebo capsules dispensed to and taken 
by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded. 


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6.5. 
Dose Modification 
This protocol allows some alterations from the currently outlined dosing schedule 
(Section 4.3.2 and Section 4.3.3), but the predicted mean plasma exposure (Cmax and 
AUC) for any single or repeat dose level to be administered will not exceed the limiting 
exposure criteria based on the plasma NOAEL dose from the monkey 6-week GLP tox 
study (Section 4.3.1). 
The dosing schedule may be modified to expand a dosing cohort to further evaluate 
safety, PK and/or PD at a given dose level.  The actual doses to be administered may 
involve either an increase or a decrease in the planned doses. The study procedures for 
these additional subject(s) or cohort(s) will be the same as that described for other study 
participants. Any cohort expansion or addition will be contingent on approval of an 
amended protocol by the UK ethics board and the MHRA. 
The details on the dose escalation committee can be found in Section 4.4 and Section 
10.1.5. Discontinuation of study intervention and study progression stopping criteria are 
located in Section 7.  
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because efficacy of the investigational product has not yet been determined. 
6.7. 
Treatment of Overdose 
For this study, study treatment will be administered by study staff.  
Any dose of GSK3884464 greater than the planned dose within a 24-hour time period ± 6 
hours will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities for at least 
72 hours. 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 


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6.8. 
Concomitant Therapy 
Any medication or vaccine (including over the counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements such as St John’s Wort) 
within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 
(whichever is longer) before the start of study drug until completion of the follow-up 
visit, unless, in the opinion of the investigator and sponsor, the medication will not 
interfere with the study.  
Paracetamol/Acetaminophen at doses of 2 grams/day or Ibuprofen 1200 mg/day, is 
permitted for use at any time during the study. Other concomitant medication may be 
considered on a case-by-case basis, in consideration of the recommendations as follows, 
by the investigator in consultation with the Medical Monitor if required. 
In vitro incubations of GSK3884464 with recombinant human UGT enzymes and human 
liver microsomes indicated that the metabolism of GSK3884464 was dependent on 
UDPGA, a cofactor required for UGT enzyme activity, with contributions from UGT1A3 
and UGT1A9. The overall victim drug-drug interaction (DDI) risk with single inhibition 
of these enzymes may be low due to the multiple clearance mechanisms.  However, since 
glucuronidation was a predominant metabolic route in human hepatocytes, co-
administration of a potent inducer, eg, phenytoin and rifampin, can result in decreased 
levels of GSK3884464. Contraindication or replacement thereof is recommended.  The 
following classes of therapies and examples are prohibited for concomitant or prior use 
within 2 weeks: 
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone  
Antimycobacterials: rifampin, rifapentine  
Herbal product: St John’s wort (Hypericum perforatum) extract 
Estrogen containing oral contraceptive: ethinylestradiol/levonorgestrel 
In vitro, GSK3884464 is an inducer of CYP3A4, UGT1A1 and UGT1A4 as well as an 
inhibitor of drug metabolising enzyme UGT2B15 and transporters Pgp, BCRP, 
OATP1B1, OAT1 and OAT3. Based on the intended clinical dose and predicted systemic 
plasma concentration of GSK3884464, preliminary SIMCYPTM (Fit-for-Purpose PBPK) 
modelling suggested a low risk of perpetrator DDIs against these enzymes and 
transporters, at the predicted human dose up to 500 mg, QD [GlaxoSmithKline Document 
Number 2021N467036_00, 2021].  


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Notwithstanding the modelling and DDI risk prediction will be a continuous exercise of 
optimization and improvement as the human PK data become available during the current 
study and future clinical investigation. Consequently, the recommendations and criteria 
for concomitant medications will be reviewed and updated accordingly. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation or Early Withdrawal) study intervention. If study intervention 
is definitively discontinued, the participant will remain in the study to be evaluated for 
final safety, PK, PD and follow up assessments. See the SOA in Section 1.3 for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed. 
Discontinuation of study intervention and study progression stopping criteria are located 
in Section 7. Relevant reporting and discussion with the Medical Monitor, relevant GSK 
personnel, and with the Ethics Committee will then take place prior to any resumption of 
dosing. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm or 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, if the investigator considers that it is in the best interest of the 
participant. 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met: 
 


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 5. 
7.1.1.1. 
Study intervention restart or rechallenge after liver stopping criteria are 
met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.1.2. 
Study temporary halt criteria and potential study stopping criteria 
If the following criteria are met in at least one subject, in any arm of the study, the study 
will be put on temporary halt: 
• ALT≥3xULN AND bilirubin ≥2xULN (>35% direct bilirubin) OR (International 
Normalized Ratio) INR >1.5. 
7.1.1.3. 
Dose expansion criteria 
If ≥ 2 subjects in any dose level experience an isolated ALT≥3xULN (on active 
treatment) then the following dose expansion criteria applies: 
Up to four additional participants on active and 2 additional participants on placebo may 
be recruited at the same dose level. Any further cohort expansion will be contingent on 
approval of an amended protocol by the UK ethics board and the MHRA.   
7.1.2. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion below based on the average of triplicate 
ECG readings will be withdrawn from the study.   
• 
QTcF > 500 msec, 
• 
Change from baseline in healthy volunteer participants: QTcF >60 msec 


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7.1.3. 
Left Ventricular (LV) Ejection Fraction Stopping Criteria 
A subject that meets the criteria below on any scheduled or unscheduled study 
echocardiogram will be withdrawn from the study: 
LV ejection fraction is lower by 10% or more than the pre-dose baseline value and the 
investigator, in consultation with the Medical Monitor, think there is a reasonable chance 
the change in ejection fraction is attributable to the investigational product. 
7.1.4. 
Cardiac Arrhythmia Stopping Criteria 
A clinically concerning cardiac arrhythmia in this study is any type of arrhythmia or 
divergent QRS complex morphology that is deemed by the Investigator to be reasonably 
attributable to GSK3884464 - rather than within normal variation for each type of 
affected subject receiving repeat dose GSK3884464. 
Furthermore, a clinically concerning arrhythmia is an adverse event which is deemed by 
the Investigator in consultation with the Medical Monitor to be of sufficient temporal 
duration and / or character to potentially affect subject safety.  
All clinically concerning cardiac arrhythmias in individual participants will be reviewed 
by the Investigator in consultation with the Medical Monitor at the earliest possible 
opportunity after the event. In addition, cardiac arrhythmias will also be reviewed by a 
cardiologist where it is deemed appropriate to do so by the Investigator in consultation 
with the Medical Monitor on a case-by-case basis. 
Detection of any of the following during baseline assessment or following administration 
of study intervention will lead to withdrawal: 
a). Sustained monomorphic or polymorphic ventricular tachycardia (VT). 
b). Non-sustained but symptomatic or hemodynamically significant monomorphic 
or polymorphic (VT). 
c). High-grade or complete heart block. 
d). Symptomatic bradycardia.  
Additional clinically significant cardiac events could include, but are not restricted, 
to:  
• A non-sustained wide-complex tachyarrhythmia ≥ 100 beats per minute (BPM) 
that is: 
o accompanied by symptoms, hemodynamic compromise, or other new 
ECG changes (e.g. new ST depression). 
o repetitive (e.g. repeated short salvos). 
o greater than 10 seconds in duration. 
Participants who either have a clinically concerning arrhythmic event during the study, or 
where there is electrophysiological diagnostic uncertainty on cardiac telemetry / ECG, 


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must be withdrawn from the study and be appropriately followed up immediately. 
Medical consultation with a cardiologist should be obtained. The Medical Monitor should 
be informed as soon as possible. This includes participants who develop non-sustained 
but asymptomatic and hemodynamically tolerated monomorphic or polymorphic VT who 
will be evaluated to determine the cause of the VT. 
A plasma sample for PK analysis should be obtained as soon as possible after detecting a 
clinically concerning or life-threatening cardiac arrhythmia, or within 48 hours of last 
dose. 
Figure 7 
Algorithm for Management of Participants having received one or 
more doses of study treatment based on Arrhythmia 
Characterization 
 
7.1.5. 
Renal Stopping Criteria 
Any of the following events which are reasonably attributable to GSK3884464 will be 
nominally categorized as a severe adverse event and will constitute individual stopping 
criteria for participants: 
• New onset of any clinically significant and persistent (for 48 hours) hematuria as 
confirmed by microscopy (in the absence of any other clinical cause). 
• New onset of clinically significant and persistent (for 48 hours from the dosing 
day in the SAD part and at any point in the MAD) proteinuria (Spot Urine 
Albumin Creatinine ratio [ACR] ratio 30 mg/mmol) in absence of another 
clinical explanation e.g. calculus/infection  


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• If there is any change in serum creatinine > 26µmol/L (>0.3 mg/dl), repeat within 
24 hours. If confirmed, the participant will be withdrawn, and further 
investigations will be performed. 
• Increase in serum creatinine (ΔsCr) of >25% from baseline on 2 consecutive 
assessments within 24 hours. 
• A 25% decline in eGFR below baseline on two consecutive assessments within 24 
hours.  If confirmed, the participant will be withdrawn. If a participant meets the 
withdrawal criteria for eGFR, then further investigations will be performed. 
All abnormal results that meet the above criteria should be discussed with the Medical 
Monitor as soon as possible to arrange for follow-up testing. 
If 2 or more participants in a given dose cohort develop any of the above withdrawal 
criteria, when considered related to study drug, then that cohort will be temporarily 
halted. 
7.1.6. 
Pharmacokinetic Stopping Criteria 
The following dose adjustment / PK stopping criteria will apply: 
• 
Stopping criteria will be mean exposure exceeding or predicted to exceed the 
exposure observed at plasma NOAEL in the 6-week GLP monkey toxicity study (50 
mg/kg/day), corresponding to Day 42 monkey plasma AUC of 316000 ng.mL×h and 
Cmax of 48300 ng/mL.  
• 
Throughout all parts of the study, PK data from previous dose levels will be used to 
predict exposure to the next dose level or study Part. If the mean exposure at the next 
dose level is predicted to exceed the PK stopping criteria exposure, dose escalation 
will be stopped, or dose adjustment will be planned, as appropriate.  
The GSK DEC team will decide based on safety, tolerability, and PK information 
whether to evaluate any lower doses or repeat doses already evaluated in remaining 
periods to collect additional safety and PK data.  
7.1.7. 
Additional Stopping Criteria 
7.1.7.1. 
Neuropsychiatric Issues 
Suicidal Ideation and Behavior:  
If Columbia Suicide Severity Rating Scale (C-SSRS) assessment indicate a clinically 
relevant increase in suicidal ideation or behavior or a subject shows new signs or 
symptoms during the study treatment period suggestive of an increase in suicidal ideation 
and behavior, psychiatric consultation will be obtained and the Sponsor’s Medical 
Monitor should be contacted. Discontinuation of study intervention is mandated in case 
the participant scores “yes” on item four or item five of the Suicidal Ideation Section of 
the Columbia Suicide Severity Rating Scale (C-SSRS) or “yes” on any item of the 
Suicidal Behavior Section. In addition, study investigators may also decide to discontinue 
dosing based on their clinical judgment for observations that do not specifically meet 
these thresholds, if they feel this is appropriate for best ensuring the safety of study 
subjects. See SRM for additional information. 


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Cognitive Safety: 
If cognitive test results of the 6-item cognitive impairment test (6-CIT) indicate a 
clinically significant effect of GSK3884464 on cognitive safety or the subject shows new 
signs or symptoms during the study treatment period suggestive of an effect on cognitive 
safety, psychiatric consultation should be obtained and the Sponsor’s Medical Monitor 
should be contacted. If the increased risk can be confirmed the subject must be 
discontinued from the study. 
In case there is objective evidence that a subject is in psychological distress, the subject 
will be immediately evaluated and the subject must be discontinued from the study if the 
investigators based on their clinical evaluation feel this is appropriate for best ensuring 
the safety of study subjects. Concerning symptoms might include: 
Nervousness,  
Anxiety, irritability 
Sudden worsening of mood 
Sudden outbursts of anger (“anger attacks”) 
Sudden panic or anxiety attacks 
Agitation 
Feeling unreal or detached 
Confusion or trouble concentrating 
Forgetfulness or problems with memory 
Mood swings 
Trouble sleeping, insomnia 
Fatigue, tiredness 
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7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the Section 1.3 (SoA). Refer to the SoA 
in Section 1.3 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
• 
Every effort will be made to take a blood sample at the time of the event of 
discontinuation or study withdrawal for pharmacokinetic analysis. 
• 
The participant will be permanently discontinued both from the study 
intervention and from the study at the same 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. 
• 
Participants testing positive for COVID-19 will be discontinued from study 
treatment and appropriate contact tracing conducted within the unit will be done 
according to local legislation. Decisions to terminate all study participation and 
how to maintain adequate safety follow up will be agreed upon by the study 
investigator in consultation with the Medical Monitor. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
• 
Site personnel, or an independent third party, will attempt to collect the vital 
status of the participant within legal and ethical boundaries for all participants 


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randomized, including those who did not get study intervention. Public sources 
may be searched for vital status information.  If vital status is determined as 
deceased, this will be documented, and the participant will not be considered 
lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information. 
Discontinuation of specific sites or of the study, as a whole, are handled as part of 
Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (See Section 1.3).  
Protocol waivers or exemptions are not allowed.  
Immediate safety concerns should be discussed with the Medical Monitor 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 
(Section 1.3), is essential and required for study conduct. Supplementary study conduct 
information not mandated to be present in this protocol is provided in the SRM. The 
SRM will provide the site personnel with administrative and detailed technical 
information that does not impact participant safety. The following points must be noted:  
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order: 
o 12-lead ECG 
o vital signs 
o blood draws 
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time. 
The timing and number of planned study assessments, including safety, PK, 
PD/biomarker or other assessments may be altered during the course of the study based 
on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.  
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File which is approved by the relevant GSK study team 
member and then archived in the study sponsor and site study files, but this will not 
constitute a protocol amendment.  
The UK ethics board, the MHRA and investigator will be informed of any significant 
safety issues, including those that require amendment of the Patient Information Sheet 
and Consent Form (PICF). 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 


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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 (Section 1.3). 
• 
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. 
• A table defining the allowed variance in timings of assessments without being 
considered a protocol deviation will be included in the SRM. 
8.1. 
Efficacy Assessments 
Not Applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded. 
• 
A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• 
Participants who report symptoms suggestive of COVID-19 while in the 
research unit should be isolated in the unit or at home and tested for COVID-19 
infection using an approved molecular test.   
8.2.2. 
Vital Signs 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available. 
• 
Blood pressure and pulse measurements will be assessed in a semi-supine 
position after at least 5 minutes of rest for the participant in a quiet setting 
without distractions (e.g., television, cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 


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rea di n gs will be rec or de d at i nter vals of at least 1 mi n ute). T he 3 bl o o d press ure 
rea di n gs will be rec or de d i n t he C R F. 
8. 2. 3.  
C ar di a c A s s e s s m e nt s  
8. 2. 3. 1.  
1 2 -l e a d s af et y E C G s 
•  
Si n gle  1 2 -lea d E C G will be  meas ure d i n se mi -s u pi ne p ositi o n after 5 mi n utes 
rest as o utli ne d i n t he S o A ( Secti o n 1. 3. 1 ) usi n g a n E C G mac hi ne t hat 
a ut o maticall y calc ulat e s t he heart rate a n d meas ures P R, Q R S, Q T, a n d Q TcF  
i nter vals. Refer t o Secti o n 7. 1. 3  f or Q TcF  wit h dra wal criteri a a n d a d diti o nal 
Q Tc F  rea di n gs t hat ma y be necessar y. 
•  
At eac h ti me p oi nt  a si n gle E C G  is re q uire d. Tri plicate E C Gs will be perf or me d 
o nl y if a n a b n or malit y is detecte d . T h e 3 i n di vi d ual E C G traci n gs s h o ul d be 
o btai ne d as cl osel y as p ossi ble i n s uccessi o n, b ut n o m ore t ha n 2  mi n utes a part.  
•  
Safet y E C Gs will be pri nte d a n d i nter prete d o n -sit e b y t h e I n vesti gat or t o e ns ure 
s u bject safet y. Safet y E C Gs ma y b e pri nte d fr o m t he Gl o bal I nstr u me ntati o n 
H olter de vice ( See Secti o n 8. 2. 3. 2 ).  
8. 2. 3. 3.  
C o nti n u o u s C ar di a c T el e m etr y  
C o nti n u o us car diac tele m etr y will start i n a s u pi ne p os iti o n after at least 5 mi n utes rest at 
t he ti me p oi nt i n dicate d i n t he S o A ( Secti o n 1. 3 ). Partici pa nts are n ot r e q uire d t o re mai n 
i n a s u pi ne p ositi o n d uri n g t he re mai ni n g d urati o n of c ollecti o n of car diac tele metr y, as 
i n dicate d i n t he S o A ( Secti o n 1. 3 ). F ull discl os ures will be re vie we d i n d etail a n d t he 
re vie w mai ntai ne d as part of t he partici pa nt’s s o ur ce d oc u me nts. Partici p a nts i n eac h Part 
are per mitte d u p t o a t otal of 3 0  mi n utes off m o nit ori n g per da y i n t he e ve ni n g t o all o w 
f or s h o weri n g wit h o ut t his bei n g c o nsi dere d a de vi ati o n, e x ce pt w he n t he y ha ve seri al P K 
da ys w he n t he m o nit or s h o ul d be c o nti n u o us . I n a d diti o n, partici pa nts are p er mitte d t o be 
off tele metr y d uri n g t h e 3 D ec h ocar di o gra m pr oce d ure i n C o h orts 4, 5 a n d 6.  See S R M 
f or a d diti o nal details. 
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8. 2. 3. 5.  
E c h o c ar di o gr a m s  
T hree -di me nsi o n al  ec h o car di o gra ms will be perf or me d  at scree ni n g a n d  i n Part 2 of t he 
st u d y acc or di n g t o t he S o A (Secti o n 1. 3 ). T his pr o ce d ure us es s o u n d wa v es t o create 
pict ures of t he heart a n d will pr o vi de detaile d i nf or mati o n o n h o w well ( or h o w har d) t he 
heart is w or ki n g. A n ec h ocar di o gra m  d oes n ot e x p ose partici pa nts t o ra di ati o n.  
8. 2. 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  
•  
Refer t o A p pe n di x 2  f or t he list of cli nical la b orat or y tests t o be p erf or me d a n d 
t o t he S o A ( Secti o n 1. 3 ) for t he ti mi n g a n d fre q u e nc y.  
•  
T he i n vesti 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 rele va nt c ha n ges o cc urri n g d uri n g t he st u d y i n t he a d v erse 
e ve nt (A E ) s ecti o n of t he C R F. T he la b orat or y re p orts m ust be file d wit h t he 
s o urce d oc u m e nts. Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose 
w hic h are n ot ass ociate d wit h t he u n derl yi n g dise ase, u nless j u d ge d b y t he 
i n vesti gat or t o be m or e s e vere t h an e x pecte d f or t he partici pa nt's c o n diti o n.  
•  
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifi ca ntl y a b n or mal 
d uri n g partici pati o n i n t he st u d y , or wit hi n 6  da ys after t he l ast d ose of st u d y 
i nter ve nti o n, s h o ul d be re peate d u ntil t he val ues retur n t o n or mal or baseli n e or 
are n o l o n ger c o nsi dere d si g nifica ntl y a b n or mal b y t he i n vesti gat or or me dical 
m o nit or.  
•  
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d ge d 
reas o na bl e b y t he i n vesti gat or, t h e eti ol o g y of t he a b n or ma lit y s h o ul d be 
i de ntifie d a n d t he s p o ns or n otifie d. 
•  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he  S o A ( Secti o n 1. 3 ).  
•  
If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifi e d la b orat or y tests perf or me d at 
t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge m e nt or 
are c o nsi d ere d cli nicall y si g nifica nt b y t he i n v esti gat or (e. g., S A E or A E or d ose 
m o dificati o n) , t he n t he res ults m ust be rec or de d. 
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8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Based on evidence of limited distribution to the brain in rats and monkeys, GSK 
considers it important to monitor for any increased risk of suicidal thinking or behavior 
when GSK3884464 is given to human participants before or during clinical studies with 
compounds such as this. Subjects being treated with GSK3884464 should be assessed 
and monitored appropriately for suicidality and unusual changes in behavior.  
8.2.6.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline assessment of suicidal ideation and behaviour and treatment emergent suicidal 
ideation and behaviour will be assessed during this study using the Columbia Suicide 
Severity Rating Scale (C-SSRS). C-SSRS is a brief questionnaire designed to assess 
severity and change in suicidality by integrating both behavior and ideation. The C-SSRS 
was designed to address the need for a summary measure to track changes in the 
severity/intensity of suicidality across both clinical settings and treatment trials. It 
assesses intensity of ideation (a potentially important marker of severity), specifically 
asking about frequency, duration, intrusiveness, controllability and deterrents. In 
addition, both the modal and most severe forms of ideation are captured. This procedure 
should be performed in participants receiving repeat doses in Part 2 as listed in the SoA. 
The questionnaires should be completed by a health professional trained in this procedure 
following discussions with the subject at each visit. If additional information is provided 
by a caregiver, relative, friend etc then this information should also be taken into account 
when completing the questionnaire. Any suicide attempts or Investigator concerns about 
issues raised during the completion of this questionnaire should be discussed immediately 
(with 24hr) with the GlaxoSmithKline Medical Monitor. Refer to SRM for additional 
information. 
8.2.6.2. 
Six-Item Cognitive Impairment Test (6-CIT) 
The 6-CIT is a brief neuropsychological screening test for cognitive impairment taking 
less than 5 minutes (three orientation items, count backwards from 20, months of the year 
in reverse order, and learn an address). 
8.3. 
Adverse Events, Serious Adverse Events (SAEs) and Other 
Safety Reporting 
The definitions of an adverse event (AE) or serious adverse events (SAEs) can be found 
in Appendix 3. 
The definitions of unsolicited and solicited adverse events can be found in Appendix 3, 
Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7).  


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T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 3 , 
Secti o n  1 0. 3 . 
8. 3. 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 
•  All S A Es  will be c ollecte d fr o m t he start of st u d y i nter ve nti o n u ntil t he f oll o w-u p 
visit  at t he ti me p oi nts s pecifie d i n t he S o A  ( Secti o n 1. 3. 1 ). 
•  H o we ver, a n y S A Es assesse d as relat e d t o st u d y p artici pati o n (e. g., st u d y 
i nter ve nti o n, pr ot oc ol-ma n date d pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g 
t hera p y) or relat e d t o a G S K pr o d uct will be rec or de d fr o m t he ti me a p ar tici pa nt 
c o nse nts t o partici pate i n t he st u d y .  
•  All S A Es will be rec or de d a n d re p ort e d t o t he s p o ns or or desi g nee i m me di atel y 
a n d u n der n o circ u msta n ce s h o ul d t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x 
3 . T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 
2 4  h o urs of it bei n g a vail a ble  
•  All A Es  will be c ollecte d fr o m t he start of i nter ve nti o n u ntil t he f oll o w -u p visit at 
t he ti me p oi nts s pecifie d i n t he S o A  ( Secti o n 1. 3. 1 ). 
•  
Me dical  occ urre n ces t hat be gi n b ef ore t he start of st u d y i nter ve nti o n b ut aft er 
o btai ni n g i nf or me d c o nse nt will be rec or de d as Me dical Hist or y/ C urre nt 
Me dical C o n diti o ns , n ot as A E s. 
•  
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k i nf or mati o n o n A Es or S A Es  
after t he c o ncl usi o n of t h e st u d y p artici pati o n. H o we ver, if t h e i n vesti gat or 
lear ns of a n y S A E, i n cl u di n g a d eat h, at a n y ti me after a partici pa nt h as bee n 
disc har ge d fr o m t he st u d y, a n d h e/s he c o nsi ders t he e ve nt t o be reas o n a bl y 
relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he i n vesti gat or m ust 
pr o m ptl y n otif y t he s p o ns or.  
8. 3. 3.  
F oll o w -u p of A E s a n d S A E s  
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All S A Es  will be f oll o we d u ntil t he e ve n t is 
res ol ve d, sta bilize d, ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w -u p (as 
defi ne d i n Secti o n 7. 3 ). F urt her i nf or mati o n o n f oll o w -u p pr oce d ures is gi v e n i n 
A p pe n di x 3 . 
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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
UK ethics board, the MHRA and investigators. 
• 
An investigator who receives an investigator safety report describing a 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 UK ethics board, and the MHRA if appropriate according to local 
requirements. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female partners of male participants will be collected after 
the start of study intervention and until time period for reporting pregnancies and should 
align with the time period for post-intervention contraception determined in Section 5.1 
and Section 10.3.3. 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner becomes pregnant while participating in this study. This applies only to 
male participants who receive study intervention. 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 24 hours of learning of the partner’s pregnancy.  
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.  
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   


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T he Deat h C R F is pr o vi d e d i m me diatel y after t h e occ urre nce or o utc o me of deat h is 
re p orte d. I nitial a n d f oll o w-u p re p orts re gar di n g d eat h m ust be c o m plete d wit hi n  o ne 
wee k of w he n t he d eat h is re p orte d.  
8. 4.  
P h ar m a c o ki n eti c s  
8. 4. 1.  
Pl a s m a S a m pl e C oll e cti o n  
Bl o o d sa m ples of a p pr o xi matel y 1 m L will be c oll ecte d f or plas ma P K a nal ysis of 
G S K 3 8 8 4 4 6 4 at t he ti me p oi nts i n dicate d i n t he S o A , Secti o n 1. 3 . T he ti mi n g of t he P K 
sa m ples ma y b e 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 data t o 
e ns ure a p pr o priate m o nit ori n g (e. g., t o o btai n sa m ples cl oser t o t he ti me of pea k plas ma 
c o nce ntr ati o ns).  
A d diti o n al v ol u m es of bl o o d ( 2 m L f or all  ti m e-p oi nts fr o m pr e -d os e t o 8 hr a n d 5 m L 
f or ti m e-p oi nts 1 2 hr t o 2 4 hr) will b e c oll e ct e d i n P art 1 ( C o h ort 2  a n d 3 ) a n d P art 2 
(D a y s 1 , 1 4 & 1 5 f or C o h orts 4  a n d 5  a n d D a y s 1 , 2 1 & 2 2  f or C o h ort 6 ) o nl y, as 
s p e cifi e d i n t h e S o A ( S ecti o n 1. 3 ) t o ass ess f or G S K 3 8 8 4 4 6 4-r el at e d m et a b olit es. 
I nstr u cti o ns f or t he c ollecti o n, ha n dli n g, a n d s hi p pi n g of bi ol o gical sa m ples will be 
pr o vi de d i n t he S R M. T he act ual d ate 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.  
S a m pl es c oll e ct e d f or a n al ys es of G S K 3 8 8 4 4 6 4  pl as m a c o n c e ntr ati o n m a y  als o b e 
us e d t o e v al u at e s af et y or effi c a c y as p e cts r el at e d t o c o n c er ns arisi n g d uri n g or aft er 
t h e st u d y. R esi d u al pl as m a s a m pl es m a y b e us e d t o ass ess f or G S K 3 8 8 4 4 6 4 -r el at e d 
m et a b olit es.  
I nter ve 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 ort e d t o 
i n vesti gati ve sites or bli n de d pers o n nel u ntil t he c o h ort/st u d y Part has bee n u n bli n de d. 
8. 4. 3.  
Bil e S a m pl e C oll e cti o n  
Bile sa m ples f or a nal ysis of meta b olites will be c ollecte d via t he E nter o -Trac ker or 
E nter o -Test i n eit her t he sec o n d  c o h ort ( Da y 14 ) or t hir d c o h ort ( Da y 2 1) i n Part 2 
( de pe n di n g o n P K res ults i n Part 1  a n d C o h ort 4 ). 
T he E nter o -Trac ker or E nter o -Test c o m pris es a gelati ne ca ps ule w hic h c o ntai ns 9 0 c m or 
1 4 0  c m of n yl o n stri n g attac he d t o a 1 g ste el wei g ht. O ne e n d of t he stri n g is attac he d t o 
t he o utsi de of t he m o ut h bef ore s wall o wi n g t he ca ps ule, s o t hat it ca n still be retrie v e d. 
T he gelati ne ca ps ule  diss ol ves i n t he st o mac h w hilst t he stri n g a n d wei g ht c o nti n ue t o t he 
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d u o de n u m via peristalsis. F oll o wi n g a f o o d c u e t o sti m ulate gall bla d der e m pt yi n g t he 
stri n g is wit h dra w n. 
O n wit h dra wal of t h e stri n g t hr o u g h t he m o ut h t he steel wei g ht se parates fr o m t he stri n g 
at t he p yl ori c s p hi ncter a n d is e x crete d i n t he faeces. O nce t he stri n g h as bee n re m o ve d 
fr o m t he partici pa nt it will be fr oze n a n d s hi p pe d f or meta b olite pr ofili n g (t o be 
c o n d ucte d i n a se p arate st u d y).   
F ull details of t he E nter o -Trac k er or E nter o -T est sa m ple c ollecti o n, pr ocessi n g, st ora ge 
a n d s hi p pi n g pr oce d ures are pr o vi d e d i n t he S R M.  
8. 4. 4.  
S a m pl e A n al y si s  
A nal ysis of G S K 3 8 8 4 4 6 4 i n plas ma a n d uri ne sa m ples will be perf or me d u n der t he 
c o ntr ol of G S K BI B I VI V T.  C o nce ntrati o ns of G S K 3 8 8 4 4 6 4 will b e deter mi ne d usi n g 
t he c urre ntl y a p pr o ve d bi oa nal yti cal met h o d ol o g y.  T he bi oa nal ytical site will be detaile d 
i n t he rele va nt sa m ple pr ocessi n g d o c u me nts (e. g. S R M, C L W, S O W) a n d ra w data will 
be arc hi v e d i n t he G S K R & D arc hi ves. A d diti o nal para met ers ma y be a nal yz e d if 
deter mi ne d a p pr o priate; m ore details will be pr o vi de d i n t he Statistical A nal ysis Pla n 
(S A P ). Pr ocessi n g, st or a ge a n d s hi p pi n g pr oce d ures are pr o vi de d i n t he S R M.  
O nce t he sa m ple h as bee n a nal yze d f or G S K 3 8 8 4 4 6 4 a n y re mai ni n g sa m pl e ma y be 
a nal yze d f or ot her c o m p o u n d -relate d m eta b olites a n d t he res ults re p orte d u n der a 
se parat e pr ot oc ol. 
Dr u g c o n c e ntr ati o n i nf or m ati o n t h at m a y u n bli n d t h e st u d y will o nl y b e s h ar e d wit h 
t h e D M P K a n d Bi oi m a gi n g St u d y Dir e ct or a n d s ci e ntists w h o ar e c o n d u cti n g a n d 
r e p orti n g t h e G S K 3 8 8 4 4 6 4 m et a b olis m st u d y w hi c h is s e p ar at e fr o m t his pr ot o c ol. 
T his i nf or m ati o n is n e e d e d t o diff er e nti at e a cti v e -d os e d s u bj e cts fr o m pl ac e b o t o 
i nf or m o n t h e m et a b olit e i d e ntifi c ati o n st u d y c o n d u ct. Dr u g c o nce ntrati o n i nf or mati o n 
will n ot be re p orte d t o i n vesti gati ve site s or bli n de d pers o n nel u ntil t he c o h ort/st u d y Part 
has bee n u n bli n de d.  
8. 4. 5.  
Di s e a s e -R el at e d E v e nt s ( D R E) a n d/ or Di s e a s e -R el at e d O ut c o m e s 
( D R O) N ot Q u alif yi n g a s S A E s  
N o D R Es or D R Os n ot q ualif yi n g as S A Es will be c ollecte d i n t his st u d y.  
8. 4. 6.  
A d v er s e E v e nt s of S p e ci al I nt er e st  
A d verse E v e nts of S peci al I nt erest ( A E SI) are sel ecte d A Es t hat m ust be re p orte d t o t he 
S p o ns or’s Me dical M o nit or wit hi n 2 4 h o urs re gar dless of relati o ns hi p t o st u d y treat me nt.  
F or t his st u d y t he A E SI re prese nt m o derate or se v ere i ncreas es i n li ver f u n cti o n a nal ys es. 
8. 5.  
G e n eti c s  
Ge netics are n ot e v al uate d i n t his st u d y.  
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8. 6. 1.  
P h ar m a c o d y n a mi c s  
Precli nical i n viv o dat a h as s h o w n t hat G S K 3 8 8 4 4 6 4 de m o nstrate d r o b ust t ar get 
e n ga ge me nt as meas ur e d b y i ncreas e d e x pressi o n/acti vit y of N Q O 1, a tar get ge n e 
re g ulate d b y N R F 2, i n tiss ues a n d w h ole bl o o d. El e vati o n of N Q O 1 m R N A, f oll o wi n g 
treat me nt wit h G S K 3 8 8 4 4 6 4,  i n w h ole bl o o d sa m ples bei n g c ollecte d i n t h e st u d y w o ul d 
pr o vi de e vi de nce of pr o xi mal tar get e n ga ge me nt a n d acti vati o n of N R F 2. T heref ore, t his 
is a sec o n dar y e n d p oi nt f or t he st u d y a n d will be use d t o c haracterize t he rel ati o ns hi p 
bet wee n P K a n d P D f or G S K 3 8 8 4 4 6 4 .  
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8.7. 
Medical Resource Utilization and Health Economic 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objectives of this study are to assess the safety and tolerability of single and 
repeat ascending doses and to characterize the PK and PD of GSK3884464 in healthy 
participants. No formal statistical hypotheses will be tested.  
Descriptive statistics will be used to assess safety and tolerability objectives. Treatment 
comparisons with placebo will be based on review of descriptive statistics and individual 
participant data.  
Intercurrent events, the estimand strategy to handle such events and the changes to the 
respective analysis to implement the strategies will be highlighted in the SAP. 
9.2. 
Sample Size Determination 
A sufficient number of participants will be screened to achieve up to 51 randomly 
assigned to study intervention and up to 51 evaluable participants. It is estimated that Part 
1 will have 27 evaluable participants; Part 2 will have 24 evaluable participants (6 for 
each of the three repeat doses levels and 6 for placebo). Additional participants/cohorts 
may be enrolled to allow for evaluation of additional dose levels. If participants 
prematurely discontinue during the study, additional replacement participants may be 
enrolled at the discretion of the Sponsor. These replacement participants will be assigned 
to the same treatment/treatment sequence as the corresponding participant who 
prematurely discontinued from the study.  
The sample size has been assessed based on the evaluation of fold change from baseline 
(FCFB) of NQO1 expression, a secondary endpoint in the study to the end of repeated 
dosing. Assuming the within subject CV of 50% and based on 6 participants each in 
GSK3884464 and placebo treatment arms, 
• If the true ratio of FCFB between GSK3884464 and placebo is 5-fold, then there 
is 69% probability that the observed ratio is greater than 4.2 -fold; if the true ratio 
is 6-fold, then the probability is 83%; if the true ratio is greater than 7-fold then 
the probability is greater than 90%. This provides high confidence of observing a 
clinical meaningful effect in the expected range (>5-fold) of target engagement in 
NOQ1.  
• If the true ratio of FCFB between GSK3884464 and placebo is 1-fold, then the 
false positive rate that the observed ratio is greater than 4.2-fold is <0.1%.  


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9.3. 
Analysis Sets 
For the purpose of analysis, he following populations are defined: 
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Randomized 
All participants who were randomly assigned to treatment in the 
study. 
This population will be based on the treatment the participant was 
randomized to. 
Safety 
All randomized participants who take at least 1 dose of study 
intervention.  
Participants will be analyzed according to the intervention they 
actually received. 
PK 
All participants in the Safety population who had at least one non-
missing PK assessment (Non-quantifiable [NQ] values will be 
considered as valid PK assessment). 
This population will be based on the treatment the participant 
actually received. 
PD 
Participants in the Safety population with baseline and at least one 
post baseline PD measure (e.g. NQO1 mRNA) 
9.4. 
Statistical Analyses 
The SAP will be finalized prior to the first subject first visit 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. 
General Considerations 
9.4.1.1. 
Primary Endpoint(s) 
• The primary objectives of the study are the characterization of the adverse event 
profile and safety and tolerability. The primary endpoints: adverse events and 
serious adverse events, and significant changes from baseline in laboratory values, 
ECG, vital signs, continuous telemetry, echocardiograms, etc., will be presented 
in tabular and/or graphical format and summarised descriptively according to 
GSK's Integrated Data Standards Library standards.  
• For primary PK endpoints in this study, no formal hypotheses will be tested. All 
pharmacokinetic analyses will be performed on the PK Population and will follow 
the following rules:  
o 
Plasma concentration-time data of GSK3884464 will be analysed by 
non-compartmental methods. Calculations will be based on the actual 
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o  
Fr o m t he plas ma c o nce ntrati o n -ti me data f oll o wi n g si n gle d ose 
a d mi nistrati o n , t he f oll o wi n g p har mac o ki netic para meters will be 
deter mi ne d, as d ata per mit: ma xi m u m o bser ve d plas ma c o nce ntrati o n 
( Cma x ), ti me t o Cma x  (tma x ), area u n d er t he pl as ma c o nce ntrati o n-ti me 
c ur ve (A U C ( 0-t) a n d A U C ( 0-∞) ), a n d a p pare nt ter mi nal p hase half -life 
(t1/ 2). Ot her para m eters ma y b e deri ve d as a p pr o priate ; a d diti o nal details 
will be pr o vi de d i n t he S A P . 
o  
Fr o m t he plas ma c o nce ntrati o n -ti me data f oll o wi n g re peat d os e 
a d mi nistrati o n, t he f oll o wi n g p har mac o ki netic p ara meters will be 
deter mi ne d, as d ata per mit: ma xi m u m o bser ve d plas ma c o nce ntrati o n 
( Cma x ), ti me t o Cma x  (tma x ), tr o u g h c o nce ntr ati o ns ( Cτ), area u n d er t he 
plas ma c o nce ntrati o n -ti me c ur ve ( A U Cτ) a n d a p pare nt ter mi nal p hase 
half -life (t1/ 2). Ot her para meters ma y be d eri ve d as a p pr o priate; 
a d diti o nal details will be pr o vi de d i n t he S A P .  
o  
D ose pr o p orti o nalit y  f or si n gle d ose a d mi nistrati o n will be assesse d b y 
vis ual i ns pecti o n of d ose n or malise d A U C  (0 -∞)  a n d C ma x  val ues vers us 
d ose. A nal ysis of l o g e-tr a nsf orme d para meters m a y be carrie d o ut, usi n g 
t he p o wer m o del. D os e pr o p orti o nalit y f or re p eat d ose a d mi nistrati o n 
ma y b e assesse d usi n g si milar met h o ds t o t he si n gle d ose.  
o  
T he e xte nt of acc u m ulati o n after re peat d osi n g will be deter mi ne d via 
c o m p utati o n of acc u m ulati o n rati os base d o n A U C τ ( RA U C ), o n Cma x  
( RC ma x ), a n d o n Cτ ( RCτ ). A n assess me nt of ti me t o ac hie ve ste a d y state 
will be ma de base d o n i ns pecti o n of t he tr o u g h c o nce ntrati o ns.  
9. 4. 1. 2.  
S e c o n d ar y E n d p oi nt( s)  
N Q O 1 m R N A : T he n or maliz e d  m R N A e x pressi o n data will be a nal yse d wit h a mi x e d 
effect m o del wit h s u bject as ra n d o m effect, a n d treat me nt, visit a n d treat me nt b y visit as 
fi x e d effect. T h e rati o t o baseli ne at eac h p ost treat me nt visit will be esti mate d wit h 9 5 % 
c o nfi de nce i nter val.  
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9. 5.  
I nt eri m A n al y s e s 
Data ma y be a nal yze d at t he e n d of eac h c o m plete d c o h ort/st u d y P art. Safet y a n d 
p har mac o ki netic d ata (a n d P D data if a vaila ble) will be re vie we d b y t he D E C bef ore d os e 
escalati o n i n eac h st u d y Part, a n d bet wee n st u d y Parts. Data f or t hes e re vie ws will be 
cu m ulati ve a n d ca n i ncl u de i n di vi d ual partici pa nt data, s u m mari es b y treat me nt gr o u p, 
a n d gra p hical dis pla ys. D ose escalati o n decisi o ns will be ma de as o utli ne d i n Secti o n 4. 4 , 
Secti o n 6. 5 , a n d i n t he D E P.  
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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), and 
all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or their legally authorized representative (LAR) and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their LAR will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about the study intervention or about the study disease; publish the results of these 
research efforts; work with government agencies or insurers to have the the study 
intervention approved for medical use or approved for payment coverage.  
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a participant's agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  


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• 
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. 
10.1.5. 
Dose Escalation Committee 
Participant safety will be continuously monitored by the Sponsor’s DEC which includes 
safety signal detection at any time during the study. 
The DEC consists of the Principal Investigator (or appropriate designee), Site Senior 
Clinical Development Manager, Medical Monitor, GSK Clinical Science Lead, GSK 
Study Delivery Lead, GSK Clinical Pharmacology Modelling and Simulation (CPMS) 
representative, GSK Drug Metabolism and Pharmacokinetics Lead, a GSK Global 
Clinical Safety and Pharmacovigilance (GCSP) Lead, GSK Clinical Biomarker Lead, 
GSK Study Data Manager, and a GSK Statistician. The GSK Medical Monitor and the 
GSK CPMS representative will remain unblinded for the dose escalation review 
throughout the course of the study. Additional internal GSK safety representatives may 
be consulted and included in the dose escalation decision making, in a blinded or 
unblinded manner as deemed necessary by the DEC.  
The DEC will be used to ensure data integrity in dose selection decisions by performing 
clinical data review and appropriate quality control of data prior to making dose selection 
decisions for this study. The Committee will review emerging data and recommend 
changes to the study, and review safety parameters during the study.  
The DEC will also review the data to determine if participants are experiencing higher 
than expected adverse GI symptoms based on responses the review of adverse events. 
Further details are in the DEP. 
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 the investigators who were involved with the study 
with the full summary of the study results. 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 
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• 
GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. 
• 
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These pre-
defined parameters will be monitored during the study and deviations from the 
QTLs and remedial actions taken will be summarized in the clinical study 
report. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
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 


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currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data and its origin can be found in Source 
Data Acknowledgment. 
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open 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. 


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
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 recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/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 
participant and should assure appropriate subject 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 
All protocol required laboratory assessments, as defined in Table 7, must be conducted in 
accordance with the Laboratory Manual, and Protocol SoA (Section 1.3.1).  Laboratory 
requisition forms must be completed, and samples must be clearly labelled with the 
participant number, protocol number, site/centre number, and visit date.  Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the SRM or the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.   
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.   
• 
The clinical safety tests detailed in Table 7 will be performed by the local 
laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations, which may require 
an unscheduled visit. 
Table 7 
Protocol-Required Safety Laboratory Assessments.  
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
WBC Count 
(absolute) 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Total Protein 


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Laboratory 
Assessments 
Parameters 
Transaminase 
(SGPT) 
Glucose2  
Calcium 
Alkaline 
phosphatase 
Chloride 
 
Bicarbonate 
Albumin 
Uric Acid 
Phosphate 
 
Creatinine 
Phosphokinase 
 
 
 
 
LDL 
Triglycerides 
 
 
Other Safety 
Assessments 
• N-terminal -proBNP 
• hs Troponin 
• eGFR 
• Gamma-glutamyl transferase (GGT) 
Routine 
Urinalysis3 
• Specific gravity 
• pH, glucose, protein, blood, ketones by dipstick 
• Microscopic examination (if blood or protein is abnormal)  
• Urine albumin:creatinine ratio 
• Urine creatinine 
• Urine phosphate (only in the event a participant has persistent serum 
hypophosphataemia)4 
Core Urine 
Monitoring 
Assessments 
• Spot urine protein: creatinine (UPC) ratio 
• Urine phosphate 
Other Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• 
Estimated glomerular filtration rate (eGFR) will be calculated using the 
CKD-EPI formula 
• COVID-19 testing5 
• Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)] -- if second generation Hepatitis C antibody positive, a 
hepatitis C antibody Chiron RIBA immunoblot assay (or other third 
generation immunoassay) or Hepatitis C Virus RNA test (either quantitative 
or qualitative) should be reflexively performed on the same sample to 
confirm the result)  
The results of each test must be entered into the CRF 
Other 
assessments 
• Fasting Serum Insulin  
• Aldosterone6, Cortisol6 and ACTH6 
• HbA1c 


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Laboratory 
Assessments 
Parameters 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1and Section 10.5 All events of ALT 3 × upper limit of normal (ULN) 
and total bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, 
if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported to GSK in an 
expedited manner (excluding studies of hepatic impairment or cirrhosis). 
2. 
Glucose will be fasting for all assessments. For Part 2 Cohort 4 and 5 collect on D1, D4, D11 and D14.  For Part 2 
Cohort 6, collect D1, D4, D11, D18, and D21. 
3. 
If trace protein or blood in urine is detected, a repeat test will be performed within 24 hrs, except if the repeat test 
is required at Screening the site should repeat as soon as possible within the screening period. If results are 
considered abnormal (guidance in SRM), further quantification is required at the investigator’s discretion. If 
glucose is positive by dipstick, send for laboratory urine glucose with contemporaneous serum glucose. 
4. 
If persistent serum hypophosphatemia (less than 2 mg/dL) confirm by repeat testing. 
5. 
Two consecutive approved molecular tests (PCR or antigen test) separated by > 24 hours. The second test ideally 
should be within 72 hours of admission to the unit. If the second test is > 72 hours prior to unit admission, subjects 
should be advised to self -quarantine until entrance to the unit while awaiting final testing clearance. Ad hoc 
testing may be done based on clinical presentation and site procedure. Note: A SARS-CoV2 Ag test was recently 
approved and may be an alternative to PCR testing once the operating characteristics are understood. Other 
molecular tests for active infection are in development and may be used when approved by regulatory bodies. 
6. 
See SoA for timing of tests. 
 


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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/participant’s 
parent(s)/LAR(s)] who has signed the informed consent. Unsolicited AEs include 
serious and non-serious AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or emergency room visit, or visit to/by a health care 
provider). The [participants/ participant’s parent(s)/LAR(s)] 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/ parental /LAR’s] 
concern. Detailed information about reported unsolicited AEs will be collected by 
qualified site personnel and documented in the participant’s records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by 
[participant/participant’s parent(s)/LAR(s)] will be collected during interview with 
the [participants/participant’s parent(s)/LAR(s)] 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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Events Meeting the AE Definition 
• 
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. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. "Lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 
 
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. 


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10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
• Results in death 
• Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Is a suspected transmission of any infectious agent via an authorised medicinal 
product 
Other situations: 
• 
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. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of intervention dependency or intervention abuse. 


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10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK 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. 


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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 


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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. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 


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10.3.5. 
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. 
• 
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’ 
• 
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 and Barrier 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 enrollment. 


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


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase I liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
 
ALT≥3xULN 
If ALT≥3xULN AND bilirubin1,2  2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE. 
See additional Actions and Follow Up Assessments listed below 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below) 
MONITORING: 
If ALT≥3xULN AND bilirubin  2xULN or INR 
>1.5 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5: 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain plasma sample for pharmacokinetic 
(PK) analysis, within 48 hours of last dose4  
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
If ALT≥3xULN AND bilirubin  2xULN or INR 
>1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 


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Liver Chemistry Stopping Criteria  
liver event follow up assessments within 24-
72 hrs 
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
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 participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009].  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants 
3. Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody  
4. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK sample draw and the date/time of the last dose of study treatment 
prior to PK sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 4 1  
1 0. 6.  
A p p e n di x 6 : A b br e vi ati o n s a n d Tr a d e m ar k s 
A b bre vi ati o ns  
Δ  
C ha n ge  fr o m bas eli ne 
Δ Δ  
Place b o -c orrecte d c h a n ge-fr o m-b aseli ne  
6 -CI T  
6 -ite m c o g niti ve i m pair m e nt test 
A C E  
A n gi ote nsi n -c o n verti n g e nz y me  
A C T H  
A dre n oc ortic otr o pic h or m o ne  
A C R  
Al b u mi n Creati ni ne rati o   
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferas e  
A PI  
Acti ve p har mace utical i n gre die nt  
A P D  
Atrial Pre mat ure De p olarisati o n  
A R B  
A n gi ote nsi n II rece pt or bl oc kers  
A S T  
As partate tra nsa mi nase  
A U C  
Area u n d er t he c ur ve  
A U C ( 0-∞)  
Area u n d er c ur ve t o i nfi nit y  
A U C ( 0-t) 
Area u n d er t he c ur ve t o l ast q ua ntifia ble c o n ce ntr ati o n  
A V B  
Atri o ve ntric ular bl oc k  
β  
Beta  
B B B  
B u n dle bra nc h bl oc k  
BI B  
Bi o a n al ysis, I m m u n o g e ni cit y a n d Bi o mar k ers  
B MI  
B o d y mass i n de x  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 4 2  
B P M  
Beats p er mi n ute  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C F R  
C o de of Fe d eral Re g ul ati o ns  
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntr ati o n  
C τ 
Plas ma tr o u g h c o n ce ntr ati o n  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O P D  
C hr o nic o bstr ucti ve p ul m o nar y disease  
C P K  
Creati ne p h os p h o ki nase  
C P M S  
Cli nical P har mac ol o g y M o delli n g a n d Si m ulati o n  
Cr  
Creati ni ne  
C R F  
Case re p ort f or m  
C S R  
Cli nical st u d y re p ort  
C U C  
Cli nical U nit Ca m bri d ge  
C V  
Car di o vasc ular  
D B L  
Data base l o c k  
D E C  
D ose Escalati o n C o m mittee  
D E P  
D ose Escalati o n Pla n  
d L  
Deciliter  
D M P K  
Dr u g Meta b olis m a n d P har mac o ki netics  
D R E  
Disease relate d e v e nts  
D R O  
Disease relate d o utc o me  
E C G  
Electr ocar di o gra m  
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 4 3  
e C R F 
Electr o nic case re p ort f or m  
E F  
Ejecti o n fracti o n  
e G F R  
Esti mate d gl o mer ular filtrati o n rate  
E W  
Earl y wit h dra wal  
F S H  
F ollicle sti m ulati n g h or m o ne  
F TI H  
First ti me i n h u ma n  
g m  
Gra ms  
G C P  
G o o d Cli nical Practice  
G C S P  
Gl o bal Cli nical Safet y a n d P har mac o vi gila nce  
G E R D  
Gastr oes o p ha geal r efl u x disease  
G L P  
G o o d la b orat or y practice  
G R  
Gastr o -resista nt 
G S K  
Gla x o S mit h Kli ne  
h  
H o ur  
H b A 1c  
Gl ycate d he m o gl o bi n  
H Bs A g  
He patitis B s urface a nti ge n  
H D P E  
Hi g h de nsit y p ol yet h yle ne  
H F  
Heart fail ure  
H F p E F  
Heart fail ure preser ve d ej ecti o n fracti o n 
H Fr E F  
Heart fail ure re d uce d ejecti o n fracti o n  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
H P M C -A S  
H y dr o x y pr o p yl met h yl cell ul ose Acetate S ucci n ate  
C CI
C CI


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 4 4  
H R  
Heart rate  
H R T  
H or m o nal re place me nt t h era p y  
I B 
I n v esti gat or’s br oc h ure 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I C F 
I nf or me d C o nse nt F or m 
I E C 
I n d e pe n de nt Et hics C o m mittees 
I M P 
I n v esti gati o nal me dici nal pr o d uct 
I N R 
I nter nati o nal n or malize d rati o 
I P 
I n v esti gati o nal pr o d uct 
i P S C-C M  
I n d u ce d Pl uri p ote nt Ste m Cell-Deri ve d car di o m y o c yt e  
I R B 
I nstit uti o nal Re vie w B oar d 
I U D 
I ntr a uteri ne de vice 
I U S 
I ntr a uteri ne s yste m 
I VI V T 
I n Vitr o/I n Vi v o Tra nslati o n 
k g  
kil o gra m  
L  
Liter  
L A M  
Lactati o nal a me n orr h oea met h o d  
L A R  
Le gall y a ut h orize d re pres e ntati ve  
L B B B  
Left b u n dle bra n c h bl oc k  
L D H  
Lactate d e h y dr o ge n ase  
m 2 
S q uare meter  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m g  
Milli gra m  
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MHRA 
Medicines and Healthcare products Regulatory Agency 
min 
Minute 
mL 
Mililiter 
mRNA 
Messenger RNA 
ms 
Millisecond 
MSDS 
Material safety data sheet  
mV 
Millivolt 
ng 
Nanogram 
NIMP 
Non-Investigational Medicinal Product 
 
NOAEL 
No observed adverse effect level 
NQ 
Non-quantifiable 
NQO1 
NAD(P)H dehydrogenase (quinone 1) 
NSVT 
Non-sustained ventricular tachycardia 
NTI 
Narrow Therapeutic Index  
NYHA 
New York Heart Association 
PD 
Pharmacodynamic  
pg 
Picograms 
PICF 
Participant Information Sheet and Consent Form 
PK 
Pharmacokinetic  
PR 
PR interval of the ECG 
QD 
Once daily 
QRS 
QRS interval of the ECG 
QT 
QT Interval of the ECG 
QTc 
Corrected QT interval 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 4 6  
Q Tc F  
C orrecte d Q T i nter val usi n g Fri derici a’s f or m ula  
R A U C  
Acc u m ulati o n rati os base d o n A U Cτ  
R C ma x  
Acc u m ulati o n rati os base d o n C ma x  
R Cτ  
Acc u m ulati o n rati o c o m p ute d base d o n Cτ  
R D  
Re peat d ose  
R N A  
Ri b o n ucleic aci d  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S D  
Si n gle d ose  
S G O T  
Ser u m Gl uta mic -O xal oacetic Tra nsa mi nase  
S o A  
Sc he d ule of Acti vities  
S R M  
St u d y R efere nce M a n ual  
t½  
Ter mi nal half -life 
tma 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 M F  
Trial master file  
U L N  
U p per li mit of n or mal  
V P D  
Ve ntric ular Pre mat ure De p olarisati o n  
V S  
Vital Si g ns  
V T  
Ve ntric ular t ac h ycar dia  
W O N C B P  
W o ma n of N o nc hil d beari n g P ote ntial  
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Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
COMPAS 
 
 
Entero-Test  
 
 
Entero-Tracker 
 
 
Tecfidera 


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10.7. 
Appendix 7: Protocol Amendment History 
DOCUMENT HISTORY 
List dates of original protocol and all amendments in reverse chronological order. 
Document 
Date 
TMF Number 
Amendment 03 
17-FEB-2022 
TMF- 14464572 
Amendment 02 
04-JAN-2022 
TMF-14366164 
Amendment 01 
19-AUG-2021 
TMF-13947787 
Original Protocol 
09-JUN-2021 
TMF-13810865 
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 [because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study]. 
Amendment 03 17-FEB-2022 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment:  This Protocol Amendment 03 is being 
implemented to provide additional safety monitoring. 
Where the Amendment Applies: 
This Protocol Amendment 03 applies to all countries and sites participating in the study. 
Table of Specific Changes: 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 


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149 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Previous: 
Disclosure Statement: This is a 
First Time in Human Study. 
Sentinel dosing will be 
incorporated in each Part of the 
study and at each dose level.  
 
Revised: 
Disclosure Statement: This is a 
First Time in Human Study. 
Sentinel dosing will be 
incorporated in each Part of the 
study and at each dose level. For 
Part 1, only 2 to 3 participants 
will be dosed at a time and their 
LFTs will be monitored until Day 
6 before the next participants in 
the cohort are dosed. 
 
This change was made to the 
dosing schedule to permit closer 
safety monitoring of LFTs for 
participants in Part 1 of the 
study. 
Section 1.3.1 Part 1: Single Dose 
Administration in Healthy 
Participants (Cohorts 1, 2 and 3) 
 
Revised:  Clinical laboratory 
assessments 
(hema/chem/urinalysis-including 
liver chemistries) added to Day 4 
Additional day chemistry blood 
draws added on Day 4 in Part 1 
to monitor for liver chemistry 
changes. This is a safety update. 
Section 4.1 Overall Design 
 
Previous: 
Participants will be randomized 
to treatment sequences such that 
in each period up to 6 
participants will receive active 
dose and up to 3 participants will 
receive placebo.  
 
Revised: 
Participants will be randomized 
to treatment sequences such that 
in each period up to 6 
participants will receive active 
dose and up to 3 participants will 
receive placebo. Up to 2 to 3 
participants will be dosed at a 
time, and their LFTs will be 
closely monitored before the next 
participants receive study 
treatment.   
 
Previous: 
In Part 1, sentinel participants 
will be followed clinically for 48 
hrs (predicted half-life for 
GSK3884464 is approximately 
12hrs) to allow for adequate 
observation of safety. 
 
This change was made to the 
dosing schedule to permit closer 
safety monitoring of LFTs for 
participants in Part 1 of the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The sentinel dosing regimen for 
the SAD portion of the study 
(Cohorts 2 and 3) was amended 
from 48 hours between doses to 
6 days for safety monitoring for 
LFT changes. 
 
 
 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 5 0  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Re vise d:  
I n P art 1, se nti nel partici pa nts 
will be f oll o we d cli nicall y f or 6 
da ys   t o all o w f or a de q uate 
o bser vati o n of safet y.  
 
Pre vi o us:  
I n P art 2, se nti nel partici pa nts 
will be f oll o we d cli nicall y f or 
6 0 hrs ( or 5 half -li ves, w hic he ver 
is l o n ger) t o all o w f or a de q uat e 
o bser vati o n of safet y t o m o nit or 
f or e mer ge nce of a d verse e ve nts 
 
Re vise d:  
I n P art 2, se nti nel partici pa nts 
will be f oll o we d cli nicall y f or 1 4 
da ys  t o all o w f or a de q uate 
o bser vati o n of safet y t o m o nit or 
f or e mer ge nce of a d verse e ve nts 
 
  
 
 
 
 
 
 
 
M ulti ple Asce n di n g D ose 
( M A D) p hase of t he st u d y: 
o bser vati o n peri o d f or se nti nel 
d osi n g will be i ncrease d fr o m 
6 0 h o urs t o 1 4 da ys f or safet y 
m o nit ori n g f or L F T c ha n ges.  
 
Secti o n 6. 8 C o nc o mita nt T her a p y  
Pre vi o us:  
 
P araceta m ol/ Aceta mi n o p he n at 
d oses of ≤ 2 gra ms/ da y, is 
per mitte d f or use at a n y ti me 
d uri n g t he st u d y.  
Re vise d:  
P araceta m ol/ Aceta mi n o p he n, at 
d oses of ≤2 gra ms/ da y, or 
I b u pr ofe n ≤1 2 0 0 m g/ da y, is 
per mitte d f or use at a n y ti me 
d uri n g t he st u d y  
 
T he i n vesti gat or is  per mitte d a n 
o pti o n t o a d mi nister 
paraceta m ol or i b u pr ofe n t o 
partici pa nts if nee de d, i n li g ht of 
t he p ote ntial i m pact of 
i nfre q ue nt paraceta m ol use o n 
L F T c ha n ges.  
 
A me n d me nt 0 2  0 4 -J A N-2 0 2 2  
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial. 
O ver all R ati o n ale f or t he A me n d me nt:   T his Pr ot oc ol A me n d me nt 0 2 is bei n g 
i m ple me nte d t o u p date t he ti mi n g of t he P K sa m pli n g, t o clarif y t he ti mi n g of t he 
 
 i n Part 1, a n d t o u p date i nf or mati o n on t he D ose Escalati o n a n d 
St u d y Pr o gressi o n. T y p o gra p hical err ors were als o c orrecte d.  
W here t he A me n d me nt A p plies:  
T his Pr ot oc ol A me n d me nt 0 2 a p plies t o all c o u ntries a n d sites partici pati n g i n t he st u d y.  
T a ble of S pecific C h a n ges:  
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NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 
Section # and Name 
Description of Change 
Brief Rationale 
1.0 Protocol 
Summary; Figure 1 
PREVIOUS TEXT: 
(before progression to next Part) 
REVISED TEXT: 
Text and Star removed between Part 1 and Part 
2 
Figure 1 wording was updated 
to match removal of sentence 
from Section 4.4 as described 
below. 
1.3. Schedule of 
Activities  
1.3.1 Part 1  Single 
Dose Administration 
in Healthy 
Participants (Cohorts 
1, 2 and 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2 Part 2 (Cohorts 4 
and 5): Multiple Dose 
Administration to 
Healthy Participants 
for 14 days of 
Treatment and 1.3.3  
Part 2 (Cohort 6): 
Multiple Dose 
Administration to 
Healthy Participants 
for 21 days of 
PREVIOUS TEXT: 
PK plasma samples will be collected at the 
following time points: 
Pre-dose, post dose: 30min, 1hr, 1.5hr, 2hr, 3hr 
4hr, 6hr, 8hr, 12hr; 18hr, 24hr, 36hr, 48hr,72hr, 
96hr, 120hr (morning of D6).  
Metabolite plasma samples to be collected 
from Cohorts 2 and 3 only. 
REVISED TEXT: 
PK plasma samples will be collected at the 
following time points: 
Pre-dose, post dose: 15 min, 30min, 1hr, 1.5hr, 
2hr, 4hr, 6hr, 8hr, 12hr; 18hr, 24hr, 36hr, 
48hr,72hr, 96hr, 120hr (morning of D6).  
Metabolite plasma samples to be collected 
from Cohorts 2 and 3 only (See Section 8.4.1 
and SRM). 
PREVIOUS TEXT: 
**Metabolite plasma samples only on D1, D14 
and D15 (to collect 24 hr sample only) with 
same timepoints as described for PK plasma 
sample above. 
**Metabolite plasma samples only on D1, D21 
and D22 (to collect 24 hr sample only) with 
same timepoints as described for PK plasma 
sample above. 
REVISED TEXT: 
**Metabolite plasma samples only on D1, D14 
and D15 (to collect 24 hr sample only) with 
same timepoints as described for PK plasma 
sample above (See Section 8.4.1 and SRM). 
The PK sampling time points 
were modified to better capture 
Tmax and Cmax, based on 
emerging PK information in 
Study Part 1. This is in-scope 
of the original protocol 
wording. 


T M F -1 4 5 7 7 7 3 9  
C O N FI D E N TI A L  
2 1 3 3 7 6  
 
Pr ot A m e n d 4  
 
1 5 2  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Treat me nt  
 
**Meta b olite plas ma sa m ples o nl y o n D 1, D 2 1 
a n d D 2 2 (t o c ollect 2 4 hr sa m ple o nl y) wit h 
sa me ti me p oi nts as descri be d f or P K plas ma 
sa m ple a b o ve ( See Secti o n 8. 4. 1 a n d S R M). 
Secti o n 4. 4 Criteria 
f or D ose Escalati o n 
a n d f or Pr o gressi n g 
B et wee n P arts of t he 
St u d y  
P R E VI O U S T E X T:  
It will be a p pr o xi matel y 2 wee ks bet wee n d ose 
escalati o n i n P art 1 a n d a p pr o xi matel y 4 wee ks 
bet wee n P arts 1 a n d 2.  
R E VI S E D T E X T:  
T e xt was re m o ve d  
P R E VI O U S T E X T:  
T he d ose le vels i n P art 2 will o nl y be starte d 
after t he sa me or hi g her d ose c o h orts are 
c o m plete i n P art 1 wit h n o d ose escalati o n 
st o p pi n g criteria ha vi n g bee n met. I n a d diti o n, 
t he ma xi m u m d ose f or P art 2 ca n n ot e xcee d t he 
ma xi m u m d ose i n P art 1.  
R E VI S E D T E X T:  
T he d ose le vels i n P art 2 will o nl y be starte d 
after t he sa me or hi g her d ose c o h orts are 
As per pr ot oc ol S ecti o n 4. 3. 3 
a n d S ecti o n 4. 4, a n d as 
c o nfir me d b y M H R A, d ose 
le vels i n P art 2 will be teste d 
o nl y w he n sa me or hi g her d ose 
le vels will ha ve bee n teste d i n 
P art 1 wit h o ut meeti n g a n y 
d ose escalati o n st o p pi n g 
criteria. T his s u perse des t he 
nee d f or se parati o n of P art 1 
a n d P art 2 b y 4 wee ks.  
 
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Section # and Name 
Description of Change 
Brief Rationale 
complete in Part 1 with no dose escalation 
stopping criteria having been met, therefore, 
Part 2 may start before the completion of Part 
1. At a minimum, MAD Cohort dose levels 
will be defined based upon DEC review of the 
first five SAD dose levels. Additional MAD 
cohorts will be based on DEC review of 
subsequent SAD dose levels and the previous 
MAD.  Lastly, the maximum dose for Part 2 
cannot exceed the maximum dose in Part 1.  
 


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Amendment 01 19-AUG-2021 
Overall Rationale for the Amendment:  This Protocol Amendment 01 is being 
implemented to correct typographical errors, to update information on the Dose 
Escalation Plan and Committee, Exclusion Criteria and provide information on 
Concomitant therapy. 
Where the Amendment Applies: 
This Protocol Amendment 01 applies to all countries and sites participating in the study. 
Table of Specific Changes: 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for REVISED 
TEXT, text deleted from the original has a dotted underline and text added has a solid 
underline. 
Section # and Name 
Description of Change 
Brief Rationale 
1 Protocol Summary 
PREVIOUS: The Committee will review 
emerging data and recommend changes to the 
study, and review safety parameters during the 
study. The details and composition of the DEC 
will be included in a charter to be completed 
prior to commencement of study enrolment. 
REVISED: The Committee will review 
emerging data and recommend changes to the 
study, and review safety parameters during the 
study. The details and composition of the DEC 
will be included in the Dose Escalation Plan 
(DEP), to be completed prior to 
commencement of study enrolment. 
Protocol was updated to refer to 
the Dose Escalation Plan which 
will replace the charter. 
1.3. Schedule of 
Activities 
Addition of missing X’s to table, missing 
asterisks, and missing words. 
For example: 
Adrenocorticotropic hormone (ACTH) and 
Cortisol 
Plasma PK and metabolite sampling  
To correct typographical errors. 


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Section # and Name 
Description of Change 
Brief Rationale 
4.2 Scientific 
Rationale for Study 
Design 
Previous:  The review of adverse events may 
trigger the switch to gastro-resistant capsules 
and the questionnaire will further capture 
tolerability information related to both 
capsules (Refer to Dose Escalation Plan [DEP] 
for switching criteria). 
REVISED: The review of adverse events may 
trigger the switch to gastro-resistant capsules 
and the questionnaire will further capture 
tolerability information related to both 
capsules (Refer to Section 4.4 for switching 
criteria)  
Specific section in protocol was 
updated and referred to instead 
of separate plan. 
4.3.2 Prediction of 
Dose Levels for Part 1 
PREVIOUS: In the event the observed 
exposure at the starting dose (1 mg) is lower 
than the corresponding predicted exposure, the 
next dose will target the exposure at the 
MABEL. In this case the escalation increment 
can be greater than 3-fold. 
REVISED: In the event the observed exposure 
at the starting dose (1 mg) is lower than the 
corresponding predicted exposure, the next 
dose will target the exposure at the MABEL. 
In this case the escalation increment can be 
greater than 3-fold. In the event the observed 
exposure at the starting dose (1 mg) is 
substantially higher than the corresponding 
predicted exposure, the next dose will be 
revised to produce a 2-3-fold increment in 
exposure, consistent and no greater than the 
currently planned increments, if the dose 
escalation stopping criteria are not met. 
This statement adds flexibility 
to adjust the predicted doses 
based on the data from Part 1. 
4.3.3 Prediction of 
Dose Levels for Part 2 
PREVIOUS: The decision to progress to Part 2 
and the selection of the actual dose levels, of 
the repeat dose regimen and of the number of 
cohorts will be made by the DEC, based on 
safety, tolerability and PK data from Part 1 
(see Section 4.4 and Section 10.1.5). 
This statement adds flexibility 
to adjust the predicted doses 
based on the data from Part 1. 
 
REVISED: The decision to progress to Part 2 
and the selection of the actual dose levels, of 
the repeat dose regimen and of the number of 
cohorts will be made by the DEC, based on 
safety, tolerability and PK data from Part 1 
(Section 4.4, Section 10.1.5). The predicted 
doses to be explored in Part 2 may be adjusted 
to the new start and maximum doses pending 
data obtained in Part 1. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
4.4 Criteria for Dose 
Escalation and for 
Progressing Between 
Parts of the Study 
PREVIOUS: The decision to proceed to the 
next dose level, to progress through each 
Part/Cohort, and to include an additional 
cohort/dose level (if necessary) will be made 
by the DEC. The anticipated mean plasma 
exposure (Cmax and AUC) for any dose level to 
be administered will not exceed the limiting 
exposure criteria based on the plasma NOAEL 
dose from the monkey 6-week GLP tox study 
(Section 4.3.1). The DEC consists of the 
Principal Investigator (or appropriate 
designee), Medical Monitor, GSK Clinical 
Science Lead, GSK Study Delivery Lead, 
GSK Clinical Pharmacology Modelling and 
Simulation (CPMS) representative, a GSK 
Global Clinical Safety and Pharmacovigilance 
(GCSP) representative and a GSK Statistician. 
The GSK Medical Monitor and the GSK 
CPMS representative will remain unblinded 
for the dose escalation review throughout the 
course of the study. Additional internal GSK 
safety representatives may be consulted and 
included in the dose escalation decision 
making, in a blinded or unblinded manner as 
deemed necessary by the DEC. Details of the 
DEC membership, data to be reviewed, and 
stopping criteria will be outlined in the DEP 
(see also Section 10.1.5). 
REVISED The decision to proceed to the next 
dose level, to progress through each 
Part/Cohort, and to include an additional 
cohort/dose level (if necessary) will be made 
by the DEC. The anticipated mean plasma 
exposure (Cmax and AUC) for any dose level to 
be administered will not exceed the limiting 
exposure criteria based on the plasma NOAEL 
dose from the monkey 6-week GLP tox study 
(Section 4.3.1)  
This deleted text was moved to 
Section 10.1.5 


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Section # and Name 
Description of Change 
Brief Rationale 
4.4 Criteria for Dose 
Escalation and for 
Progressing Between 
Parts of the Study 
PREVIOUS: The possibility to include 
additional cohort(s), to investigate higher 
dosing levels (with exposure capped at 
monkey NOAEL), might be considered in the 
event that no safety signals are observed in the 
three planned cohorts. 
REVISED: In the event the observed exposure 
at the starting dose (1 mg) is substantially 
higher than the corresponding predicted 
exposure, the next dose will be revised to 
produce a 2-3-fold increment in exposure, 
consistent and no greater than the currently 
planned increments, if the dose escalation 
stopping criteria are not met. 
 
4.4 Criteria for Dose 
Escalation and for 
Progressing Between 
Parts of the Study 
PREVIOUS: Dose escalation decisions will be 
based on data obtained from 4 or more 
participants on active treatment at the prior 
dose level and will be approximately 2 weeks 
between dose escalation; approximately 4 
weeks between Parts 1 and 2 (Refer to DEP). 
The review data set will at minimum consist of 
AE listings, safety labs, electrocardiograms 
(ECG), vital signs (VS), and PK results 
derived from at least 24-hour plasma profiles 
Pharmacodynamic (PD) data will be reviewed 
as available but will not be required for an 
escalation decision.  Flagged vital signs, 
cardiac monitoring (telemetry), ECG and 
laboratory findings will also be reviewed. The 
decision to switch to the GI resistant capsules 
will be made by the DEC after review of the 
AE listings. 
Additional detail in protocol to 
describe dose level progression. 
References made to the Dose 
Escalation Plan and charter have 
been changed to reference 
Section 4 throughout the 
protocol. 


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Section # and Name 
Description of Change 
Brief Rationale 
 
REVISED: GSK will conduct regular dose 
escalation meetings throughout the course of 
Part 1 and Part 2. Each meeting will be 
scheduled to occur at the end of each cohort 
and / or treatment period on data obtained after 
each dose level. Dose escalation decisions will 
be based on data obtained from 4 or more 
participants on active treatment at the prior 
dose level. It will be approximately 2 weeks 
between dose escalation in Part 1 and 
approximately 4 weeks between Parts 1 and 2. 
The review data set will consist at minimum 
AE listings, safety labs, electrocardiograms 
(ECG), vital signs (VS), and PK results 
derived from at least 24-hour plasma profiles 
Pharmacodynamic (PD) data will be reviewed 
as available but will not be required for an 
escalation decision. Flagged vital signs, 
cardiac monitoring (telemetry), ECG and 
laboratory findings will also be reviewed. The 
decision to switch to the gastro resistant 
capsules will be made by the DEC after review 
of the AE listings and will be based on clinical 
judgement. 
 
4.4 Criteria for Dose 
Escalation and for 
Progressing Between 
Parts of the Study 
Progression to the next higher dose level will 
be halted if: 
• 
Two or more participants in the same 
cohort experience severe non-serious 
adverse reactions (i.e. severe non-serious 
adverse events considered as at least 
possibly related to the administration of 
GSK3884464), independent of within or 
not within the same system-organ-class; 
and independent of whether it is related 
to study intervention or not. 
• 
Any participant experiences a serious 
adverse reaction (i.e. a serious adverse 
event considered at least possibly related 
to the administration of GSK3884464). 
• 
Three or more participants in a cohort 
experience the same adverse event of 
moderate severity that can be reasonably 
attributed to dosing with GSK3884464. 
Additional detail in protocol to 
describe dose level progression 
based on Adverse Events. 


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Section # and Name 
Description of Change 
Brief Rationale 
 
The dose escalation will stop, and no further 
participants will be dosed at that dose level or 
any higher level. Lower doses and progression 
to Part 2 may occur. If after consultation the 
Sponsor deems that dosing can resume at that 
level or higher, the Sponsor will submit an 
application for a substantial amendment to the 
Regulatory Agency  
 
4.4 Criteria for Dose 
Escalation and for 
Progressing Between 
Parts of the Study 
PREVIOUS: Criteria for progression from one 
part of the study to the next are further 
expanded upon in the dose escalation charter, 
to be completed prior to the commencement of 
the study. 
REVISED: The dose levels in Part 2 will only 
be started after the same or higher dose 
cohorts are complete in Part 1 with no dose 
escalation stopping criteria having been met. 
In addition, the maximum dose for Part 2 
cannot exceed the maximum dose in Part 1 
Expansion of criteria for dose 
expansion from Part 1 to Part 2. 
5.2 Exclusion Criteria 
PREVIOUS: Serum troponin I or troponin-T 
greater than 2x the upper limit of normal 
Alanine transaminase (ALT) > 1.5x upper 
limit of normal (ULN).  
Bilirubin >1.5x ULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).  
 
REVISED: Serum troponin I or troponin-T 
greater than the upper limit of normal (ULN). 
Alanine transaminase (ALT) > ULN.  
Bilirubin > ULN.  
PREVIOUS: 
Unable to refrain from the use of prescription 
or non-prescription drugs, including vitamins, 
herbal and dietary supplements (including St 
John’s Wort)  
1. Clarification of Exclusion 
criteria to match Risk table 
and meet Healthy Volunteer 
expectations.  
2. Update exclusionary 
prescription and non-
prescription medications 
3. Update eGFR equation 


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Section # and Name 
Description of Change 
Brief Rationale 
 
REVISED: Unable to refrain from the use of 
prescription or non-prescription drugs, 
including vitamins, herbal and dietary 
supplements within 7 days (or 14 days if the 
drug is a potential enzyme inducer [e.g. 
Rifampin, St John’s Wort extract]) 
PREVIOUS: Estimated glomerular filtration 
rate (eGFR)  90 ml/minute/1.73m2 calculated 
by the Cockroft-Gault equation as below: 
eGFR = [[140 - age(yr)] *weight(kg)] 
/ [72*serum Cr(mg/dL)]  
(multiply by 0.85 for women).    
REVISED: Estimated glomerular filtration 
rate (eGFR)  90 ml/minute/1.73m2 calculated 
by the CKD-EPI equation as below:  
eGFR = 141 x min (SCr/κ, 1)α x max(SCr 
/κ, 1)-1.209 x 0.993Age x 1.018 [if 
female] x 1.159 [if Black] 
 
6.8 Concomitant 
Therapy 
PREVIOUS: However, since glucuronidation 
was a predominant metabolic route in human 
hepatocytes, co-administration of a potent 
inducer, e.g., phenytoin and rifampin, can 
result in decreased levels of GSK3884464. 
Contraindication or replacement thereof is 
recommended. Please refer to the SRM for an 
exclusion criteria list of Prior and Concomitant 
medications. 
REVISED:  However, since glucuronidation 
was a predominant metabolic route in human 
hepatocytes, co-administration of a potent 
inducer, e.g., phenytoin and rifampin, can 
result in decreased levels of GSK3884464. 
Contraindication or replacement thereof is 
recommended. The following classes of 
therapies and examples are prohibited for 
concomitant or prior use within 2 weeks: 
Anticonvulsants: carbamazepine, 
oxcarbazepine, phenobarbital, phenytoin, 
primidone  
Antimycobacterials: rifampin, rifapentine  
Estrogen containing oral contraceptive: 
ethinylestradiol/levonorgestrel 
Additional detail in protocol to 
describe the excluded classes of 
prohibited concomitant 
medications. 


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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1.3 Dose 
Expansion Criteria 
PREVIOUS: If ≥ 2 subjects in any dose level 
experience an isolated ALT≥3xULN (on 
active treatment) then the following dose 
expansion criteria applies: 4 additional 
subjects on active and 2 additional subjects on 
placebo will be recruited at the same dose 
level.  
REVISED: If ≥ 2 subjects in any dose level 
experience an isolated ALT≥3xULN (on 
active treatment) then the following dose 
expansion criteria applies: Four additional 
subjects on active and 2 additional subjects on 
placebo will be recruited at the same dose 
level. Any cohort expansion will be contingent 
on approval of an amended protocol by the 
UK ethics board and the MHRA. 
MHRA requested cohort 
expansion result in protocol 
amendment to be approved by 
MHRA and UK ethics board. 
7.1.8 Safety Stopping 
Criteria for Dose 
Escalation / Study 
Progression in 
Healthy Participants 
Progression to the next higher dose level will 
be halted if: 
• 
Two or more participants in the same 
cohort experience severe non-serious 
adverse reactions (i.e. severe non-serious 
adverse events considered as at least 
possibly related to the administration of 
GSK3884464), independent of within or 
not within the same system-organ-class; 
and independent of whether it is related 
to study intervention or not. 
• 
Any participant experiences a serious 
adverse reaction (i.e. a serious adverse 
event considered at least possibly related 
to the administration of GSK3884464). 
• 
Three or more participants in a cohort 
experience the same adverse event of 
moderate severity that can be reasonably 
attributed to dosing with GSK3884464. 
The dose escalation will be temporarily halted, 
and no further participants will be dosed until 
a full safety review of the study has taken 
place. Relevant reporting and discussion with 
the GSK medical monitor, relevant GSK 
personnel, and with UK ethics board and the 
MHRA will then take place prior to any 
resumption of dosing, which may include the 
evaluation of lower doses. 
This section was moved to 
Section 4.4 


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Section # and Name 
Description of Change 
Brief Rationale 
8.4.4 Sample Analysis 
PREVIOUS: Analysis of GSK3884464 in 
plasma and urine samples will be performed 
under the control of GSK BIB IVIVT.  
Concentrations of GSK3884464 will be 
determined using the currently approved 
bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site for a 
specified portion of the retention period. 
Additional parameters may be analyzed if 
determined appropriate; more details will be 
provided in the Statistical Analysis Plan 
(SAP). Processing, storage and shipping 
procedures are provided in the SRM.  
REVISED: Analysis of GSK3884464 in 
plasma and urine samples will be performed 
under the control of GSK BIB IVIVT.  
Concentrations of GSK3884464 will be 
determined using the currently approved 
bioanalytical methodology. The bioanalytical 
site will be detailed in the relevant sample 
processing documents (e.g. SRM, CLW, 
SOW) and raw data will be archived in the 
GSK R&D archives. 
Updated description of where 
documents and raw date will be 
archived. 
10.1.5 Dose 
Escalation Committee 
PREVIOUS: The DEC will also review the 
data to determine if participants are 
experiencing higher than expected adverse GI 
symptoms based on responses the review of 
adverse events. Further details are in the DEP. 
REVISED: The DEC consists of the Principal 
Investigator (or appropriate designee), Site 
Senior Clinical Development Manager, 
Medical Monitor, GSK Clinical Science Lead, 
GSK Study Delivery Lead, GSK Clinical 
Pharmacology Modelling and Simulation 
(CPMS) representative, GSK Drug 
Metabolism and Pharmacokinetics Lead, a 
GSK Global Clinical Safety and 
Pharmacovigilance (GCSP) Lead, GSK 
Clinical Biomarker Lead, GSK Study Data 
Manager, and a GSK Statistician. The GSK 
Medical Monitor and the GSK CPMS 
representative will remain unblinded for the 
dose escalation review throughout the course 
of the study. 
Further description of the Dose 
Escalation Committee in the 
protocol and movement of 
committee description from 
Section 4.4. 


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Section # and Name 
Description of Change 
Brief Rationale 
 
Additional internal GSK safety representatives 
may be consulted and included in the dose 
escalation decision making, in a blinded or 
unblinded manner as deemed necessary by the 
DEC.  
The DEC will be used to ensure data integrity 
in dose selection decisions by performing 
clinical data review and appropriate quality 
control of data prior to making dose selection 
decisions for this study. The Committee will 
review emerging data and recommend changes 
to the study, and review safety parameters 
during the study.  
The DEC will also review the data to 
determine if participants are experiencing 
higher than expected adverse GI symptoms 
based on responses the review of adverse 
events. Further details are in the DEP. 
 
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
PREVIOUS: Other Screening Tests 
• 
Follicle-stimulating hormone and 
estradiol (as needed in women of non-
childbearing potential only) 
• 
Urine alcohol and drug screen (to include 
at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and 
benzodiazepines5 
• 
Urine cotinine level 
• 
Estimated glomerular filtration rate 
(eGFR) will be calculated using the 
CKD-EPI formula 
• 
COVID-19 testing6 
• 
Serology [(HIV antibody, hepatitis B 
surface antigen [HBsAg], and hepatitis C 
virus antibody)] -- if second generation 
Hepatitis C antibody positive, a hepatitis 
C antibody Chiron RIBA immunoblot 
assay (or other third generation 
immunoassay) or Hepatitis C Virus RNA 
test (either quantitative or qualitative) 
should be reflexively performed on the 
same sample to confirm the result)  
REVISED: Other Screening Tests 
• 
Follicle-stimulating hormone and 
estradiol (as needed in women of non-
childbearing potential only) 
• 
Urine cotinine level 
Removal of Urine alcohol and 
drug screen as this is performed 
as a breath test and footnote. 


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Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Estimated glomerular filtration rate 
(eGFR) will be calculated using the 
CKD-EPI formula 
• 
COVID-19 testing6 
• 
Serology [(HIV antibody, hepatitis B 
surface antigen [HBsAg], and hepatitis C 
virus antibody)] -- if second generation 
Hepatitis C antibody positive, a hepatitis 
C antibody Chiron RIBA immunoblot 
assay (or other third generation 
immunoassay) or Hepatitis C Virus RNA 
test (either quantitative or qualitative) 
should be reflexively performed on the 
same sample to confirm the result)  
PREVIOUS: 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 CRF will only 
collect drug screen results of those that are 
positive. 
PREVIOUS: Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones by 
dipstick 
• 
Microscopic examination (if blood or 
protein is abnormal)  
• 
Urine albumin:creatinine ratio 
• 
Urine creatinine 
• 
Urine phosphate (only in the event a 
participant has persistent serum 
hypophosphataemia)4 
• 
eGFR 
REVISED: Other Safety Assessments 
• 
N-terminal -proBNP 
• 
hs Troponin 
• 
eGFR 
Removal of incorrect placement 
of eGFR from Routine 
Urinalysis and added to Other 
Safety Assessments 


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11. 
REFERENCES 
Axelsson AS, et al. Sulforaphane reduces hepatic glucose production and improves 
glucose control in patients with type 2 diabetes. Sci. Transl Med. 2017; 9:eaah4477. 
(2017). 
Darpo B, Garnett C, Benson CT, Keirns J, Leishman D, et. al. Cardiac safety research 
consortium: Can the thorough QT/QTc study be replaced by early QT assessment in 
routine clinical pharmacology studies? Scientific update and a research proposal for a 
path forward. Am Heart J. 2014; 168:262-72. 
Dinkova- Kostova AT, Kostov RV, Canning P. KEAP1, the cysteine-based mammalian 
intracellular sensor for electrophiles and oxidants. Arch Biochem Biophys. 2017; 617:84-
93. 
Drazner MH. The progression of hypertensive heart disease. Circulation 2011; 123:327-
334 (2011). 
European Medicines Agency. "Guideline on the investigation of drug interactions." 
Committee for Human Medicinal Products (CHMP) (2012). 
GlaxoSmithKline Document Number 2020N459103_01. Prediction of human PK 
parameters for GSK3884464. 19-Jan-2021 
GlaxoSmithKline Document Number 2021N467036_00. Preliminary Predictions for 
Enzyme Inhibition/Induction Mediated, and Transporter Inhibition-Mediated Perpetrator 
Drug-Drug Interactions by GSK3884464 Using Physiologically Based Pharmacokinetic 
Modelling. 27 May 2021 
GlaxoSmithKline Document Number 2021N473852_00. Pharmacodynamic Simulations 
for GSK3884464 in Humans based on non-clinical data. 05-May-2021 
GlaxoSmithKline Document Number RPS-CLIN-000167. GSK3884464 Investigator's 
Brochure. 07-Jun-21. 
Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards 
D.  Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the 
James biliary disposition of drugs. Br J Clin Pharmacol. 2011;72:133–142 
James LP Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharm.acokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784. 
Shah KS, et al. Heart failure with preserved, boarderline and reduced ejection fraction: 5 
year outcomes. J Am Coll Cardiol. 2017; 70:2476–2486. 
Sharma RS,  et al. Experimental nonalcoholic steatohepatitis and liver fibrosis are 
ameliorated by pharmacologic activation of Nrf2 (NF- E2 p45-related factor 2). Cell Mol 
Gastroenterol Hepatol. 2018; 5:367–398. 


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Shimizu I & Minamino T. Physiological and pathological cardiac hypertrophy. J Mol 
Cell Cardiol.2016; 97:245-262. 
Tecfidera Pharmaceuticals (Revised February 2020). Bardoxylone. Prescribing 
Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf 
US Food and Drug Administration. "In Vitro Drug Interaction Studies – Cytochrome 
P450 Enzyme – and Transporter-Mediated Drug–Drug Interaction Studies: Guidance for 
Industry." US Food and Drug Administration, Silver Spring, MD (2020). 


Si g nat ure Pa ge f or  2 1 3 3 7 6 T M F- 1 4 5 7 7 7 3 9 v 2. 0
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Date of si g nat ure: 0 6- A pr- 2 0 2 2 1 4: 5 8: 2 9 G M T + 0 0 0 0
P P D

SAP_001.pdf: 
 
 
 
 
Reporting and Analysis Plan 
 
 
Study ID: 213376 
 
Official Title of Study A Two-Part First Time in Human (FTIH) Study to Evaluate 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Oral Doses 
of GSK3884464 in a Randomized, Double Blind, Placebo-Controlled, Dose Escalation Study in 
Healthy Participants 
 
NCT ID-NCT05044325     
 
Date of Document: 16-Mar-2023 
 
 


CONFIDENTIAL 
 
Page 1  
 
Information Type: 
Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title:   
A Two-Part First Time in Human (FTIH) Study to Evaluate 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
of Single and Repeat Oral Doses of GSK3884464 in a 
Randomized, Double Blind, Placebo-Controlled, Dose 
Escalation Study in Healthy Participants 
 
Study Number: 
213376 
Compound Number: GSK3884464 
Abbreviated Title: 
A FTIH study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single and repeat 
doses of GSK3884464 in healthy participants. 
 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s): 2021-001724-17  
 
Registry 
 
ID 
Clintrials.gov  
NCT05044325 
 
 
 
Copyright 2023 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


C O N FI D E N TI A L  
 
P a g e 2   
 
T A B L E O F C O N T E N T S  
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.  
E sti m a n d s  ...................................................................................... 9  
1. 2.  
St u d y D e si g n  .............................................................................................. 1 1  
2.  
S T A TI S TI C A L H Y P O T H E S E S  ............................................................................... 1 4  
3.  
A N A L Y SI S S E T S  ................................................................................................... 1 5  
4.  
S T A TI S TI C A L A N A L Y S E S  ..................................................................................... 1 6  
4. 1.  
G e n er al C o n si d er ati o n s  .............................................................................. 1 6  
4. 1. 1.  
G e n er al M et h o d ol o g y  .................................................................. 1 6  
4. 1. 2.  
B a s eli n e D efi niti o n  ....................................................................... 1 6  
4. 2.  
S af et y A n al y s e s  .......................................................................................... 1 6  
4. 2. 1.  
E xt e nt of E x p o s ur e  ...................................................................... 1 6  
4. 2. 2.  
A d v er s e E v e nt s ............................................................................ 1 6  
4. 2. 3.  
A d diti o n al S af et y A s s e s s m e nt s (if a p pli c a bl e)  .............................. 1 7  
4. 3.  
Pri m ar y P h ar m a c o ki n eti c A n al y s e s  ............................................................. 1 8  
4. 3. 1.  
D efi niti o n of e n d p oi nt s/ e sti m a n d s  ................................................ 1 8  
4. 3. 2.  
M ai n a n al yti c al a p pr o a c h  ............................................................. 2 2  
4. 4.  
S e c o n d ar y E n d p oi nt( s) A n al y s e s  ................................................................ 2 4  
4. 4. 1.  
S e c o n d ar y e n d p oi nt  ..................................................................... 2 5  
4. 6.  
I nt eri m A n al y s e s ......................................................................................... 2 9  
4. 7.  
C h a n g e s t o Pr ot o c ol D efi n e d A n al y s e s  ....................................................... 3 0  
5.  
S A M P L E SI Z E D E T E R MI N A TI O N  ......................................................................... 3 1  
6.  
S U P P O R TI N G D O C U M E N T A TI O N  ....................................................................... 3 2  
6. 1.  
A p p e n di x 1 St u d y P o p ul ati o n A n al y s e s  ....................................................... 3 2  
6. 1. 1.  
P arti ci p a nt Di s p o siti o n  ................................................................. 3 2  
6. 1. 2.  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  .................................. 3 2  
6. 1. 3.  
Pr ot o c ol D e vi ati o n s  ...................................................................... 3 2  
6. 1. 4.  
Pri or a n d C o n c o mit a nt M e di c ati o n s  ............................................. 3 3  
6. 1. 5.  
St u d y I nt er v e nti o n C o m pli a n c e  .................................................... 3 3  
6. 2.  
A p p e n di x 2 D at a D eri v ati o n s R ul e  .............................................................. 3 3  
6. 2. 1.  
Crit eri a f or P ot e nti al Cli ni c al I m p ort a n c e  ...................................... 3 3  
6. 2. 2.  
St u d y P eri o d  ................................................................................ 3 6  
6. 2. 3.  
St u d y D a y a n d R ef er e n c e D at e s  .................................................. 3 6  
6. 2. 4.  
A s s e s s m e nt Wi n d o w  ................................................................... 3 7  
6. 2. 5.  
M ulti pl e m e a s ur e m e nt s at O n e A n al y si s Ti m e P oi nt  .................... 3 7  
6. 2. 6.  
H a n dli n g of P arti al D at e s  ............................................................. 3 7  
6. 2. 7.  
E arl y P K A c c e s s K e y A cti viti e s  .................................................... 3 8  
6. 2. 8.  
A b br e vi ati o n s  ............................................................................... 3 9  
6. 2. 9.  
Tr a d e m ar k s  ................................................................................. 4 1  
7.  
R E F E R E N C E S  ....................................................................................................... 4 2  
C CI


CONFIDENTIAL 
 
Page 3  
 
Version history 
SAP 
Version 
Approval 
Date 
Protocol 
Version 
(Date) 
on 
which 
SAP is 
Based 
Change 
Rationale 
SAP 
20 Sep 
2021 
19-
AUG-
2021 
Not Applicable 
Original version 
SAP 
amendment 
1 
16 Mar 
2023 
06-APR-
2022 
All sections: 
Changes made to 
align with the latest 
protocol amendment. 
Few sections have 
been rearranged.  
Protocol Amendment 
Section 1.1.1: A 
table added for the 
estimands 
framework. 
To ensure clear 
understanding of the 
intercurrent events and 
corresponding strategies  
Section 4.3.2, 
Section 4.4.1.1, 
Section 4.5.1.2: 
Definition of 
statistical models 
modified.  
To allow for correct and 
clear description of 
analyses.   
Section 4.3.2: Level 
of significance 
changed to 10% for 
all PK analyses.  
Modified as per the 
suggestion from CPMS 
team.   
Section 6.1.4: 
Wording for 
reporting modified.  
To align with the 
requirements reporting 
standards. 
Section 6.2.1: PCI 
ranges updated.  
To allow reporting of 
only the critical 
parameters.  


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SAP 
Version 
Approval 
Date 
Protocol 
Version 
(Date) 
on 
which 
SAP is 
Based 
Change 
Rationale 
Section 6.2: List of 
abbreviations added.  
To allow for better 
understanding and 
interpretation. 
 


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report (CSR) for Study 213376. Details of the final analyses, descriptive study 
population analyses such as summary of demography and baseline characteristics and 
additional detail with regards to data handling conventions are provided in this document.  
 
Details about the planned displays are provided in the Output and Programming 
Specification (OPS) document. 
 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To characterize the safety and 
tolerability profile of GSK3884464 in 
healthy participants. 
 
 
 
 
• Number and percentage of healthy 
participants with adverse events. 
• Clinically significant changes from 
baseline in laboratory values, vital 
signs, continuous telemetry, 12-lead 
electrocardiogram (ECG), and 
echocardiograms (in Part 2 only) up 
to and including the follow up visit 
(7-10 days post final dose). 
• To characterize the plasma 
Pharmacokinetics (PK) of 
GSK3884464 in healthy participants. 
• Plasma pharmacokinetic parameters 
following single oral doses including 
Area Under the Curve (AUC)(0-t), 
AUC(0-∞), maximum concentration 
(Cmax), time to maximum observed 
plasma drug concentration (tmax), and 
terminal half-life (t½). 
• Plasma pharmacokinetic parameters 
following repeat oral doses including 
AUCτ, Cmax, trough plasma 
concentration (Cτ), peak-to-trough 
(PTT) ratio (Cmax /Cτ), tmax, t½, 
accumulation ratios based on AUCτ 
(RAUC), on Cmax (RCmax), and on Cτ 
(RCτ). 


C O N FI D E N TI A L  
 
P a g e 6   
 
O bjecti ves  
E n d p oi nts  
Sec o n dar y  
 
•  T o e val uate tar get e n ga ge me nt 
f oll o wi n g si n gle a n d re peat oral d oses 
of G S K 3 8 8 4 4 6 4 i n healt h y 
partici pa nts.  
•  Ma xi m u m c ha n ges fr o m baseli ne i n 
N Q O 1 m R N A i n w h ole bl o o d p ost 
treat me nt wit h G S K 3 8 8 4 4 6 4 i n all 
parts of t he st u d y.  
C CI


C O N FI D E N TI A L  
 
P a g e 7   
 
O bjecti ves  
E n d p oi nts  
C CI


C O N FI D E N TI A L  
 
P a g e 8   
 
O bjecti ves  
E n d p oi nts  
 
 
C CI


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1.1.1. 
Estimands 
Table 1 describes the possible intercurrent events and the corresponding strategies to be used. Once a participant discontinues study 
treatment, they will proceed to follow up. Individual participant data will be included in data listings regardless of the strategy followed 
for the analyses. 
Table 1 
Estimands 
• Treatment: GSK3884464 or Placebo  
• Population: Healthy Volunteers 
 
Endpoint 
Population Level Summary 
Measure 
Intercurrent Event –Corresponding Estimand 
Strategy 
Primary Objective (1) - To characterize the safety and tolerability profile of GSK3884464 in healthy participants. 
• Number and percentage of healthy 
participants with adverse events 
(Part 1 and 2 of the study) 
• 
Clinically significant changes from 
baseline in laboratory values, vital 
signs, continuous telemetry, 12-
lead ECG, and echocardiograms 
(in Part 2 only) up to and including 
the protocol defined follow up. 
Frequency and percentages; 
Descriptive summary including 
mean, median, standard deviation, 
minimum, maximum, reported 
separately for each dose.  
1) Study treatment discontinuation – While-on-
treatment strategy will be used. Data until the 
protocol defined last follow-up day post treatment 
discontinuation will be considered for analysis. 
2) Use of concomitant/prohibited medication – 
Treatment policy strategy. The data post 
consumption of concomitant/prohibited 
medications (intercurrent event) will be analysed 
as is. 
Primary Objective (2) - To characterize the plasma PK of GSK3884464 in healthy participants. 
• Plasma PK parameters following 
single oral doses including AUC(0-
t), AUC(0-∞), Cmax, tmax, and t½. 
• Descriptive statistics for log 
transformed and untransformed 
data.  
1) Study treatment discontinuation – While-on-
treatment strategy will be used. Data until the 
protocol defined last follow-up day post treatment 
discontinuation will be considered for analysis. If 


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Endpoint 
Population Level Summary 
Measure 
Intercurrent Event –Corresponding Estimand 
Strategy 
• Plasma PK parameters following 
repeat oral doses including AUCτ, 
Cmax, Cτ, PTT, tmax, t½, RAUC, 
RCmax, and RCτ.  
• 
Other derived PK parameters 
listed in Table 2 of Section 4.3.1.1. 
• Estimate of slope and 
corresponding 90% Confidence 
Interval (CI) for dose 
proportionality and steady state 
analyses. 
a subject withdraws consent during a period, the 
missing data post withdrawal will not be imputed. 
The PK parameters of that partially completed 
period will be calculated as data permits.  
2) Use of concomitant/prohibited medication – 
Treatment policy strategy will be used. The data 
post consumption of concomitant/prohibited 
medications (intercurrent event) will be analysed 
as collected. 
3) Site being shut down due to COVID-19 – The 
missing data after shutdown will be assumed to be 
missing at random. The PK parameters of the last 
fully or partially completed period will be 
calculated as data permits. 
Secondary Objective - To evaluate target engagement following single and repeat oral doses of GSK3884464 in healthy participants 
• Maximum changes from baseline 
in NQO1 mRNA in whole blood 
post treatment with GSK3884464 
in all parts of the study. 
• Descriptive statistics for log 
transformed or untransformed 
data  
• Mean and corresponding 90% CI 
from the fitted model (Section 
4.3.2). 
1) Study treatment discontinuation – While-on-
treatment strategy will be used. Data until the 
protocol defined last follow-up day post treatment 
discontinuation will be considered for analysis. 
2) Use of concomitant/prohibited medication – 
Treatment policy strategy will be used. The data 
post consumption of concomitant/prohibited 
medications (intercurrent event) will be analysed 
as collected. 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
Overall design: 
 
Part 1 – Single Dose: 
 
 
Part 2 – Repeat Dose: 
 
 
 
 


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Overview of Study Design and Key Features 
Part 2 cohorts 4 and 5: 
 
 
Part 2 cohort 6: 
 
 
Design 
Features 
This FTIH study, 213376, will be a randomized, double-blind, placebo-
controlled study of the oral administration of GSK3884464 in healthy 
participants. As this will be the first time GSK3884464 will be given to 
humans, the study design may change based on emerging data as the 
study progresses. 
 
The study is planned to have two parts and will be conducted at a single 
center. 
 
Part 1 (Single Dose): 
 
This will be a 3-period crossover design, single dose (SD), dose 
escalation study in healthy participants. Participants will receive 
GSK3884464 or matching placebo as an oral dose. There will be up to 
three cohorts with 9 participants in each cohort, each cohort will have 
up to 3 time periods. 
 
Part 2 (Repeat Dose): 
 
This will be a sequential design, 14-day (Cohorts 4 and 5) and up to 21-
days (Cohort 6) repeat-dose (RD), dose escalation study in healthy 
participants. It will consist of up to 3 ascending dose cohorts with 8 
participants per cohort. Participants in each cohort will receive 
GSK3884464 or matching placebo; not all participants will receive 
placebo. 
 
 


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Overview of Study Design and Key Features 
Study 
intervention 
Part 1 (Single Dose): 
This part will be a 3-period crossover design, SD, dose escalation study 
in healthy participants. Each participant will participate in up to 3 
dosing periods and will receive up to 2 doses of GSK3884464 and 1 
dose of placebo in a randomized fashion. There will be a minimum of 7 
days (or 5 half-lives, whichever is longer) washout period between 
dosing in each period. 
 
Each cohort will have approximately 9 participants who will be 
randomized to one of 3 treatment sequences, with 3 participants per 
sequence in a 1:1:1 ratio. Within each sequence, an increasing dose of 
GSK3884464 will be administered in each period. Within each period, 
allocation to GSK3884464 and placebo will be 2:1.  
 
Part 2 (Repeat Dose): 
 
This part will be a sequential design, 14-day (Cohorts 4 and 5) and up to 
21-day (Cohort 6) RD, dose escalation study in healthy participants. 
Each cohort will consist of approximately 8 participants. Participants in 
each cohort will receive GSK3884464 or matching placebo in a 3:1 
ratio. 
 
Study 
intervention 
Assignment 
Part 1 (Single Dose): 
Each cohort will have approximately 9 participants and will be 
randomized to one of 3 treatment sequences, with 3 participants per 
sequence in a 1:1:1 ratio. Within each sequence, an increasing dose of 
GSK3884464 will be administered in each period. Within each period, 
allocation to GSK3884464 and placebo will be 2:1.  
Part 2 (Repeat Dose): 
Each dose cohort will have approximately 8 participants and will be 
randomized to receive either GSK3884464 or placebo in sequential 
design using a 3:1 allocation ratio. 
Interim 
Analysis 
No formal interim analysis is planned; data may be analyzed at the end 
of each completed cohort/study Part. Safety and PK data will be 
reviewed by the Dose Escalation Committee (DEC) before dose 
escalation in each study part, and between study parts. 
 


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2. 
STATISTICAL HYPOTHESES  
The focus of this FTIH study is to evaluate the safety, tolerability, PK and PD of 
GSK3884464. As such there is no formal hypothesis being tested. However, wherever 
appropriate, an estimation approach will be taken, and point estimates and CIs will be 
constructed.  
 
Intercurrent events, the estimand strategy to handle such events and the changes to the 
respective analyses to implement the strategies are highlighted in Section 1.1.1. 


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3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Enrolled 
• All participants who sign the informed 
consent form (ICF). 
• Study 
Population 
Randomized  
• All participants who were randomly 
assigned to treatment in the study. 
• 
This population will be based on the 
treatment the participant was randomized to. 
• Study 
Population 
Safety 
• All randomized participants who take at 
least 1 dose of study intervention. 
• Participants will be analysed according to 
the intervention they actually received. 
• Safety 
PK 
• All participants in the Safety population 
who had at least one non-missing PK 
assessment (Non-quantifiable [NQ] values 
will be considered as valid PK assessments). 
• This population will be based on the 
treatment the participant actually received.* 
• PK 
PD 
• Participants in the Safety population with 
baseline and at least one post baseline PD 
measure (e.g., NQO1 mRNA) 
• PD  
*Subjects on active only will be included in the PK analysis set.


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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Analyses planned will be mainly descriptive in nature involving frequencies and 
percentages for categorical variables and number of subjects (n), mean, standard 
deviation, median, minimum and maximum for continuous variables. Where appropriate, 
statistical modelling will be performed and point estimates with CIs will be constructed 
(for e.g., analysis of evaluation of dose proportionality, steady state). 
4.1.2. 
Baseline Definition 
Unless stated otherwise, the baseline value will be the latest pre-dose assessment with a 
non-missing value, including those from unscheduled visits. If time is not collected, Day 
1 assessments are assumed to be taken prior to first dose and used as baseline. When pre-
dose data is completely missing for a subject, then no derivation will be performed, and 
the baseline will be set to missing. 
For each period within a cohort, the period baseline is defined in a similar manner, by 
considering the latest available non-missing pre-dose assessment in that period. 
 
Where pre-dose data is captured multiple times, the baseline will be defined as the mean 
of the assessments (e.g., Triplicate measurements for all BP readings.) 
 
4.2. 
Safety Analyses 
The primary objectives of this study include the assessment of the safety and tolerability 
of single and repeat ascending doses in healthy participants. 
The safety analyses will be based on the safety population, unless otherwise specified. 
The intercurrent events mentioned in Section 1.1.1. along with the corresponding 
estimand strategies will be considered for these analyses. 
4.2.1. 
Extent of Exposure 
The extent of exposure will be summarised using GSK Core Data Standards. Further 
details of the planned displays are given in the OPS. 
4.2.2. 
Adverse Events 
Adverse Events (AE) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionary. Adverse events analyses will be based on GSK 
Core Data Standards. The following displays for Adverse events shall be generated: All 
Adverse Events by System Order Class and Preferred Term, Adverse Events by 
maximum intensity, Common Serious and Non-Serious Adverse Events, Serious Adverse 


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Events, Drug-related Adverse Events. Further details of the planned displays are given in 
the OPS. 
 
4.2.2.1. 
Adverse Events of Special Interest (AESI) 
For this study, AESI represent moderate or severe increases in liver function analyses. 
Further details of the planned displays are given in the OPS and will be reported as data 
permit. 
 
4.2.2.2. 
COVID-19 Assessment and COVID-19 AEs 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
If required, some additional (optional) COVID-19 displays may be reported. Further 
details of the planned displays are given in the OPS. 
 
4.2.3. 
Additional Safety Assessments (if applicable) 
4.2.3.1. 
Laboratory Data 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, Core Urine Monitoring Assessments, Renal, 
Liver function tests, fasting serum insulin and other biomarkers will be based on GSK 
Core Data Standards. Based upon the concern ranges in Section 6.2.1, the laboratory test 
results will be categorized according to the normal range as low (below the lower limit), 
normal (within the normal range) and high (above the upper limit). Summary statistics for 
change from baseline will also be tabulated. The details of the planned displays are given 
in the OPS. 
4.2.3.2. 
Vital Signs 
The analyses of vital signs will be based on GSK Core Data Standards, unless otherwise 
specified. 
Mean Arterial Pressure (MAP) will be derived (Section 4.5.1.2) and reported in the 
summaries for vital signs.  
BMI will be computed for all the visits where weight information is available, using 
height from the screening visit. Derivation will be done using the standard formula.   
 
Further details of the planned displays and derivations are given in the OPS. 
4.2.3.3. 
ECG 
The analysis of 12 lead ECG and 24-hour telemetry along with any ECG findings will be 
reported according to the GSK Core Data Standards. 


C O N FI D E N TI A L  
 
P a g e 1 8   
 
T he Q Tc d ata a n al ysis will use t he c ollecte d val u es base d o n  t he f oll o wi n g Fri deri cia 
f or m ula: 
𝑄𝑇𝑐𝐹 =  𝑄𝑇
√𝑅𝑅
3
 
W here R R is t he d urati o n of R R i nter val  a n d a re prese nts  t he ti me ela pse d b et wee n t w o 
s uccessi ve R wa v es of t h e Q R S si g nal o n t he E C G.  
T he c ha n ges i n Q Tc val u es will be cate g orize d i nt o t he cli nical c o ncer n ra n ges w hic h are 
s pecific t o c h a n ges i n Q T c as me nti o ne d i n Secti o n 6. 2. 1 . A s u m mar y of c h a n ge i n Q Tc 
val ue will dis pla y t he n u m ber a n d perce nt a ge of s u bjects wit h a c ha n ge wit hi n eac h ra n ge 
f or t he w orst-case p ost -b aseli ne. S u bjects wit h missi n g baseli ne v al ues will b e e x cl u de d 
fr o m t his s u m mar y. 
F urt her details of t he pla n ne d dis pla ys are gi ve n i n t he O P S.  
 
4. 3.  
Pri m ar y P h ar m a c o ki n eti c A n al y s e s  
T he pri mar y o bje cti ves of t his st u d y i ncl u de t he assess me nt of t he P K of G S K 3 8 8 4 4 6 4 
f oll o wi n g si n gle a n d re peat asce n di n g d oses i n healt h y partici pa nts.  
All P K  a nal ys es will be base d o n t he P K p o p ulati o n , u nless ot her wise s pecifie d. 
4. 3. 1.  
D efi niti o n of e n d p oi nt s/ e sti m a n d s  
4. 3. 1. 1.  
D eri v e d P h ar m a c o ki n eti c P ar a m et er s  
 
P K para meters will be calc ulate d usi n g sta n d ar d n o n-c o m part me ntal a nal ysis ( N C A) 
acc or di n g t o c ur re nt w or ki n g practices a n d usi n g t he c urre ntl y s u p p orte d versi o n of 
Wi n N o nli n (versi o n 8. 2 or hi g her). All calc ulati o ns of n o n -c o m part me nt al para meters 
will be base d o n act u al sa m pli n g ti mes f or t he fi nal a nal ysis .  
 
F or plas ma P K para meter deri vati o n, N Q v al ues b ef ore t h e first meas ura ble c o nce ntr ati o n 
will be assi g ne d a val ue of zer o, w hile si n gle N Q val ues bet wee n meas ura ble 
c o nce ntr ati o ns, c o nsec uti ve N Q val ues b et wee n meas ura bl e c o nce ntrati o ns a n d a n y 
s u bse q ue nt meas ur a ble c o nce ntrati o ns, a n d N Q  val ue s after t he l ast meas ura ble 
c o nce ntr ati o n will be set t o missi n g . 
 
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PK parameters listed in Table 2 will be determined from the plasma concentration time 
data, provided there is enough evaluable data available for the calculations. Additional 
plasma PK parameters may be derived as data permit. 
 
Table 2 
Derivations for plasma PK parameters 
 
Parameter 
Parameter Description 
Part 1: 
Cmax 
 
Maximum observed concentration, determined directly from the 
concentration-time data. 
Cmax/D 
 
Maximum observed concentration normalized by dose: 
𝐶𝑚𝑎𝑥/𝐷= 𝐶𝑚𝑎𝑥
𝐷𝑜𝑠𝑒 
Tmax 
Time to reach Cmax, determined directly from the concentration-time 
data. 
Tlast 
Time of last quantifiable concentration 
t1/2 
Apparent terminal half-life will be calculated as: 
𝑡1/2 = 𝑙𝑛2
λ𝑧
  
NOTE: 𝜆𝑧 is the terminal phase rate constant. 
AUC(0-24h)* 
Area under the concentration-time curve from time zero to 24 
hours post-dose. 
AUC(0-t) 
Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration (C(t)) will be calculated 
using the linear trapezoidal rule for each incremental trapezoid and 
the loge trapezoidal rule for each decremental trapezoid (linear up/log 
down calculation method in Phoenix WinNonlin). 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity 
will be calculated as: 
𝐴𝑈𝐶(0−∞) = 𝐴𝑈𝐶(0−𝑡) + 𝐶(𝑡)
λ𝑧
 
NOTE: λ𝑧 is the terminal phase rate constant and C(t) is the last 
quantifiable concentration and 𝜆𝑧 is the terminal phase rate constant.  
AUC(0-∞)/D 
Area under the concentration-time curve extrapolated to infinity 
normalized by dose: 
𝐴𝑈𝐶(0−∞)/𝐷= 𝐴𝑈𝐶(0−∞)
𝐷𝑜𝑠𝑒
 
  
CL/F 
The apparent clearance will be calculated as Dose/AUC(0-∞) 
%AUCex 
The percentage of AUC(0-∞) obtained by extrapolation will be 
calculated as follows: 


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Parameter 
Parameter Description 
%𝐴𝑈𝐶𝑒𝑥= 𝐴𝑈𝐶(0−∞) −𝐴𝑈𝐶(0−𝑡)
𝐴𝑈𝐶(0− ∞)
 ×  100 
NOTE: % of the extrapolated area should not exceed 20%. Any value 
of %AUCex > 20% should be flagged and excluded from summary 
statistics if >40%. Derived parameter (AUC(0-∞), AUC(0-∞)/D and 
CL/F) values should be flagged or excluded from statistical analysis 
accordingly. 
λ𝑧 
λ𝑧 is the terminal phase rate constant. A minimum number of three 
data points in the terminal phase will be used starting at any post- Cmax 
data point, only those data points that are judged to describe the 
terminal log-linear decline will be used in regression.  
 
NOTE:  
• 
The adjusted correlation coefficient (R2 adjusted) in general 
should be greater than 0.85. Any value < 0.85 will be flagged but 
may be used at the PK Scientist’s discretion.  
• 
The interval used to determine λ𝑧 should be equal or greater than 
2- fold the estimated t1/2 or otherwise flagged and used at the PK 
Scientist’s discretion. 
All the derived parameters that include λz in their calculation (i.e., t½, 
AUC(0-∞), AUC(0-∞)/D, %AUCex, CL/F) will need to be flagged or 
excluded from statistical analysis accordingly.  
λ𝑧 upper limit 
The upper limit on time for values to be included in the calculation 
of λ𝑧. 
λ𝑧 lower limit 
The lower limit on time for values to be included in the calculation 
of λ𝑧. 
λ𝑧 number of points 
The number of time points used in computing λ𝑧. 
Part 2: 
Cτ 
Trough concentration prior to dosing, determined directly from 
concentration-time data at Day 2, 4, 7, 11, 14, and 15 for Part 2 
Cohorts 4 and 5 and at Day 2, 4, 7, 11, 18, 21, and 22 for Part 2 
Cohort 6. 
NOTE: Day 15 (Cohorts 4 and 5) and Day 22 (Cohort 6) trough 
concentrations are determined from concentration-time data at the end 
of dosing period for protocol defined last dosing day (24h post Day 14 
or 21 doses, in case of QD dosing). 
Cτ/D 
Trough concentration prior to dosing on last dosing day normalized by 
dose: 
𝐶𝜏/𝐷= 𝐶𝜏 (𝐷𝑎𝑦 𝑁)
𝐷𝑜𝑠𝑒
  
where N is the protocol defined last dosing day. 


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Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the 
concentration-time data after dosing on Day 1 and protocol defined 
last dosing day.  
Cmax/D 
Maximum observed concentration after dosing on protocol defined 
last dosing day normalized by dose: 
𝐶𝑚𝑎𝑥/𝐷= 𝐶𝑚𝑎𝑥 (𝐷𝑎𝑦 𝑁)
𝐷𝑜𝑠𝑒
  
where N is the protocol defined last dosing day. 
Tmax 
Time to reach Cmax, determined directly from the concentration-time 
data after dosing on Day 1 and protocol defined last dosing day. 
AUC(0-24)* 
Area under the concentration-time curve from time zero to 24 hours 
post-dose on Day 1. 
AUCτ 
Area under the concentration-time curve over the dosing interval will 
be calculated after dosing on the protocol defined last dosing day, 
using the linear trapezoidal rule for each incremental trapezoid and the 
loge trapezoidal rule for each decremental trapezoid (linear up/log 
down calculation method in Phoenix WinNonlin). 
AUCτ/D 
Area under the concentration-time curve over the dosing interval 
normalized by dose: 
𝐴𝑈𝐶𝜏/𝐷= 𝐴𝑈𝐶𝜏
𝐷𝑜𝑠𝑒 
AUC(0-∞)** 
Area under the concentration-time curve extrapolated to infinity 
on Day 1 will be calculated as: 
𝐴𝑈𝐶(0−∞) = 𝐴𝑈𝐶(0−𝑡) + 𝐶(𝑡)
λ𝑧
 
NOTE: λ𝑧 is the terminal phase rate constant and C(t) is the last 
quantifiable concentration on Day 1.  
t1/2 
Apparent terminal half-life will be calculated after dosing on Day 1**, 
and on the protocol defined last dosing day: 
𝑡1/2 = 𝑙𝑛2
λ𝑧
  
NOTE: 𝜆𝑧 is the terminal phase rate constant. 
λ𝑧 
λ𝑧 is the terminal phase rate constant (after dosing on Day 1** and after 
dosing on last dosing day). A minimum number of three data points in 
the terminal phase will be used starting at any post- Cmax data point, 
only those data points that are judged to describe the terminal log-
linear decline will be used in regression.  
 
NOTE:  
• 
The adjusted correlation coefficient (R2 adjusted) in general 
should be greater than 0.85. Any value < 0.85 will be flagged but 
may be used at the PK Scientist’s discretion.  


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Parameter 
Parameter Description 
• 
The interval used to determine λ𝑧 should be equal or greater than 
2- fold the estimated t1/2 or otherwise flagged and used at the PK 
Scientist’s discretion. 
All the derived parameters that include λz in their calculation (i.e., t½) 
will need to be flagged or excluded from statistical analysis 
accordingly.  
λ𝑧 upper limit 
The upper limit on time for values to be included in the calculation 
of λ𝑧. 
λ𝑧 lower limit 
The lower limit on time for values to be included in the calculation 
of λ𝑧. 
λ𝑧 number of points 
The number of time points used in computing λ𝑧. 
RAUC 
Accumulation ratio based on AUCτ will be calculated as: 
𝑅𝐴𝑈𝐶 = 
𝐴𝑈𝐶𝜏
𝐴𝑈𝐶(0−24)
 
RCmax 
Accumulation ratio based on Cmax will be calculated as: 
𝑅𝐶𝑚𝑎𝑥 = 𝐶𝑚𝑎𝑥(𝐷𝑎𝑦 𝑁) 
𝐶𝑚𝑎𝑥 (𝐷𝑎𝑦 1) 
where N is the protocol defined last dosing day. 
RCτ 
Accumulation ratio based on Cτ will be calculated as the ratio of Cτ for 
last dose (pre-dose on Day N) and Cτ after first dose (concentration at 
24 h post- Day 1 dose, in case of QD regimen): 
𝑅𝐶𝜏  = 𝐶𝜏(𝐷𝑎𝑦 𝑁) 
𝐶𝜏 (𝐷𝑎𝑦 2) 
where N is the protocol defined last dosing day. 
PTT 
Peak-to-trough ratio at steady-state will be calculated as: 
𝑃𝑇𝑇 = 𝐶𝑚𝑎𝑥(𝐷𝑎𝑦 𝑁)
𝐶𝜏(𝐷𝑎𝑦 𝑁)   
where N is the protocol defined last dosing day. 
*Other partial areas might be evaluated based on the dosing interval to be used in Part 2. AUC0-24 is 
relevant in case of QD repeat dosing regimen. 
**These Day 1 parameters might not be calculable, depending on half-life. 
 
 
4.3.2. 
Main analytical approach 
The intercurrent events mentioned in Section 1.1.1. along with the corresponding 
estimand strategies will be considered for the PK analyses. 
The summaries and models defined in this section will be reported only as data permits. 
4.3.2.1. 
Descriptive Statistics 
The following summaries for log transformed (base e) as well as untransformed data will 
be provided for PK parameters listed in Table 2. All data will be summarised by dose:  


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Page 23  
 
• Untransformed data: N (number of subjects in the population), n (number of 
subjects used for the analysis), arithmetic mean, 90% CI for the arithmetic mean, SD, 
median, minimum, maximum. 
• 
Log transformed data: N (number of subjects in the population), n (number of 
subjects used for the analysis), geometric mean, 90% CI for the geometric mean, SD 
of loge-transformed data and %CVb or %CVw (except tmax and tlast). 
 
4.3.2.2. 
Dose proportionality (Part 1 and 2): 
Part 1 (SD): Dose proportionality will be assessed by visual inspection of dose 
normalised AUC(0-∞) (AUC(0-∞)/D) and dose normalized Cmax (Cmax/D) values versus dose 
for all cohorts together.  
Part 2 (RD): Dose proportionality will be assessed by visual inspection of dose 
normalised AUCτ (AUCτ/D), Cmax (Cmax/D), and Cτ (Cτ/D) values for protocol defined 
last dosing day versus dose for all cohorts together.  
Dose proportionality may also be assessed using the power model as described below: 
Endpoints:  
Part 1: Dose normalized AUC(0-∞) , Cmax 
Part 2: Dose normalized AUCτ , Cmax , Cτ   
Part 1: Terms fitted in the model  
Model specification: log𝑒(𝑦)= log𝑒(𝛼)+ 𝛽1 × log𝑒(𝑑𝑜𝑠𝑒) + 𝛽2 × period + 𝛽3 × sequence 
Where y is the endpoint of interest, dose is the actual dose received, 𝛽1 is the coefficient 
associated with dose, 𝛽2 and 𝛽3 are the coefficients associated with period and sequence 
respectively, and 𝛼 is the subject-specific random effect.  
Response: log transformation of the endpoint of interest (base e) 
Fixed continuous covariate: log𝑒(𝑑𝑜𝑠𝑒) 
Fixed effects: Period, Sequence  
Random: Subject (intercept only) 
Kenward-Roger method for approximating the denominator degrees of freedom. 
Part 2: Terms fitted in the model 
For part 2, dose proportionality will be assessed and reported only on Day 14 for cohort 
4,5 and on Day 21 for cohort 6, hence, no random effects are required in the model for 
Part 2.  
Model specification: log𝑒(𝑦)= log𝑒(𝛼)+ 𝛽 × log𝑒(𝑑𝑜𝑠𝑒) 


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Page 24  
 
Where y is the endpoint of interest, dose is the actual dose received, 𝛽  is the coefficient 
associated with dose and log𝑒(𝛼) is the intercept.  
Response: Log transformation of the endpoint of interest (base e)  
Fixed continuous covariate: log𝑒(𝑑𝑜𝑠𝑒) 
Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e., checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are reasonable.  
For both Part 1 and 2, the beta estimates and corresponding 90% CIs of loge(dose) will be 
presented. Given that the endpoints are dose normalised, note that a beta coefficient ≈ 0 
implies dose proportionality. 
 
4.3.2.3. 
Steady state analysis (Part 2) 
A preliminary assessment of time to achieve steady state will be made based on visual 
inspection of trough concentration levels (Cτ, collected at pre-dose as per Table 2) on Y-
axis versus collection day on X-axis, by dose. The time points (days) to be included in the 
statistical analysis will be determined from assessment of the figure 
 
Terms fitted in the model:  
 
Response: Log transformed (base e) trough plasma concentration (Cτ)  
Fixed continuous covariate: Visit  
Random: Subject effect (intercept only) 
Kenward-Roger method for approximating the denominator degrees of freedom will be 
used. 
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. 
The slope (beta estimate) along with the corresponding 90% CIs for the slope for each 
dose will be presented. A slope of 0 will indicate steady state. 
4.4. 
Secondary Endpoint(s) Analyses 
All analyses for secondary endpoint(s) will be based on the PD population, unless 
otherwise specified. The intercurrent events mentioned in Section 1.1.1. along with the 
corresponding estimand strategies will be considered for the analyses. 
 


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4.4.1. 
Secondary endpoint 
The secondary endpoint is the maximum fold change from baseline of NQO1 mRNA in 
whole blood post treatment with GSK3884464 in Parts 1 and 2 of the study. 
The summaries and models defined in this section will be reported only as the data 
permits. 
4.4.1.1. 
Main analytical approach 
For Parts 1 and 2, the maximum fold change from baseline mRNA expression data will 
be analysed together for all cohorts. The data will be inspected visually. If the maximum 
fold change from baseline in NQO1 mRNA expression is not normally distributed, log 
(base e) transformation will be applied. Fold-change from baseline of NQO1 mRNA will 
be calculated as the absolute NQO1 mRNA observation divided by the baseline NQO1 
mRNA observation (pre-dose). 
 
In Part 1, maximum fold-change value for each subject and dose will be computed from 
all observations collected in each period separately. In Part 2, maximum fold-change 
values at Day 1, 7, and Day 14 (Cohorts 4 and 5) or Day 21 (Cohort 6) will be computed 
from all observations collected on those days. The following will be fitted in the model. 
 
Part 1: Terms fitted in the model  
 
Response: Maximum fold change from baseline in NQO1 mRNA expression (log 
transformed (base e) if not normally distributed) 
 
Fixed effect: Treatment (placebo and active doses of GSK3884464) as categorical 
variable, Period, Sequence 
 
Fixed continuous covariate: Age  
 
Random: Subject effect (intercept only) 
 
 
Kenward-Roger method for approximating the denominator degrees of freedom will be 
used. 
 
Part 2: Terms fitted in the model 
 
The model will be fitted by visits (Day 1, Day 7, and Day 14 (Cohorts 4 and 5) and Day 
21 (Cohort 6)). A mixed model will not be fit for Part 2 data.  
 
Response: Maximum fold change from baseline in NQO1 mRNA expression (log 
transformed (base e) if not normally distributed) 
 
Fixed effect: Treatment (placebo and active doses of GSK3884464) as categorical 
variable 
  


C O N FI D E N TI A L  
 
P a g e 2 6   
 
Fi x e d c o nti n u o us c o variate:  A ge  
 
Distri b uti o nal ass u m pti o ns u n derl yi n g t he m o d el use d f or a n al ysis will be e x a mi ne d b y 
o btai ni n g a n or m al pr o ba bilit y pl ot of t he resi d uals a n d a  pl ot of t he resi d u als vers us t he 
fitte d val ues (i.e., c h ec ki n g t he n or malit y ass u m pti o n a n d c o nsta nt varia nce ass u m pti o n 
of t he m o del res pecti vel y) t o gai n c o nfi de n ce t hat t he m o del ass u m pti o ns are reas o n a ble.  
F or b ot h parts, for n o n -tr a nsf or me d dat a , adj uste d mea ns wit h c orres p o n di n g 9 5 % CI a n d 
treat me nt differe nces wit h place b o al o n g wit h c orres p o n di n g 9 5 % CI’s will  be prese nt e d . 
If t he data  is l o g-tr a nsf or me d, bac k-tr a nsf or me d a dj uste d ge o metric mea ns wit h 
c orres p o n di n g 9 5 % CIs a n d bac k -tr a nsf or me d ratio of t he ge o metric m ea ns f or eac h 
treat me nt wit h place b o al o n g wit h 9 5 % CI will be prese nte d. F or part 2, a ll res ults will be 
prese nte d se p aratel y f or eac h visit [ Da y 1, 7 , Da y 1 4  ( C o h orts 4 & 5) a n d Da y 2 1 ( C o h ort 
6)].  
T he ma xi m u m c ha n ges fr o m baseli ne w ill als o be descri pti vel y s u m marize d.  P l ots will be 
re p orte d as per G S K C ore Data Sta n dar ds. T he details of t he pla n ne d dis pla ys are gi v e n 
i n t he O P S. 
C CI


C O N FI D E N TI A L  
 
P a g e 2 7   
 
C CI


C O N FI D E N TI A L  
 
P a g e 2 8   
 
 
 
 
1 W here M A P is calc ulate d as: D B P + 1/ 3( S B P –  D B P)  
 
C CI
C CI


C O N FI D E N TI A L  
 
P a g e 2 9   
 
4. 6.  
I nt eri m A n al y se s  
N o f or mal i nteri m a nal ys es were pla n ne d d uri n g t he c o urse of t he st u d y. Base d o n 
e mer gi n g bli n de d st u d y d ata a n d i nter nal safet y b o ar d rec o m me n dati o n ( G S B), a n a d -h oc 
u n bli n de d safet y a n al ysis was perf or me d t o assess safet y, P K a n d P D of G S K 3 8 8 4 4 6 4 
after c o m pleti o n of C o h ort 4 . T he details a b o ut t his a nal ysis are a d de d i n t h e A d-h oc 
Safet y A nal ysis C harter ( T M F –  1 5 0 4 9 7 8 8 ). T he res ults disse mi nati o n pla n a n d details of 
all u n bli n de d me m bers i n v ol ve d are arc hi v e d i n a N ote -t o-file (T M F –  1 4 9 1 8 7 0 3 ). 
 
C CI


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4.7. 
Changes to Protocol Defined Analyses 
Changes from the originally planned statistical analysis specified in the protocol are 
detailed in Table 4. 
Table 4 
Changes to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
Analysis for Secondary 
Endpoint(s): 
The normalized mRNA 
expression data will be analysed 
with a mixed 
effect model with subject as 
random effect, and treatment, 
visit and treatment by visit as 
fixed effect.  
Analysis for Secondary 
Endpoint(s): 
For both parts, the normalized 
maximum change from 
baseline mRNA expression 
data will be analysed with a 
mixed effect model with, dose, 
and age as fixed effects and 
subject as random visit. 
Age added as a covariate 
as per the study team’s 
suggestion 
 


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5. 
SAMPLE SIZE DETERMINATION 
A sufficient number of participants will be screened to achieve up to 51 randomly 
assigned to study intervention and up to 51 evaluable participants. It is estimated that Part 
1 will have 27 evaluable participants; Part 2 will have 24 evaluable participants (6 for 
each of the three repeat doses levels and 6 for placebo). Additional participants/cohorts 
may be enrolled to allow for evaluation of additional dose levels. If participants 
prematurely discontinue during the study, additional replacement participants may be 
enrolled at the discretion of the Sponsor. These replacement participants will be assigned 
to the same treatment/treatment sequence as the corresponding participant who 
prematurely discontinued from the study. 
 
The sample size has been assessed based on the evaluation of fold change from baseline 
(FCFB) of NQO1 expression, a secondary endpoint in the study to the end of repeated 
dosing. Assuming the within subject CV of 50% and based on 6 participants each in 
GSK3884464 and placebo treatment arms. 
 
• If the true ratio of FCFB between GSK3884464 and placebo is 5-fold, then there is 
69% probability that the observed ratio is greater than 4.2 -fold; if the true ratio is 6-
fold, then the probability is 83%; if the true ratio is greater than 7-fold then the 
probability is greater than 90%. This provides high confidence of observing a 
clinically meaningful effect in the expected range (>5-fold) of target engagement in 
NQO1.  
 
If the true ratio of FCFB between GSK3884464 and placebo is 1-fold, then the false 
positive rate that the observed ratio is greater than 4.2-fold is <0.1%.


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified. Please see Section 3 for more information on analysis sets. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards. Details of the planned displays 
are given in the OPS. 
6.1.1. 
Participant Disposition 
A summary of participant status and reason for study withdrawal will be provided. This 
display will show the number and percentage of participants who completed the study 
and who prematurely withdrew from the study, including reasons for study withdrawal. A 
participant is considered to have completed the study if they have completed study 
assessments until the end of the study as per the schedule of assessments, including the 
follow up visit. 
 
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have discontinued study intervention and a 
summary of the reasons for discontinuation of study intervention. A summary of the 
number of participants in each of the analysis sets described in the Section 3 will be 
provided. 
 
The data for phase conclusion in each period of Part 1 will be derived based on the 
subject visit and treatment information.  
 
All the data will be summarized based on GSK Core Data Standards. 
 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, height, baseline body 
weight and BMI (derived)) will be summarized using descriptive statistics.  
 
The summary of disease history and characteristics will be provided. Past medical 
conditions and current medical conditions as of screening will be summarized 
respectively. Substance use, including smoking history, tobacco use, alcohol and drug 
history will be summarized. 
 
All the data will be summarized based on GSK Core Data Standards. 
 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 


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Page 33  
 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important deviations 
(where possible without knowing the study intervention details) are captured and 
categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using both the GSK Drug and WHO Drug 
dictionaries. However, the summary will be based on GSK Drug dictionary only. 
Medications will be coded using the GSK Drug coding dictionary (current version at the 
time of Data Base Release (DBR)). The number and percentage of participants reporting 
the use of each concomitant medication will be summarized by GSK-Drug Anatomical 
Therapeutic Chemical (ATC) classification level 1, 2, 3 (body system) and ingredient. 
Drugs that are composed of a combination of ingredients will be displayed according to 
the ATC classifications of the ingredients, not of the combination. 
Concomitant medications include any medication that was taken at some point during the 
on-intervention period as defined in Section 6.2.2. 
6.1.5. 
Study Intervention Compliance 
A summary of overall compliance for GSK3884464 based on the exposure data will be 
summarized using descriptive summary for Part 2. 
Study intervention Compliance (%) = [Total cumulative actual dose / Total cumulative 
scheduled dose] *100. 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
A laboratory value that is outside the reference range is considered either high abnormal 
(value above the upper limit of the reference range) or low abnormal (value below the 
lower limit of the reference range). Note: a high abnormal or low abnormal laboratory 
value is not necessarily of clinical concern.  
Criteria specified below will be used to flag for potential clinical importance: 
 
 


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Page 34  
 
Clinical Chemistry 
 
Liver Functions 
 
Laboratory Parameters 
Units 
Category 
Clinical Concern Range 
Lower 
Upper 
Albumin 
g/L 
 
< 30 
 
Calcium 
mmol/L  
< 2.0 
> 2.75 
Creatinine 
umol/L 
 
 
> 1.3xULN 
Creatinine 
umol/L 
Change 
from 
baseline 
 
Increase of 40 
Glucose (Fasted) 
mmol/L  
< 3.0 
> 7.5 
Magnesium 
mmol/L  
< 0.4 
> 1.03 
Phosphate 
mmol/L  
< 0.7 
> 1.6 
Potassium 
mmol/L  
< 3.0 
> 5.3 
Sodium 
mmol/L  
< 130 
> 149 
Test Analyte   
Units  
Category 
Clinical Concern Range  
Lower 
Upper 
Alkaline phosphatase 
U/L 
 
> 2 x ULN 
AST/SGOT 
U/L 
 
> 2 x ULN 
ALT/SGPT 
U/L 
> 2 x ULN 
Gamma GT 
IU/L 
 
1.5 X ULN 
Total Bilirubin 
μmol/L 
 
> 1.5 x ULN 
TROPONIN T (HIGH 
SENSITIVITY) 
ng/L 
 
 
>14 
NTPRO BNP 
pmol/L 
 
 
>47 


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Page 35  
 
Haematology 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Lower 
Upper 
Hematocrit 
% 
Male 
 
>51 
Female 
 
>45 
Δ from BL 
N/A 
> 7.5% 
Hemoglobin 
g/L 
Male 
<100 
>175 
Female 
<95 
>150 
Δ from BL 
N/A 
> 25g/L 
Lymphocytes 
x109/ L 
 
<0.97 
 
Neutrophils 
x109/ L 
 
<1.5 
 
Platelet Count 
x109/ L 
 
<100 
>550 
While Blood Cell Count 
(WBC) 
x109/ L 
 
<2 
>18 
Red Blood Cell Count 
(RBC) 
x1012/L 
Male 
<3.0 
 
 
 
Female 
<2.5 
 
 
ECG 
ECG Parameter (Absolute) 
Units 
Clinical Concern Range 
 
 
Lower 
Upper 
Absolute QTcF during the study (i.e. 
post dose) 
msec 
 
>450 
Absolute PR Interval 
msec 
<120 
>220 
Absolute QRS Interval 
msec 
<75 
>110 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
 


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Page 36  
 
Vital Signs  
Vital Sign Parameter (Absolute) 
Units 
Clinical Concern Range 
 
 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>160 
Diastolic Blood Pressure  
mmHg 
<45 
>100 
Pulse Rate (Heart Rate) 
bpm 
<50 
>100 
temperature 
°C 
<35 
>38 
Respiratory rate  
Breaths/min <10 
>25 
 
6.2.2. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Pre-Intervention is defined as time prior to the first dose of study intervention, i.e. 
Part 1: Ref Date < Study Intervention Start Date of Period 1 in each Cohort 
Part 2: Ref Date < Study Intervention Start Date in each Cohort 
On-Intervention is defined as time from first dose to last date plus lag days, i.e.  
Part 2: Study Treatment Start Date and time ≤ Date and time ≤ Study Treatment End Date 
and time + 7 days, in each cohort. 
 
Post-Intervention is defined as any time post dosing, i.e. 
Part 1: Study Intervention Start Date and Time ≤ Ref Date < Next Study Intervention 
Start Date and Time, in each Period within a Cohort. It will additionally include any 
events occurring in the washout period before start of the next treatment dose. 
Part 2: Date and time > Study Treatment End Date and time + 7 days, in each cohort 
 
Note: For the last period in each cohort, events occurring during the follow-up (7-10 
days) will be attributed to the last dose level. 
6.2.3. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The study day is calculated as below: 
• Assessment Date = Missing             → Study Day = Missing  
• Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date 
+ 1     


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Page 37  
 
6.2.4. 
Assessment Window  
Refer to section ‘Time Deviation Windows for Study Assessments’ (Table 4) of the 
Study Reference Manual. 
6.2.5. 
Multiple measurements at One Analysis Time Point 
Unless otherwise specified, when multiple assessments are done for a single timepoint, 
the mean of the measurement will be calculated first and summary statistics will be based 
on the calculated mean. This will apply to both baseline and post baseline assessments. 
If multiple assessments are taken from the same type of lab, the worst case will be used. 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only. In addition, partial dates may be 
imputed for ‘slotting’ data to study phases or for specific analysis purposes as 
outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events), or elapsed time 
variables (e.g., time since diagnosis). 
Adverse 
Events 
• 
Missing or Partial start/end date and time are not expected for Adverse 
events. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start 
day 
If study intervention start date is missing (i.e., 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and 
year of study intervention start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date= 1st of month. 
▪ 
Else set start date = study intervention start 
date. 
 
Missing start 
day and month 
If study intervention start date is missing (i.e., 
participant did not start study intervention), then set 
start date = January 1. 


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Page 38  
 
Element 
Reporting Detail 
Else if study intervention start date is not missing: 
o If year of start date = year of study intervention 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date = January 
1. 
▪ 
Else set start date = study. intervention 
start date. 
 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on 
the month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
the month. 
Completely 
missing start/end 
date 
No imputation 
Age 
Age will not be imputed. 
 
6.2.7. 
Early PK Access Key Activities 
Items 
Details 
Roles with Authorized 
Access 
Secured Area 
Early PK Access 
Starting 
Milestone 
PK Cutoff 
Milestone 
Or  
PK Last Subject 
Last Visit  
CPMS Lead/Modeller 
including CPMS 
modelers/programmers 
from vendors 
BIB Lead 
NA 
Creation of 
PopPK/PD with 
Scrambled 
Subject ID  
PopPK/PD 
CPMS Lead/Modeler 
including CPMS 
modelers/programmers 
from vendors 
NA 
Development of 
PopPK/PD 
Preliminary 
Model  
PopPK/PD 
Preliminary 
Model 
CPMS Lead/Modeler 
including CPMS modelers 
from vendors 
NA 


C O N FI D E N TI A L  
 
P a g e 3 9   
 
Ite ms 
Det ails  
R oles wit h A ut h orize d 
Access  
Sec ure d Are a  
A d -h oc safet y 
a nal ysis 
(i ncl u des 
u n bli n de d 
P K/ P D data)  
P ost c o m pleti o n 
of C o h ort 4  
I n de pe n de nt u n bli n de d 
S D T M, Bi ostats a n d ke y 
st u d y tea m me m bers ( T M F 
–  1 5 0 4 9 7 8 8 ) 
Ser ver 1 7 5 -
/are n v/ar pr o d/ gs k 3 8 8 4 4 6 4/
mi d 2 1 3 3 7 6/trt _safet y _ 0 1  
 
 
 
6. 2. 8.  
A b br e vi ati o n s  
Δ  
C ha n ge fr o m baseli ne 
Δ Δ  
Place b o -c orrecte d c ha n ge -fr o m-baseli ne  
A E  
A d verse e ve nt  
A E SI  
A d verse E ve nts of S pecial I nterest  
A T C  
A nat o mical T hera pe utic C he mical  
A U C  
Area u n der t he c ur ve  
BI B  
Bi oa nal ysis, I m m u n o ge nicit y a n d Bi o mar kers  
B L  
Baseli ne  
B MI  
B o d y mass i n de x  
B P  
Bl o o d Press ure  
CI  
C o nfi de nce I nter val  
C O VI D -1 9  
C or o na vir us disease  
C P M S  
Cli nical P har mac ol o g y M o delli n g a n d Si m ulati o n  
C S R  
Cli nical st u d y re p ort  
C V  
C oefficie nt of Variati o n  
D E C  
D ose Escalati o n C o m mittee  
D B P  
Diast olic Bl o o d Press ure  
D B R  
Data base Release  
E C G  
Electr ocar di o gra m  
C R F  
C ase R e p ort F or m  
F C F B  
F ol d C ha n ge fr o m Baseli ne  
F TI H  
First ti me i n h u ma n  
G O F  
G o o d ness of Fit  
G S B  
Gl o bal Safet y B oar d  
G S K  
Gla x o S mit h Kli ne  
C CI
C CI


C O N FI D E N TI A L  
 
P a g e 4 0   
 
H A R P  
Har m o nisati o n F or A nal ysis & Re p orti n g Pr oject  
H R  
Heart Rate  
I C F 
I nf or me d C o nse nt F or m 
L D L  
L o w -de nsit y li p o pr otei n  
M A P  
Mea n Arterial Press ure  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y  Acti vities  
m R N A  
Messe n ger R N A  
N C A  
N o n -C o m part me ntal A nal ysis  
N Q  
N o n -q ua ntifia ble  
N Q O 1  
N A D( P) H de h y dr o ge nase ( q ui n o ne 1)  
O P S  
O ut p uts a n d Pr o gra m mi n g S pecificati o ns  
P CI  
P ote ntial Cli nical I m p orta nce  
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic  
P o p P K  
P o p ulati o n P har mac o ki netic  
P R  
P R i nter val of t he E C G  
P T T  
Pea k t o tr o u g h  
Q R S  
Q R S i nter val of t he E C G  
Q T  
Q T I nter val of t he E C G  
Q Tc  
C orrecte d Q T i nter val  
Q Tc F  
C orrecte d Q T i nter val usi n g Fri derici a’s f or m ula  
R D  
Re peat d ose  
R N A  
Ri b o n ucleic aci d  
S & P  
Statistics a n d Pr o gra m mi n g  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S B P  
S yst olic Bl o o d Press ur e  
S D  
Si n gle d ose  
S D T M  
St u d y Data Ta b ulati o n M o del  
S M Q  
S ta n dar dize d Me d D R A Q uer y ( S M Q) 
T M F  
Trial Master File  
V P Cs  
Vis ual Pre dicti ve C hec ks  
W H O  
W orl d Healt h Or ga nizati o n  
 
C CI
C CI
C CI
C CI
C CI


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6.2.9. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the Group of 
Companies 
NONE 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
  
 


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7. 
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