Clinical trial NCT04900038
Conditions: HIV Infections
Keywords: Human immunodeficiency virus-1 GSK3640254 Dolutegravir Lamivudine Treatment-naive
Sponsor: ViiV Healthcare
Start date: 2021-08-18; Completion date: 2023-05-11
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of GSK3640254 + DTG relative to lamivudine (3TC) + DTG in treatment-naïve adult participants living with human immunodeficiency virus (HIV)-1. The participants were randomized to one of the three doses of blinded GSK3640254 (100, 150, or 200 milligrams \[mgs\]) or a reference arm of blinded 3TC-each in combination with open label DTG.

Detailed description:

Arms: arm 1: Participants with human immunodeficiency virus type 1 (HIV-1) orally received low dose (100 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. arm 2: Participants with HIV-1 orally received medium dose (150 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. arm 3: Participants with HIV-1 orally received high dose (200 mg) GSK3640254 tablet blinded and 50 mg DTG unblinded. Each participant received one tablet per day of each intervention up to Week 24. arm 4: Participants with HIV-1 orally received unblinded 50 mg DTG one tablet and blinded 300 mg 3TC. Each participant received one capsule per day of each intervention up to Week 24.
Interventions: intervention 1: GSK3640254 intervention 2: Dolutegravir intervention 3: Lamivudine capsules intervention 4: Lamivudine tablets
Intervention descriptions: intervention 1: GSK3640254 was available as 25 mg or 100 mg tablets administered orally. intervention 2: DTG was available as 50 mg tablets administered orally. intervention 3: 3TC was available as 300 mg capsules administered orally as a blinded treatment. intervention 4: 3TC was available as 300 mg tablets administered orally as an unblinded treatment.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
                                                      PROTOCOL 
 
 
Study ID: 212483 
 
Official Title of Study A Phase IIb, randomized, double-blind, parallel-group study to 
assess the efficacy, safety, tolerability, and resistance profile of GSK3640254 in 
combination with dolutegravir compared to dolutegravir plus lamivudine in HIV-1 
infected, treatmentnaïve adults 
 
NCT ID-NCT04900038   
 
Approval Date of Document: 11-Aug-2022 
 
 


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
Vii V H e alt h c ar e gr o u p of c o m p a ni e s  
 
2 1 2 4 8 3  
 
1  
 
TI T L E P A G E  
Pr ot oc ol Title: A P has e II b, ra n d o mize d, d o u ble -bli n d, parallel -gr o u p st u d y t o assess t he 
effic ac y, safet y, t olera bilit y, a n d resista nce pr ofile of G S K 3 6 4 0 2 5 4 i n c o m bi nati o n wit h 
d ol ute gra vir  c o m pare d t o d ol ute gra vir pl us la mi v u di ne i n HI V -1 i nf ecte d, treat me nt -
naï ve a d ults  
Pr ot oc ol N u m ber : 2 1 2 4 8 3 /A me n d me nt 0 3  
C o m p o u n d N u m ber  or N a me : G S K 3 6 4 0 2 5 4  
Brief  Title: A P hase II b Cli nical Trial of G S K 3 6 4 0 2 5 4  + D ol ute gra vir ( D T G) i n HI V-1 
I nfect e d Treat me nt-Nai v e A d ults   
St u d y P h ase:  P hase 2 b  
Acr o n y m:  D Y N A MI C  
S p o ns or N a me a n d Le g al Re gistere d A d dress  (e xcl u di n g U S):  
Vii V Healt hcare U K 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  
U S I N D S p o ns or  N a me a n d Le g al Re gistere d A d dress : 
Vii V Healt hcare C o m pa n y  
Fi ve M o ore Dri ve  
P. O. 1 3 3 9 8  
Researc h Tria n gle Par k, N C 2 7 7 0 9 -3 3 9 8, U S A  
Tele p h o ne: + 1 9 1 9 4 3 8 2 1 0 0  
I n s o me c o u ntries, l oc al l a w re q uires t h at t he Cli nic al Tri al s p o ns or is a l oc al 
c o m p a n y le g al e ntit y.  I n t hese i nst a nces, t he a p pr o pri ate c o m p a n y t o be i de ntifie d 
as S p o ns or m ust be a gree d wit h t he gl o b al Vii V He alt hc are cli nic al te a m a n d si g ne d 
off b y t he Se ni or Vice Presi de nt, He a d of Rese arc h & De v el o p me nt.  
T his st u d y is s p o ns ore d b y Vii V H ealt hcare.  Gla x o S mit h Kli ne a n d S y n e os Healt h are 
s u p p orti n g Vii V Healt hcare i n t he c o n d u ct of t his st u d y.   
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 nce M a n u al  
Vii V Healt hcare  Researc h & De v el o p me nt  
A p pr o v al D ate:  1 1 A u g 2 0 2 2  
C o p yri g ht 2 0 2 2  t he Vii V Healt h care a n d Gla x o S mit h Kli ne  gr o u p of c o m pa nies.  All 
ri g hts res er 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


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ViiV Healthcare group of companies 
 
212483 
 
2 
 
Regulatory Agency Identifying Number(s):  
IND: 139838 
EudraCT:  2021-000016-28 
 


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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Document Number 
Amendment 03 
11 Aug 2022 
 
TMF-14435461 
Amendment 02 
02-SEP-2021 
TMF-12456180 
Amendment 01 
19-MAR-2021 
TMF-11880342 
Original Protocol 
11-FEB-2021 
TMF-2196391 
 
Amendment 03: 11 Aug 2022 
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. 
Overall Rationale for the Amendment:  
Study 212483 has always included an option for participants to have continued access to 
study treatment after they complete the study, provided they meet certain criteria. As the 
study is approaching the end of enrolment, this amendment has been prepared to provide 
detail of the visits and assessments that a participant would be expected to complete if 
they are granted continued access to study treatment. Clarification has also been added 
for the timing at a participant level of transition from non-optimal GSK3640254 dose to 
optimal dose in the double-blind phase of the study and from blinded to unblinded study 
treatment. Specifically, this amendment clarifies that participants may not have all 
transitions, depending on their entry date into the study and the timing of the interim 
analyses required for those transitions to occur. 
Additional minor clarifications and corrections have been made throughout.   
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
ViiV Healthcare copyright 
statement added 
Requirement of new protocol 
template 
1.2 Schema 
Schema Figure and footnotes 
were updated as follows: 
• Clarified that 
participants who reach 
their Week 24 visit 
before the optimal 
dose of GSK3640254 
is known will remain 
on their original 
GSK3640254 dose 
Clarity on timing of transition 
from original dose of 
GSK3640254 to optimal dose 
and about when an individual 
participant’s treatment allocation 
would be unblinded. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
until the optimal dose 
is known (expected 
prior to the overall 
study’s Week 24 
primary endpoint). 
Treatment allocation 
will remain blinded 
until after the Week 24 
primary endpoint 
analysis, then will 
become open label. 
• Clarified the treatment 
options for participants 
who meet the criteria 
for continued access 
to study treatment 
beyond the end of the 
study, depending on 
when they reach their 
Week 52 visit 
compared to the 
treatment transition 
milestones of the 
study. Participants on 
GSK3640254 arms 
may continue to 
receive study 
medication beyond 
their individual Week 
52 visit. Based on the 
above sequence of 
events and when each 
participant reaches 
Week 52 relative to 
the Week 24 primary 
endpoint analysis, 
participants on 
GSK3640254 arms 
may receive: double 
blind non-optimal 
dose, double blind 
optimal dose, and/or 
open label optimal 
dose. Participants on 
the reference arm may 
continue to receive 
Treatment options for continued 
access were not previously 
described and have been added. 


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Section # and Name 
Description of Change 
Brief Rationale 
DTG + 3TC only if they 
reach their individual 
Week 52 visit during 
the Blind Treatment 
Phase. After the Open 
Treatment Phase 
starts, DTG + 3TC will 
be discontinued for all 
participants who have 
completed Week 52.   
1.1 Synopsis 
4.1 Overall Design 
Clarified that the transition 
from the double-blind phase to 
open-label phase is linked to 
the timing of the last 
participant’s week 24 visit. 
Change made to address 
confusion about when each 
participant’s treatment allocation 
would be unblinded. All 
treatment allocations will remain 
blinded until after the primary 
endpoint analysis, which will 
occur after all participants have 
completed their Week 24 visit. 
1.1 Synopsis 
4.1.4 Study Completion 
6.6 Continued Access to 
Study Intervention after the 
End of the Study 
 
 
Expanded existing text 
regarding continued access to 
study treatment at the end of 
the study, to cover the options 
for participants who reach their 
Week 52 visit before an 
optimal dose of GSK3640254 
is determined and/or before 
the study enters the open-label 
phase.  
 
Deleted duplicated paragraph 
in the synopsis. 
The protocol was initially written 
assuming that recruitment into 
the study would be such that 
participants would all reach 
individual key milestones during 
the same phase of the study i.e. 
transition to GSK3640254 
optimal dose would occur before 
any participant reached their 
Week 24 visit and transition to 
the Open-label Phase would 
occur before any participant 
completed the study. Due to 
slower than anticipated 
recruitment this is not the case 
and the potential treatment 
allocations and transitions 
required for a participant who 
meets the criteria for continued 
access have been added.    
1.3 Schedule of Activities 
(SoA) 
Visit schedule and 
assessments have been added 
for participants who meet the 
criteria for and consent to 
continued access to study 
No visit schedule or list of 
planned assessments had 
previously been included. 
Original wording of footnote 20 
was unclear and potentially gave 


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Section # and Name 
Description of Change 
Brief Rationale 
treatment. Footnote 5 has 
been updated to add the 
separate consent required for 
continued access beyond the 
end of the study. 
 
Footnote 4 has been updated 
to clarify that, if a participant is 
unable to attend a visit during 
the protocol-defined window, 
sites should discuss measures 
to ensure continued access to 
study treatment and 
assessments with the Sponsor. 
 
Clarification to footnote 20 to 
state that urine pregnancy 
testing every 4 weeks at home 
is required only if virtual visits 
occur. 
 
Added footnote 23 to state 
requirement for dispensing 
visits every 4 weeks for 
participants who are granted 
continued access to study 
treatment while the study is in 
the Double-Blind Treatment 
Phase. 
the impression that both serum 
and urine pregnancy tests were 
required. Participants who meet 
the criteria for pregnancy testing 
are required to have a serum 
pregnancy test at each on site 
visit. Urine pregnancy tests are 
only required if virtual visits 
occur and the participant needs 
to perform the test at home.  
 
The protocol previously only 
included measures to follow to 
ensure continued access to 
study treatment and study 
assessments if a visit was 
missed or delayed due to 
COVID-19. No instructions were 
given for steps to take if a 
participant had to miss or delay 
a visit due to unforeseen 
circumstances and have now 
been added.  
 
Dispensing visits and 
requirements for continued 
access were not previously 
described and have been added. 
1.1 Synopsis 
4.1 Overall Design 
4.1.4 Study Completion 
 
Updates to reflect the fact that 
the initial IDMC review in study 
208379 has occurred and a 
no-action letter was issued for 
study 208379 with no change 
subsequently required in this 
study 212483. 
Details of the potential 
outcomes from the initial IDMC 
meeting in study 208379 and 
their impact on study 212483 
were deleted. 
Updated to reflect the outcome 
of the initial IDMC review in 
study 208379. 


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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
Clarified the contents of the 
5 bottles of study treatment 
given to participants at each 
visit and the number of 
Tablets/capsules taken by 
participants during the Double-
blind and Open-label phases of 
the study. 
Added that participants will be 
issued a spare bottle of DTG at 
Day 1 only, that they will keep 
for the whole study to provide 
overage in case of delayed 
study visits. 
Clarification added to address 
recurring queries from EC/CAs 
and sites. 
 
DTG bottles only contain 30 
Tablets and visits are scheduled 
every 4 weeks (28 days). The 
additional, spare bottle is 
intended to cover unavoidable 
delays in study visits where a 
participant would otherwise run 
out of DTG.  
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
 
 
Added that an early 
discontinuation/withdrawal visit 
should also be conducted if a 
participant who has been 
entered into the Continued 
Access Phase discontinues or 
is withdrawn from study 
treatment. 
Requirements for continued 
access were not previously 
described and have been added. 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 12 
1.1. 
Synopsis ..................................................................................................... 12 
1.2. 
Schema ...................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) ........................................................................ 17 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study Rationale .......................................................................................... 24 
2.2. 
Background ................................................................................................ 24 
2.2.1. 
Key Safety Data with a Prior Maturation Inhibitor 
(GSK3532795) ............................................................................. 24 
2.2.2. 
Preclinical Summary with GSK3640254 ....................................... 24 
2.2.3. 
Key Clinical Data on GSK3640254 to date ................................... 26 
2.2.4. 
Key Phase 2a (Study 208132) Clinical Data on 
GSK3640254 ............................................................................... 27 
2.3. 
Benefit/Risk Assessment ............................................................................ 31 
2.3.1. 
Risk Assessment ......................................................................... 33 
2.3.2. 
Benefit Assessment ..................................................................... 43 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 43 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 43 
4. 
STUDY DESIGN .................................................................................................... 45 
4.1. 
Overall Design ............................................................................................ 45 
4.1.1. 
Screening Period ......................................................................... 48 
4.1.2. 
Treatment Period ......................................................................... 48 
4.1.3. 
Follow-up ..................................................................................... 50 
4.1.4. 
Study Completion ........................................................................ 50 
4.2. 
Scientific Rationale for Study Design .......................................................... 51 
4.2.1. 
Participant Input into Design ........................................................ 52 
4.3. 
Justification for Dose .................................................................................. 52 
4.4. 
End of Study Definition ............................................................................... 57 
5. 
STUDY POPULATION ........................................................................................... 57 
5.1. 
Inclusion Criteria ......................................................................................... 58 
5.2. 
Exclusion Criteria ........................................................................................ 59 
5.3. 
Lifestyle Considerations .............................................................................. 64 
5.3.1. 
Meals and Dietary Restrictions .................................................... 64 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 64 
5.3.3. 
Activity ......................................................................................... 64 
5.3.4. 
Counsel regarding safe sex practices .......................................... 64 
5.4. 
Screen Failures........................................................................................... 64 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 65 
6.1. 
Study Intervention(s) Administered ............................................................. 66 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 66 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 67 
6.4. 
Study Intervention Compliance ................................................................... 68 
6.5. 
Dose Modification ....................................................................................... 68 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 68 


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6.7. 
Treatment of Overdose ............................................................................... 69 
6.8. 
Concomitant Therapy.................................................................................. 70 
6.8.1. 
Prohibited Medications and Non-Drug Therapies ......................... 71 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 73 
7.1. 
Discontinuation of Study Intervention .......................................................... 73 
7.1.1. 
Protocol-Defined Virologic Failure ................................................ 74 
7.1.2. 
Liver Chemistry Stopping Criteria ................................................ 78 
7.1.3. 
Columbia-Suicide Severity Rating Scale ...................................... 79 
7.1.4. 
QTc Stopping Criteria .................................................................. 79 
7.1.5. 
Temporary Discontinuation .......................................................... 79 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 80 
7.3. 
Lost to Follow Up ........................................................................................ 80 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 81 
8.1. 
Efficacy Assessments ................................................................................. 81 
8.1.1. 
Lymphocyte Subsets by Flow Cytometry ..................................... 81 
8.1.2. 
Disease Progression .................................................................... 82 
8.2. 
Safety Assessments ................................................................................... 82 
8.2.1. 
Physical Examinations ................................................................. 82 
8.2.2. 
Vital Signs .................................................................................... 83 
8.2.3. 
Cardiac Monitoring with Electrocardiograms ................................ 84 
8.2.4. 
Clinical Safety Laboratory Assessments ...................................... 84 
8.2.5. 
Pregnancy Testing ....................................................................... 85 
8.2.6. 
Suicidal Ideation and Behaviour Risk Monitoring ......................... 85 
8.2.7. 
GI Intolerability Evaluation & Monitoring Plan (with 
Stopping Criteria) ......................................................................... 87 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 90 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 91 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 91 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 91 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 92 
8.3.5. 
Pregnancy ................................................................................... 92 
8.3.6. 
Cardiovascular and Death Events ................................................ 93 
8.3.7. 
Disease-Related Events and/or Disease-Related 
Outcomes (HIV-Associated Conditions) ....................................... 93 
8.3.8. 
Adverse Events of Special Interest .............................................. 94 
8.4. 
Pharmacokinetics ....................................................................................... 94 
8.5. 
Genetics and/or Pharmacogenomics .......................................................... 96 
8.6. 
Biomarkers ................................................................................................. 96 
8.6.1. 
Viral Genotyping and Phenotyping Analyses ............................... 96 
8.7. 
Immunogenicity Assessments ..................................................................... 97 
8.8. 
Medical Resource Utilization and Health Economics .................................. 97 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 98 
9.1. 
Statistical Hypotheses................................................................................. 98 
9.2. 
Sample Size Determination ........................................................................ 98 
9.2.1. 
Sample Size Sensitivity ................................................................ 99 
9.3. 
Analysis Sets ............................................................................................ 100 


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1 0  
 
9. 3. 1.  
Int e nt -t o-Tr e at E x p o s e d P o p ul ati o n (I T T -E)  ............................... 1 0 0  
9. 3. 2.  
P er Pr ot o c ol P o p ul ati o n ( P P)  ..................................................... 1 0 1  
9. 3. 3.  
P h ar m a c o ki n eti c P o p ul ati o n ....................................................... 1 0 1  
9. 3. 4.  
S af et y P o p ul ati o n  ....................................................................... 1 0 1  
9. 4.  
St ati sti c al A n al y s e s  ................................................................................... 1 0 1  
9. 4. 1.  
Effi c a c y A n al y si s  ........................................................................ 1 0 1  
9. 4. 2.  
S af et y A n al y si s  .......................................................................... 1 0 2  
9. 5.  
Ot h er A n al y si s  .......................................................................................... 1 0 3  
9. 6.  
I nt eri m A n al y si s ........................................................................................ 1 0 3  
9. 6. 1.  
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e ................................... 1 0 4  
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 0 5  
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 0 5  
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 0 5  
1 0. 1. 2.  
Fi n a n ci al Di s cl o s ur e  ................................................................... 1 0 5  
1 0. 1. 3.  
I nf or m e d C o n s e nt Pr o c e s s ........................................................ 1 0 6  
1 0. 1. 4.  
D at a Pr ot e cti o n  .......................................................................... 1 0 6  
1 0. 1 . 5. 
C o m mitt e e s Str u ct ur e  ................................................................ 1 0 7  
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 0 7  
1 0. 1. 7.  
D at a Q u alit y A s s ur a n c e  ............................................................. 1 0 8  
1 0. 1. 8.  
S o ur c e D o c u m e nt s  .................................................................... 1 0 9  
1 0 . 1. 9. 
St u d y a n d Sit e St art a n d Cl o s ur e  ............................................... 1 0 9  
1 0. 1. 1 0.  P u bli c ati o n P oli c y  ....................................................................... 1 1 0  
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 1 1  
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 1 3  
1 0. 3. 1.  
D efi niti o n of A E  .......................................................................... 1 1 3  
1 0. 3. 2.  
D efi niti o n of S A E  ........................................................................ 1 1 4  
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 1 5  
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 1 6  
1 0. 3. 5.  
R e p orti n g of S A E t o G S K/ Vii V H e alt h c ar e/ S y n e o s H e alt h  ......... 1 1 8  
1 0. 4.  A p p e n di x 4: C o ntr a c e pti v e a n d B arri er G ui d a n c e  ..................................... 1 1 9  
1 0. 4. 1.  
D efi niti o n s:  ................................................................................. 1 1 9  
1 0. 4. 2 . 
C o ntr a c e pti o n G ui d a n c e:  ........................................................... 1 1 9  
1 0. 5.  A p p e n di x 5: G e n eti c s  ................................................................................ 1 2 2  
1 0. 6.  A p p e n di x 6: Li v er S af et y: R e q uir e d A cti o n s a n d F oll o w -u p 
A s s e s s m e nt s  ............................................................................................ 1 2 3  
1 0. 7.  A p p e n di x 7: C hil d -P u g h Cl a s sifi c ati o n  ...................................................... 1 2 7  
1 0. 8.  A p p e n di x 8: Di vi si o n of AI D S T a bl e f or Gr a di n g t h e S e v erit y of A d ult 
a n d P e di atri c A d v er s e E v e nt s C orr e ct e d V er si o n 2. 1, J ul y 2 0 1 7  ............... 1 2 8  
1 0. 9.  A p p e n di x 9: T o xi cit y M a n a g e m e nt  ............................................................ 1 2 9  
1 0. 9. 1.  
Li v er C h e mi str y St o p pi n g a n d F oll o w -u p Crit eri a  ....................... 1 3 0  
1 0. 9. 2.  
H y p er s e n siti vit y R e a cti o n  ........................................................... 1 3 0  
1 0. 9. 3.  
R a s h & S ki n R e a cti o n s  .............................................................. 1 3 1  
1 0. 9. 4.  
H y p ertri gl y c eri d e mi a/ H y p er c h ol e st er ol e mi a  ............................... 1 3 2  
1 0. 9. 5.  
Cr e ati n e P h o s p h o ki n a s e ( C P K) El e v ati o n  .................................. 1 3 2  
1 0. 9. 6.  
D e cli n e i n R e n al F u n cti o n  .......................................................... 1 3 2  
1 0. 9. 7.  
Pr o xi m al R e n al T u b e D y sf u n cti o n  .............................................. 1 3 3  
C CI


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10.9.8. 
Proteinuria ................................................................................. 133 
10.10. Appendix 10: CDC Classification for HIV-1 Infection (2014) ...................... 134 
10.11. Appendix 11: COVID-19 Pandemic and Clinical Trial Continuity ............... 136 
10.11.1. Changes to Study Visits and Study Procedures ......................... 136 
10.11.2. Changes to Informed Consent ................................................... 138 
10.11.3. Direct-To-Patient (DTP) Shipment of Study IP ........................... 138 
10.11.4. COVID-19 Therapeutic Agents .................................................. 139 
10.11.5. COVID-19 Specific Data Capture ............................................... 139 
10.12. Appendix 12: Abbreviations and Trademarks ............................................ 142 
10.13. Appendix 13: Protocol Amendment History ............................................... 147 
11. REFERENCES ..................................................................................................... 156 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase IIb, randomized, double-blind, parallel-group study to assess the 
efficacy, safety, tolerability, and resistance profile of GSK3640254 in combination with 
dolutegravir compared to dolutegravir plus lamivudine in HIV-1 infected, treatment-
naïve adults 
Brief Title: A Phase IIb Clinical Trial of GSK3640254 + Dolutegravir (DTG) in HIV-1 
Infected Treatment-Naive Adults  
Rationale: 
The Sponsor proposes conducting this Phase 2b study, the primary objective of which is 
to evaluate the efficacy of GSK3640254 (initially, at three doses: 100, 150, and 200 mg) 
+ DTG relative to DTG + 3TC by analyzing the proportion of Virologic Responders 
(HIV-1 RNA <50 c/mL at Week 24). Secondary objectives are to evaluate: 1) longer term 
efficacy at Week 48, 2) safety/tolerability, and 3) cumulative resistance. The totality of 
this data (from a planned interim analysis onwards) would inform the basis of subsequent 
Phase 3 clinical trials in treatment experienced participants living with HIV-1; 
specifically two Phase 3 clinical trials will evaluate the clinical profile of GSK3640254 + 
DTG in HIV-1 infected participants). Although the Phase 3 dose selection will be based 
on another parallel Phase 2b trial, Study 208379 (GSK3640254 100, 150 or 200 mg +2 
NRTIs in HIV-1 infected treatment naïve adults), available data from this study may be 
integrated into that decision if available/appropriate.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate antiviral efficacy of 
GSK3640254 + DTG, relative to DTG + 
3TC at Week 24 in HIV-1-infected, ART-
naïve participants  
• Proportion of participants with plasma 
HIV-1 RNA <50 c/mL at Week 24 using 
the FDA snapshot algorithm 
Secondary 
• To evaluate the antiviral activity of 
GSK3640254 + DTG relative to DTG + 3TC 
at Week 48 
• Proportion of participants with plasma 
HIV-1 RNA <50 c/mL at Week 48 using 
the FDA snapshot algorithm 
• Absolute values and changes from 
baseline in HIV-1 RNA through Weeks 24 
and 48 


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Objectives 
Endpoints 
• Absolute values and changes from 
baseline in CD4+ T-cell counts through 
Weeks 24 and 48 
• To evaluate safety and tolerability of  
GSK3640254 when given in combination 
with DTG, relative to DTG + 3TC 
• 
Frequency of SAEs, Deaths and AEs 
leading to Discontinuation through 
Weeks 24 and 48 
• 
AEs of special interest (AESIs) through 
Weeks 24 and 48 
• To assess the development of viral 
resistance to GSK3640254 and other on-
study ART in participants experiencing 
virologic failure through Week 48 
• Changes in genotypic and/or phenotypic 
profiles of virus compared to baseline 
• To assess the steady-state exposure of 
GSK3640254 when given in combination 
with DTG  
• The steady-state plasma PK parameters 
of GSK3640254 will be assessed based 
on Sparse PK sampling through Week 48  
 
Overall Design: 
Study 212483 is a Phase IIb, randomized, multicentre, double-blind, active-controlled, 
parallel group study to be conducted in approximately 80 ART-naïve adults living with 
HIV-1.  Participants will be stratified by screening plasma HIV-1 RNA, by <100,000 
c/mL or ≥100,000 c/mL, and randomized to one of the three doses of blinded 
GSK3640254 (100, 150, or 200 mg) or a reference arm of blinded 3TC – each in 
combination with open label DTG.  The study will include a Screening Phase (to a 
maximum of 30 days), a double-blind Randomized Phase (first participant Day 1 to last 
participant Week 24) and an open-label Randomized Phase (last participant Week 24 to 
all ongoing participant’s Week 52). The study will be double-blind through completion of 
the overall study’s Week 24 primary endpoint analysis (achieved at least after the last 
participant completes their Week 24 visit). 
There may be modifications to study arm recruitment and/or study arm continuation 
and/or design in 212483 based on the outcome of: 1) a 212483 IDMC review prior to the 
Week 24 primary endpoint or 2) the results of an ongoing Phase 2b trial in HIV-1 
infected treatment naïve adults (Study 208379): the 208379 Week 24 primary endpoint 
(selection of an optimal dose from either 100, 150, or 200 mg). Further details on the 
implications of the analyses from these two parallel Phase 2 studies on the experimental 
dosing arms of study 212483 are described in the protocol. 
Brief Summary: 
Approximately 80 treatment-naïve, adult participants living with HIV-1 will be 
randomized into this Phase 2b study, the primary objective of which is to evaluate the 


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efficacy of GSK3640254 (initially, at three doses: 100, 150 and 200 mg) + DTG relative 
to DTG + 3TC by analyzing the proportion of Virologic Responders (participants with 
HIV-1 RNA <50 c/mL at Week 24). Participants will be stratified by screening plasma 
HIV-1 RNA, by <100,000 c/mL or ≥100,000 c/mL, and will participate for at least 
52 weeks. Participants will be followed at visits approximately every 4 weeks.  
Number of Participants: 
Approximately 160 participants will be screened to achieve approximately 80 randomly 
assigned to one of 4 arms of the study interventions, approximately 20 per GSK3640254 
arm, and approximately 20 in the DTG + 3TC Reference Arm. Targets to increase 
diversity will be defined at a country level in the study recruitment plans. 
Intervention Groups and Duration: 
The study will include: 
• A Screening Phase to a maximum of 30 days  
• A Double-blind Randomized Phase (first participant Day 1 to last participant 
Week 24) 
• An Open-label Randomized Phase (at least last participant Week 24 to last 
participant Week 52) 
 
At Day 1, participants will be randomized to receive: 
• Arm 1: Blinded GSK3640254 100 mg + Unblinded DTG 50 mg 
• Arm 2: Blinded GSK3640254 150 mg + Unblinded DTG 50 mg 
• Arm 3: Blinded GSK3640254 200 mg + Unblinded DTG 50 mg 
• Arm 4: Unblinded DTG 50 mg + Blinded 3TC 300 mg 
 
• To provide continued access to an investigational drug to participants deriving 
therapeutic benefit, participants who have successfully completed 52 weeks of 
treatment may be given the opportunity to continue to receive their study 
treatment. During the blinded randomized phase: that could be non-optimal 
GSK3640254 + DTG, optimal GSK3640254 + DTG, or 3TC + DTG).  
• During the open label randomized phase:  
• Any participant who received 3TC + DTG beyond their individual 
Week 52 visit will discontinue from the study and be transferred to locally 
available standard of care treatment.  
• Any participant who received GSK3640254 + DTG beyond their 
individual Week 52 visit will be switched to a single optimal dose of 
GSK3640254 once it is determined from the ongoing Study 208379. After 
this occurs, participants who continue to receive GSK3640254 + DTG 
beyond their individualized Week 52 will have the option to continue on 
open label optimal dose GSK3640254 + DTG until either they or their 
healthcare provider decide to discontinue study treatment or until 


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GSK3640254 + DTG is receives local marketing authorization and is 
commercially available). 
• Continued access to GSK3640254 + DTG in Study 212483 may occur, as 
described above, provided all of the following conditions are met: 
• There is evidence of continued clinical benefit for the participant, and  
• There are no comparable alternative treatment options available, and  
• Such provision of GSK3640254 + DTG is permitted under local laws and 
regulations. 
Continued access to an investigational drug will cease if the participant no longer derives 
clinical benefit from receipt of GSK3640254 + DTG; the participant meets a protocol-
defined reason for discontinuation; or the development of GSK3640254 + DTG is 
discontinued.  
Independent Data Monitoring Committee (IDMC):  
This study will utilize an Independent Data Monitoring Committee (IDMC) to ensure 
external objective medical and/or statistical review of efficacy and safety in order to 
protect the ethical interests and well-being of participants and to protect the scientific 
validity of the study. An ad-hoc review of data by the IDMC will be triggered when the 
number of participants exceeds thresholds pre-specified in the IDMC charter for either: 
protocol-defined virologic failure criteria or number of safety/tolerability events. In 
addition, the IDMC will be triggered at least at one timepoint prior to the Week 24 
primary endpoint (independent of an event-based trigger). Full details of the methods, 


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timing, decision criteria and operating characteristics will be pre-specified in the IDMC 
Charter.  
1.2. 
Schema 
 
*Participants in this study (212483) reaching Week 24 before selection of the GSK3640254 optimal dose in 
Study 208379 will continue on their original GSK3640254 dose until the optimal dose is known (expected 
prior to the overall study’s Week 24 primary endpoint). Treatment allocation will remain blinded until after 
the Week 24 primary endpoint analysis, then will become open label. 
**Participants on GSK3640254 arms may continue to receive study medication beyond their individual 
Week 52 visit. Based on the above sequence of events and when each participant reaches Week 52 relative 
to the Week 24 primary endpoint analysis, participants on GSK3640254 arms may receive: double blind 
non-optimal dose, double blind optimal dose, and/or open label optimal dose. Participants on the reference 
arm may continue to receive DTG + 3TC only if they reach their individual Week 52 visit during the Blind 
Treatment Phase. After the Open Treatment Phase starts, DTG + 3TC will be discontinued for all 
participants who have completed Week 52. Please see protocol Section 6.6 for full details. 
 


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1.3. 
Schedule of Activities (SoA) 
 
Procedures1 
 
 
 
 
 
 
 
 
 
 
Screening  
(up to 30 days before Day 1) 
Intervention Period2 
Continued 
access phase4 
Early Discontinuation/withdrawal 
Follow- up5 
Day 1 (Baseline) 
Week 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
523 
Every 
12 
weeks 
after 
Week 
52 
 
Clinical and Other Assessments 
Informed consent6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior ARV history to ensure naïve status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight (W) and BMI8 
X 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Physical exam (F=Full, T=Targeted)10 
 
F 
 
 
 
 
T 
 
T 
 
 
 
 
 
T 
 
T 
 
 
CDC HIV-1 Classification11 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-associated conditions11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Columbia Suicidality Severity Rating Scale 
(C-SSRS)13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adherence review14 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event (AE)/SAE assessments 
SAE 
Only 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG: single reading15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECG: single reading PRE-dose15 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG: triplicate readings PRE-dose to 
establish baseline average QTcF15 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedures1 
 
 
 
 
 
 
 
 
 
 
Screening  
(up to 30 days before Day 1) 
Intervention Period2 
Continued 
access phase4 
Early Discontinuation/withdrawal 
Follow- up5 
Day 1 (Baseline) 
Week 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
523 
Every 
12 
weeks 
after 
Week 
52 
ECG: single readings POST-dose at 2, 4 
and 6 hours15 
 
X 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG: single reading POST-dose any time 
between 2-6 hrs15 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Laboratory Assessments 
Quantitative plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
T-cell Lymphocyte subset 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma for storage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma for Geno/Phenotypic Resistance 
Assays17 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
PT/INR (For Child-Pugh) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipids and glucose18 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Urine Drugs of Abuse panel19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy test for POCBP only20 
S 
U/S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
HBsAg, anti-HBc, Anti-HBs, and reflex 
HBV DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV antibody and reflex HCV RNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Rapid Plasma Reagin (RPR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics – Sparse21 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 


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Procedures1 
 
 
 
 
 
 
 
 
 
 
Screening  
(up to 30 days before Day 1) 
Intervention Period2 
Continued 
access phase4 
Early Discontinuation/withdrawal 
Follow- up5 
Day 1 (Baseline) 
Week 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
523 
Every 
12 
weeks 
after 
Week 
52 
Optional Genetics sample22 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X23 
X 
X 
Dispense IP 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X23 
 
 
IP accountability (pill counts) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X23 
X 
 
Abbreviations: BMI: Body mass index; CDC: Center for Disease Control and Prevention; HIV: Human immunodeficiency virus; ECG: Electrocardiogram; RNA: Ribonucleic 
Acid; POCBP: Participant of Childbearing Potential; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C Virus; IVRS/IWRS: Interactive Voice/Web Response System 
 
1. Order of Assessments (pre-dose): C-SSRS –  ECG – Vital Signs – Blood Draws (see notes in Section 8.4 regarding order for blood draw and ECG during the Week 2 visit) 
2. The acceptable window around any visit, Week 4 and beyond, is ± 2 days. Participant must come in no later than +2 days of the visit windows or participant will run out of 
drug supply. If, due to unforeseen circumstances, a participant is unable to attend a visit during the visit window, measures for ensuring continued antiretroviral treatment and 
safety monitoring of the participant (e.g., those described in Section 10.11 for missed visits due to COVID-19), should be discussed and agreed with the Sponsor before 
implementation. 
3. Participants with plasma HIV-1 RNA ≥50 c/mL at Week 48 must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later, occurring prior to 
Week 52. 
4. Participants who meet the criteria to be offered continued access to study treatment after Week 52 (see Section 6.6) will take part in the Continued Access Phase. Any 
participant who discontinues study treatment while in the Continued Access Phase for any reason, will attend withdrawal and follow-up visits. 
5. See Section 4.1.3. 
6. Inclusion/exclusion criteria will be assessed fully at the Screening visit. Changes between the Screening visit and the Day 1 visit should be considered to ensure eligibility 
including review of additional assessments performed at Day 1. Consent for the continued access phase of the study must be obtained from the patient before or at their 
Week 48 visit, to allow additional medication to be allocated and dispensed at their Week 52 visit.  


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7. Medical History includes substance usage and the Medical Conditions listed in Exclusion Criteria in Section 5.2, as well as assessments of cardiovascular, metabolic (e.g., 
Type I or II diabetes mellitus), and, in particular, but not limited to, cardiac, psychiatric, renal (e.g., nephrolithiasis, nephropathy, renal failure), and bone disorders including 
current medical conditions. 
8. See Section 8.2.1.1. 
9. See Section 8.2.2. 
10. See Section 8.2.1. 
11. See Section 10.10. 
12. The Concomitant Medication review at Screening includes those listed in Section 6.8 to be considered relative to dosing requirements. 
13. On Day 1, participants will provide response to the eC-SSRS Baseline form prior to the RAMOS task of Randomization.  The eC-SSRS will be in electronic format, 
responses provided by participants either by phone or computer, whether they are in clinic or if they are remote (virtual visits). Participants can complete the eC-SSRS 7 
days from each visit post-randomization. See Section 8.2.6. 
14. Adherence review includes pill count, review of any recorded missed doses, and a conversation about other possible missed doses if the pill count does not match those 
recorded and/or verbally reported. 
15. See Section 8.2.3 for details.  Window for ECGs is  15 minutes. 
16. If there are COVID-19 impacts that restrict the ability for a participant to come to the clinic for the day-long visit at Week 2, then, at the least, all participants should attend the 
clinic visit for the collection of HIV-1 RNA and as many of the ECGs as possible. 
17. See Section 7.1.1. Unused plasma samples collected for the potential need of resistance testing will enter long-term storage and are then included in the pool of samples that 
can be used for further research, if participant has consented. 
18. An overnight fast is preferred prior to visits that include lipid assessments, but a minimum of 6 hours is acceptable.  
19. Also to be done for any Grade 3-4 Psychiatric AE. See Section 8.2.6. 
20. At Screening, and for POCBP only, sites will submit serum for FSH and Estradiol, and for Pregnancy testing. On Day 1, in addition to the serum sample sent to the central 
lab, a urine pregnancy test will be done in the clinic to confirm negative status prior to IP administration. If the urine test result is ambiguous, the site should await the results 
of the Day 1 serum test before study treatment can be initiated. On Treatment, a blood sample will be collected at each visit for serum pregnancy testing.  Urine pregnancy 
tests will be done every 4 weeks at home, only if virtual visits occur (results need to be reported to the site). Any ambiguous urine result will need to be retested in serum. 
S=serum, U=urine 
21. See Section 8.4 for details. 
22. A separate genetics ICF is required. 
23. If a participant is granted continued access to study treatment while the study is still in the Double-blind Treatment Phase, they will be required to return every 4 weeks to 
collect new study treatment. No other procedures or assessments will be performed at those dispensing visits. 
 
 


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2. 
INTRODUCTION 
Infection with Human immunodeficiency virus-1 (HIV-1) continues to be a serious health 
threat throughout the world, with more than 40 million individuals living with HIV 
worldwide. The current standard of care treatment for HIV-1 is combination anti-
retroviral therapy (cART) with recommendations to start regardless of CD4+ T-cell 
count, committing people living with HIV to lifelong, life-saving therapy (European 
AIDS Clinical Society (EACS) Guidelines, 2020). However, the chronic exposure to 
cART has identified anti-retroviral (ARV)-associated long-term toxicities (e.g. central 
nervous system (CNS) or cardiovascular (CV)/metabolic effects, renal disease, etc.), 
creating a need to address and prevent these co-morbidities. Also, treatment failure 
remains a continuing concern in clinical care due to the presence and emergence of 
resistant strains and tolerability issues.  The aging population of people living with HIV 
drives a need for drugs with fewer drug-drug interactions. In this environment, medicines 
with novel mechanisms of action (MoA) that can be used as part of a preferred cART 
regimen have an important role to play. However, to be successful, a new ARV agent 
must be safe and effective, provide a relatively high barrier to resistance, have low 
toxicity, have minimal drug-drug interactions, and preferably be a relatively low-dose 
once-a-day drug that can be combined with other agents as part of a fixed-dose regimen. 
GSK3640254, a next generation HIV-1 maturation inhibitor (MI), has the potential to 
meet such valued features for a new ARV medicine. 
Rationale for 2 Drug Regimen 
Fixed-dose combination therapy as a single Tablet regimen (STR) is preferred by many 
patients and has well-recognized benefits. These include the simplification of therapy by 
combining two products in fixed proportions into a single Tablet with the potential to 
increase patient adherence due to it being a simpler regimen. This also avoids the risk of 
“partial adherence”, where patients take some, but not all, of their medicines. Better 
compliance with full treatment regimens can decrease the likelihood of virologic failure 
and subsequent development of resistance.  While some STR options are now available, 
the opportunity to develop new STRs to better address toxicities and simplify treatment 
regimens for treatment-experienced patients while concurrently suppressing the 
emergence of resistance remains. 
Current treatment guidelines recommend the use of 2-3 drugs to construct a complete 
regimen for the treatment of HIV-1 in treatment naïve adults: 1) an integrase inhibitor 
based regimen with two nucleoside reverse transcriptase inhibitors (NRTIs) or 2) 
dolutegravir (DTG)/lamivudine (3TC), except for individuals with HIV ribonucleic acid 
(RNA) >500,000 c/mL or HBV coinfection [Panel on Antiretroviral Guidelines for 
Adults and Adolescents, 2021; European AIDS Clinical Society (EACS) Guidelines, 
2020]. There continues to be an interest in the use of 2-drug regimens due to the potential 
of reduced drug-related toxicities and preserving future treatment options.  


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Rationale for Dolutegravir  
Dolutegravir is a potent dual cation binding INSTI, exhibiting rapid reduction in viral 
load, best in class efficacy, and a high barrier to resistance.  In addition, due to its 
mechanism of metabolism, DTG lacks many of the frequent drug interactions associated 
with other medications commonly taken by people living with HIV. To date, the efficacy, 
pharmacokinetics (PK), safety and drug interaction potential of DTG has been evaluated 
in an extensive program of Phase I to IIIB clinical trials [GlaxoSmithKline Document 
Number RM2007/00683/14]. 
Dolutegravir in combination with other antiretroviral(s) has been shown to be beneficial 
to treatment naïve and treatment experienced patients (with or without prior Integrase 
resistance associated mutations). Given the Sponsor’s Phase 3 clinical plans to evaluate a 
fixed dose combination (FDC) of GSK3640254/DTG in HIV-1 infected virologically 
suppressed treatment experienced adults, the efficacy and resistance profiles of 
contemporary two-drug regimens containing DTG are summarized here: either as 
maintenance of suppression or induction of therapy. 
ViiV Healthcare’s SWORD-1 and -2 studies (DTG + Rilpivirine; switch indication in 
suppressed patients without prior failure or known resistance) showed non-inferiority in 
the maintenance of virologic suppression over 48 weeks following a switch to 
dolutegravir-rilpivirine compared with continuing current ARV regimen in both the 
individual studies and in the pooled SWORD data analysis [Llibre, 2018].  At Week 100 
in the Early Switch group, 456 (89%) had VL <50 c/mL. One participant with RPV 
resistance at confirmed virologic withdrawal (Early Switch group, Week 100) had pre-
existing non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations at baseline. 
No participants developed INSTI resistance [Aboud, 2019].   
ViiV Healthcare’s GEMINI-1 and -2 studies showed non-inferior efficacy and similar 
tolerability profiles of dolutegravir plus lamivudine to a guideline-recommended three-
drug regimen at 48 weeks in ART-naive adults and supports its use as initial therapy for 
patients with HIV-1 infection [Cahn, 2019]. The 2-drug regimen, dolutegravir/lamivudine 
(DTG/3TC) FDC, has a robust antiviral activity, safety profile, high barrier to resistance, 
low potential for DDIs, and can be administered as a once-daily single Tablet regimen 
(STR) through Week 96 [Cahn, 2019].   
ViiV Healthcare’s TANGO study (dolutegravir plus lamivudine switch in suppressed 
patients for > 6 months without prior failure or known NRTI or INI major resistance 
mutations) remains ongoing. Data through Week 96 showed the combination of DTG and 
3TC is non-inferior to continuing a TAF based three-drug regimen [Van Wyk, 2020]. 
These five studies show DTG plus an additional ARV agent is an effective treatment 
option for adults living with HIV-1. 
Finally, beyond the five clinical trials summarized above, DTG-based regimens have 
demonstrated robust clinical outcomes in other Phase III studies.  Further, DTG has been 
shown to be potent and to have a high barrier to resistance, and in clinical studies of 
treatment-naïve participants, DTG-based regimens have not been associated with the 
development of resistance to any component, demonstrating the clinical benefit of DTG-
based regimens in this population. 


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Rationale for Maturation Inhibitor (MI) 
GSK3640254 is a next-generation HIV-1 MI which binds near a key structural element 
within the group-specific antigen (Gag) polyprotein that is required for virion maturation 
and assembly. MIs block the last protease cleavage event between Gag protein segments 
designated as 24-kilodalton (kDa) HIV capsid (CA) protein p24 (CA [p24]) and spacer 
peptide 1 (SP1). Blockage at this step results in the release of immature non-infectious 
virus particles. Other small molecules within this class have demonstrated a 
Pharmacokinetic (PK)/Pharmacodynamic (PD) relationship and longer-term efficacy 
through Phase 2a-2b trials. 
 
As of February 2021, GSK3640254 has completed a Phase 2a study 
(short-term, monotherapy, proof of concept [POC]). Additionally, the safety, tolerability, 
and PK have been evaluated in eight other completed Phase 1 studies in healthy 
volunteers. The totality of the clinical data shows: 1) GSK3640254 is generally well-
tolerated in short-term studies, and 2) GSK3640254 has a short-term PK/PD (decline in 
HIV-1 RNA) relationship. Summaries of the pre-clinical and clinical studies are included 
in the Clinical Investigator's Brochure (CIB) [GlaxoSmithKline Document Number 
2018N379610_02]. A multinational dose range finding study (Study 208379) is ongoing 
utilizing the same three doses of GSK3640254 as this proposed study (100, 150, and 200 
mg). 
 
Rationale for GSK3640254 + DTG 
The sponsor has generated a growing body of evidence on the clinical efficacy, 
safety/tolerability, and resistance with a two ARV regimen containing DTG. As noted 
above, there is a clinical gap in these regimens with respect to the treatment experienced 
population (with DTG/3TC) or those patients with underlying NNRTI/NRTI resistance 
(either DTG/3TC or DTG/RPV).  
Chronic exposure to NRTIs may lead to telomerase and mitochondrial dysfunction, 
processes that may lead to accelerated aging, lipodystrophy, steatohepatitis and other 
aging-related morbidities [Solomon, 2014]. A novel 2DR regimen combining DTG with 
GSK3640254 may limit the risk of many common adverse reactions associated with other 
ARV drugs.  This regimen could be particularly valuable for patients with co-morbid 
conditions such as bone or cardiovascular disease, and due to both drugs’ potential 
tolerability, as well as ease of use (once daily dosing and limited potential for drug-drug 
interactions).  The proposed combination of GSK3640254 + DTG may address this 
clinical gap and warrants further investigation. 
GSK3640254 + DTG may show a clinically advantageous profile in treatment-naïve 
people living with HIV-1. Understanding the efficacy, safety/tolerability, and resistance 
profile in the treatment naïve population (which has additional treatment options 
available and provides a high bar for clinical safety/tolerability) is necessary prior to 
investigating the combination in Phase 3 studies in treatment-experienced virologically 
suppressed adults living with HIV-1.  


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2.1. 
Study Rationale  
The Sponsor proposes conducting this Phase 2b study, the primary objective of which is 
to evaluate the efficacy of GSK3640254 (initially at three doses: 100, 150, and 200 mg) + 
DTG relative to DTG + 3TC by analyzing the proportion of Virologic Responders (HIV-
1 RNA <50 c/mL at Week 24). Secondary objectives are to evaluate: 1) longer term 
efficacy at Week 48, 2) safety/tolerability, and 3) cumulative resistance. The totality of 
this data (from a planned interim analysis onwards) would inform the basis of subsequent 
Phase 3 clinical trials in treatment-experienced virologically suppressed adults living with 
HIV-1. 
2.2. 
Background 
2.2.1. 
Key Safety Data with a Prior Maturation Inhibitor (GSK3532795) 
Previously, ViiV Healthcare studied a structurally similar MI, GSK3532795, in the Phase 
2b study 205891. The Week 24 primary endpoint analysis showed GSK3532795 was not 
optimal for Phase 3 development due to gastrointestinal (GI) intolerability and treatment-
emergent resistance. Specifically, a relatively higher rate of GI intolerability 
(predominately Grade 1-2 diarrhea in 38-61% of participants and abdominal pain in 8-
22% of participants) and higher rate of nucleoside reverse transcriptase inhibitor (NRTI) 
resistance (6.5%) with clinically significant changes in GSK3532795 susceptibility was 
observed across all three GSK3532795 treatment arms [Morales-Ramirez, 2018]. Given 
these clinical and tolerability issues, ViiV Healthcare terminated study 205891 and did 
not advance GSK3532795 into Phase 3 studies. 
Aside from mild to moderate GI intolerability, 2 serious adverse events (SAEs) occurred 
in the Phase I Thorough QT study AI468044/206220 [BMS Document Control 
Number 930109388] at supra-therapeutic doses: 1 healthy participant had an episode of 
acute psychosis and another had suicidal ideation/homicidal ideation as diagnosed 
through an interview by a psychiatrist. The 2 participants received GSK3532795 240 mg 
twice daily and 240 mg once daily (QD) with food, respectively. These events were 
assessed as related to study intervention but were not observed in any other clinical study 
with GSK3532795. The most frequent neuropsychiatric adverse events (AEs) in studies 
with GSK3532795 were headache, dizziness, and sleep abnormalities (e.g., insomnia, 
abnormal dreams). 
Importantly, neither of these GI or psychiatric safety trends/findings have been 
reproduced in the completed or ongoing clinical trials of GSK3640254 in healthy 
volunteers or treatment-naïve participants living with HIV-1. 
2.2.2. 
Preclinical Summary with GSK3640254 
Nonclinical pharmacology and virology 
Activity toward a panel of clinical isolates was similar among subtypes, with median 
50% inhibitory effect (EC50) values of 2.0 and 3.0 nM, for subtypes B and C, 
respectively, and 3 nM for subtypes A and CRF01_AE. GSK3640254 was active against 
1 of 3 human immunodeficiency virus type-2 (HIV-2) isolates (EC50 = 2.5 nM). Based 


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upon in vitro potency, GSK3640254 is projected to demonstrate efficacy toward the 
majority of subtype B, C and CRF01_AE isolates at a trough concentration (Ctrough) value 
of 150 nM. Data suggest that GSK3640254 may be used in combination therapies with 
agents from any of the nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside 
reverse transcriptase inhibitors (NNRTI), integrase strand transfer inhibitor (INSTI) and 
protease inhibitor (PI) antiretroviral (ARV) classes.  
Mechanism studies indicate that GSK3640254 blocks production of infectious virus by 
specifically inhibiting HIV-1 protease-mediated cleavage at the CA (p24)/SP1 junction. 
GSK3640254 specifically binds to purified HIV-1 VLPs (Ki 0.7 nM) and dissociates 
slowly, with a half-life of 6 h. These mechanistic studies confirm that GSK3640254 
inhibits via a novel mechanism of action (MoA) that is distinct from current ARVs.  The 
A364V amino acid substitution was the most common change selected by GSK3640254 
in cell culture resistance selection experiments, appearing in several different group-
specific antigen (Gag) polymorphic backgrounds. 
Pharmacokinetics and product metabolism in animals 
Following intravenous (IV) administration, GSK3640254 exhibited low systemic 
clearance, high volume distribution, and elimination half-lives of 5.06, 4.0, 18.7 and 5.3 h 
in mouse, rats, dogs and monkeys, respectively. GSK3640254 was eliminated mainly by 
direct glucuronidation followed by biliary excretion in bile-duct-cannulated (BDC) rats. 
Following repeat oral administration in the rat and dog, increases in systemic exposure to 
GSK3640254 was generally sub-proportional with dose. There was no or minimal 
accumulation of GSK3640254 after repeat dosing, and no consistent indication of a 
difference in exposure between genders.  
Metabolic pathways observed in vitro included mono-oxidation, N-dealkylation and 
direct glucuronidation, with no unique metabolites generated in human liver microsomes 
or hepatocytes. In rat and dog plasma, GSK3640254 was either the only or the 
predominant drug-related component with minor oxidative metabolites.  
Based on the predicted systemic exposures in human, there is a potential risk for 
GSK3640254 to act as a perpetrator of drug-drug interactions of substrates of OATP1B3 
and MRP2. GSK3640254 was an inhibitor of UGT1A1 and clinical drug-drug 
interactions via this mechanism could be possible. 
Toxicology 
The primary target organ of toxicity in non-clinical studies with GSK3640254 was the 
stomach, with microscopic changes affecting parietal and chief cells in mice, rats and 
dogs.  Due to microscopic changes in the stomach of rats at the lowest dose tested after 
26 weeks, a no observed adverse effect level (NOAEL) in rats was unable to be 
determined.  Microscopic findings in the stomach of rats were minimal to mild at the 
lowest observed adverse effect level (LOAEL) of 10 mg/kg/day (AUC = 18.9 µg.hr/mL), 
corresponding to 0.63-fold the predicted highest average human exposure.  Following 39-
weeks of dosing in dogs, the NOAEL for microscopic changes in the stomach was 0.2 
mg/kg/day, and exposures were 0.28-fold the highest clinical exposure.  Microscopic 
stomach changes were associated with increases in serum gastrin when evaluated in the 


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26- and 39-week studies in rats and dogs, respectively. All microscopic findings in the 
stomach of rats and dogs and changes in serum gastrin were shown to be reversible 
following a 4-week recovery period.  Microscopic findings in the stomach were minimal 
to mild at the LOAELs of 10 mg/kg/day (AUC = 18.9 ug.hr/mL) and 1 mg/kg/day (AUC 
= 46.4 ug/hr/mL) in rats and dogs, respectively, corresponding to 0.63-fold and 1.6-fold 
highest clinical exposure.  Potential effects in the stomach of humans are being 
investigated in a Stomach Substudy of the Phase 2b Study 208379, where HIV-1 infected 
treatment naïve adults are undergoing serial Esophagogastroduodenoscopy with biopsies 
of the stomach. 
With correction for protein binding, compared to the IC50 for the hERG/IKr potassium 
channel, there is a 15.8-fold margin above the predicted average clinical maximum 
concentration (Cmax) exposure for the highest dose. Exposure where a minimal increase in 
QT interval was seen in a single dog in the single-dose safety pharmacology study in 
telemeterized dogs was 3.6-fold higher than the predicted Cmax at the highest dose. In 
addition, there were no effects on electrocardiogram (ECG) parameters in dogs given up 
to 25 mg/kg/day for 4 weeks at 19.3-fold above the predicted average Cmax at the highest 
dose. 
2.2.3. 
Key Clinical Data on GSK3640254 to date 
A summary of safety data from the completed clinical studies performed to date is 
succinctly described here for convenience. 
• No deaths or treatment-related SAEs have been reported during clinical studies with 
GSK3640254.  
• Treatment-related dermatologic AEs (including AEs leading to study discontinuation) 
included rash, drug eruption, pruritis, urticaria, and maculopapular rash. AEs of 
urticaria and maculopapular rash led to discontinuation.  
• Treatment emergent drug-related Grade 2-4 AEs included: 1) Headache (2 
participants both Grade 2; one participant in Studies 207187 and 208132, each), 2) 
Nausea (2 participants both Grade 2; one participant in Studies 208134 and 208132, 
each), and Abdominal Pain (1 participant with Grade 2 AE in Study 208132). 
• Clinically notable AEs of elevated transaminases occurred in Studies 207187 
(SAD/MAD, n = 1 healthy volunteer) and 208135 (DDI with oral contraceptive Portia 
[Ethinyl Estradiol and Levongestrel], n = 8 healthy volunteers with elevated 
transaminases, 5 of which were reported as AEs). Subsequent analysis in Study 
208135 showed no PK/PD relationship with either GSK3640254 or Portia and 
elevated transaminases. The elevated transaminases were likely due to the recent 
initiation of hormonal contraception in study participants. 
• Treatment-related AEs reported in more than 1 study included headache 
(Studies 207187, 208131, and 208132) and nausea (Studies 207187 and 208132). 
• Across studies, low grade GI intolerability has been observed: the majority of AEs 
were mild. Both Studies 207187 (MAD) and 208312 (POC) are relevant to this study 
given dosing of 7-14 days; most AEs in 207187 were unrelated and most AEs in 
208132 were related. 


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• Across studies, there were generally no clinically significant changes in vital sign 
measurements, ECG results, or safety laboratory parameters (other than the elevated 
transaminases due to Portia, noted above). Specifically, no participant has 
demonstrated QT prolongation: absolute value >500 msec, or increase from baseline 
>60 msec. 
A comprehensive description of other clinical data of GSK3640254 can be found in 
Section 5 of the Investigator Brochure and the supporting Clinical Study Reports 
(available upon request). 
2.2.4. 
Key Phase 2a (Study 208132) Clinical Data on GSK3640254  
Study Design  
Study 208132 was a two-part, Phase 2a, global, multicenter, randomized, partially-blind 
(Sponsor unblinded), placebo-controlled, adaptive clinical trial to evaluate the antiviral 
effect, safety, tolerability and PK/ PD of GSK3640254 in ART-naïve adults living with 
HIV-1. Part 1 evaluated placebo (n=2 participants) and two active doses (10 and 200 mg 
QD) of GSK3640254 in two dose arms (n=6 participants in each dose arm) – all given for 
10 days. Due to the mitigation of treatment emergent A364A/V and A364V genotypic 
changes seen in the 200 mg arm (described below), Part 2 evaluated placebo (n=2 
participants) and three active doses (40, 80, and 140 mg QD) of GSK3640254 in three 
dose arms (n=6 participants in each dose arm) – only given for 7 days.  
Primary Objective: Antiviral decline after 7 to 10 days of monotherapy 
Of the 34 randomized participants in Part 1 and 2 combined, the average age was 32 
years. Two females were randomized. The short-term antiviral response is shown in 
Table 1. 
Table 1 
Summary of Plasma HIV-1 RNA (log 10 c/mL) Change from Baseline 
and Maximum Decline from Baseline in 208132 
 
GSK3640254 
Placebo 
10 mg 
Part 1 
40 mg 
Part 2 
80 mg 
Part 2 
140 mg 
Part 2 
200 mg 
Part 1 
Part 1 
Part 2 
N = 6 
N = 6 
N = 6 
N = 6 
N = 6 
N = 2 
N = 2 
Baseline  
 
 
 
 
 
 
Mean 
4.187 
4.672 
4.433 
4.533 
4.820 
4.245 
4.750 
Median 
4.180 
4.690 
4.255 
4.455 
4.825 
4.245 
4.750 
Change from Baseline at Day 8, 9, or 10 (Part 1) or Day 8 (Part 2) 
 
Mean 
-0.137 
-1.178 
-1.015 
-1.450 
-1.700 
0.155 
0.150 
Median 
-0.125 
-1.145 
-1.035 
-1.410 
-1.570 
0.155 
0.150 
SD 
0.3730 
0.4358 
0.3299 
0.2353 
0.3447 
0.0354 
0.2263 
Maximum Change from Baseline within Study Period 
 
Mean 
-0.363 
-1.178 
-1.015 
-1.488 
-2.013 
-0.205 
-0.030 
Median 
-0.280 
-1.145 
-1.035 
-1.445 
-1.960 
-0.205 
-0.030 
SD 
0.2519 
0.4358 
0.3299 
0.2671 
0.3292 
0.2616 
0.1273 


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Secondary Objective: Assessment of Safety/Tolerability 
There were no deaths. There were two SAEs: 1) unrelated severe dilated congestive 
cardiomyopathy (Grade 3), and 2) anal abscess (Grade 1). The participant with unrelated 
severe dilated congestive cardiomyopathy also had an AE of unrelated idiopathic 
myocarditis (Grade 3). Both SAEs and the AE were unrelated to study medication. Note, 
the participant with congestive cardiomyopathy received GSK3640254 10 mg. An in-
depth discussion of this participant’s clinical course is located in Section 5.3.2.5. of the 
IB. 
There were no AEs which led to discontinuation. There were 9 participants with 14 
related AEs. Of these 14, 11 were Grade 1 (mostly gastrointestinal in nature) and three 
were Grade 2 (rash maculo-papular, abdominal pain, and nausea).  
Of the 34 participants randomized, 22 participants developed 50 individual AEs. There 
were 7 participants with seven Grade 2 AEs: abdominal pain (related), nausea (related), 
pyrexia, spine pain, rash maculo-papular (related), headache, and neutropenia. The 
remaining AEs are shown in Table 2. The most frequent AEs occurred in the 
Infections/Infestations SOC (8 participants). The most frequent individual AE was 
headache (4 participants). Although not shown, all GI AEs and Neuropsychiatric AEs 
were less than 1 day in duration except: 1) one participant had a headache (Grade 1) from 
Study Day 1-2, 2) one participant had diarrhea and vomiting (both Grade 1) from Study 
Day 4-9, and 3) one participant had constipation (Grade 1) from Study Day 1-5.  


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Table 2 
Summary of All Adverse Events by Preferred Term (Safety 
Population)  
Preferred Term 
GSK 
10 mg 
(N=6) 
GSK 
40 mg 
(N=6) 
GSK 
80 mg 
(N=6) 
GSK 
140 mg 
(N=6) 
GSK 
200 mg 
(N=6) 
Placebo 
(N=4) 
Total 
(N=34) 
Any Event 
3 (50) 
5 (83) 
4 (67) 
5 (83) 
5 (83) 
0 
22 (65) 
Headache 
0 
1 (17) 
0 
1 (17) 
2 (33) 
0 
4 (12) 
Diarrhea 
1 (17) 
1 (17) 
0 
0 
1 (17) 
0 
3 (9) 
Oropharyngeal pain 
0 
0 
0 
1 (17) 
2 (33) 
0 
3 (9) 
Nasopharyngitis 
0 
0 
0 
0 
2 (33) 
0 
2 (6) 
Vomiting 
1 (17) 
0 
0 
0 
1 (17) 
0 
2 (6) 
Abdominal pain 
0 
0 
2 (33) 
0 
0 
0 
2 (6) 
Lymphadenopathy 
1 (17) 
0 
0 
0 
1 (17) 
0 
2 (6) 
Anal abscess 
0 
0 
0 
1 (17) 
0 
0 
1 (3) 
Meningococcal infection 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Pharyngitis 
0 
0 
0 
0 
1 (17) 
0 
1 (3) 
Upper respiratory tract 
infection 
0 
0 
0 
0 
1 (17) 
0 
1 (3) 
Urinary tract infection 
0 
0 
0 
1 (17) 
0 
0 
1 (3) 
Viral infection 
0 
1 (17) 
0 
0 
0 
0 
1 (3) 
Constipation 
0 
0 
0 
1 (17) 
0 
0 
1 (3) 
Nausea 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Migraine 
0 
0 
1 (17) 
0 
0 
0 
1 (3) 
Presyncope 
0 
1 (17) 
0 
0 
0 
0 
1 (3) 
Asthenia 
0 
0 
0 
0 
1 (17) 
0 
1 (3) 
Fatigue 
0 
1 (17) 
0 
0 
0 
0 
1 (3) 
Nodule 
0 
0 
1 (17) 
0 
0 
0 
1 (3) 
Pyrexia 
0 
0 
0 
0 
1 (17) 
0 
1 (3) 
Catarrh 
0 
0 
0 
0 
1 (17) 
0 
1 (3) 
Epistaxis 
0 
1 (17) 
0 
0 
0 
0 
1 (3) 
Neutropenia 
0 
0 
1 (17) 
0 
0 
0 
1 (3) 
Pain in extremity 
0 
0 
1 (17) 
0 
0 
0 
1 (3) 
Spinal pain 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Dermatitis atopic 
0 
0 
1 (17) 
0 
0 
0 
1 (3) 
Pruritus 
0 
0 
0 
1 (17) 
0 
0 
1 (3) 
Rash maculo-papular 
0 
0 
0 
1 (17) 
0 
0 
1 (3) 
Congestive 
cardiomyopathy 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Myocarditis 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
ALT increased 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
AST increased 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Hyperglycaemia 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Insulin resistance 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Vitamin D deficiency 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Chromaturia 
1 (17) 
0 
0 
0 
0 
0 
1 (3) 
Source Data: Table 3.2 of CSR 208132 
 
There were no abnormal clinically significant arrhythmias or corrected QT interval (QTc) 
prolongations (values >500 msec or increases >60 msec from baseline) observed for any 
participant. There were no clinically significant trends in vital signs, chemistry laboratory 
values, or hematology laboratory values across the arms. 


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
3 0  
 
Sec o n d ary O bj ective: C h ar acteriz ati o n of P K Pr ofile  
G S K 3 6 4 0 2 5 4 P K para meters deri ve d b ase d o n n o mi nal ti mes f oll o wi n g o nce -dail y 
a d mi nistrati o n of 1 0 m g a n d 2 0 0 m g o n ce dail y f or 1 0 da ys were det er mi ne d o n Da y 1 
( Part 1 a n d 2) a n d eit her Da y 8-9 ( Part 1) or Da y 7 ( Part 2) ( Ta ble 3 ). F oll o wi n g o nce-
dail y a d mi nistrati o n of G S K 3 6 4 0 2 5 4 o ver 1 0 m g t o 2 0 0 m g d ose ra n ge wit h a m o derate 
fat meal, Da y 1 m e dia n Tma x  ra n ge d bet w ee n 3. 0 0 –  5. 5 0  h o urs. Varia bilit y i n t he P K 
para meters [ % bet wee n -p artic i pa nt c oefficie nt of v ariati o n ( C V b)] ra n ge d fr o m 1 9 % t o 
5 2 %.  
Stea d y -st ate ( D a y 8-9 or 7 f or Part 1 a n d Part 2, res pecti vel y) me dia n T ma x  ra n ge d 
bet wee n 4. 0 0 h a n d 5. 5 0 h. Varia bilit y i n t he P K para meters [ % C V b] was l o w t o 
m o derate, ra n gi n g fr o m 1 9. 5 % t o 4 7 %.  
Alt h o u g h t he sa m ple siz e is s mall, G S K 3 6 4 0 2 5 4 de m o nstrate d ge n erall y d ose -
pr o p orti o nal P K o ver t he d ose ra n ge st u die d ( 1 0 –  2 0 0 m g). C o nsiste nt wit h a nti viral 
decli ne descri be d a b o v e, t he P K para meters of: a) 4 0 a n d 8 0 m g a p pr o xi mate d eac h ot h er, 
a n d b) 1 4 0 a n d 2 0 0 m g a p pr o xi mate d eac h ot her. T here were t hree p artici p a nts i n t he 
8 0  m g ar m w h o ha d e x p os ure si milar t o t hat o bser ve d at 4 0 m g d os e ( dat a n ot s h o w n).  
C CI


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Table 3 
Summary Statistics of Day 1 and Day 8-9 (Part 1) or Day 7 (Part 2) PK 
Parameters Following Multiple Daily Dose Administration of 
GSK3640254 in Study 208132 
PK Parameter 
10 mg 
n=6 
40 mg  
n=6 
80 mg 
n=6 
140 mg 
n=6 
200 mg 
n=61 
Geometric Mean [CVb%] (95% CI) 
Day 1 
AUC(0-24)  
(µg*h/mL) 
0.695 [13.5] 
(0.588, 
0.821) 
3.25 [31.7] 
(2.35, 4.50) 
6.12 [38.8] 
(4.13, 9.07) 
14.0 [36.6] 
(9.67, 20.4) 
12.4 [91.3] 
(5.48, 28.0) 
Cmax (µg/mL) 
0.059 
[177.4] 
(0.017, 
0.207) 
0.232 [30.5] 
(0.169, 
0.317) 
0.433 [33.6] 
(0.307, 
0.610) 
0.918 [41.5] 
(0.604, 
1.395) 
0.938  [82.3] 
(0.441, 2.00) 
Tmax (h) 
(median)[range] 
2.93 
[0.00, 5.00] 
4.42 
[3.97, 8.00] 
4.08 
[2.95, 6.17] 
5.51 
[3.00, 6.25] 
5.53 
[3.92, 8.05] 
Steady 
State 2 
AUC(0-24)  
(µg*h/mL) 
0.908 [44.7] 
(0.580, 
1.422) 
7.46 [26.8] 
(5.66, 9.84) 
11.8 [26.7] 
(8.98, 15.6) 
29.3 [27.9] 
(22.0, 39.0) 
27.9 [18.4] 
(23.1, 33.8) 
Cmax (µg/mL) 
0.055 [41.3] 
(0.036, 
0.083) 
0.469 [20.6] 
(0.379, 
0.581) 
0.747 [23.7] 
(0.585, 
0.955) 
1.86 [26.0] 
(1.42, 2.43) 
1.86 [19.5] 
(1.51, 2.27) 
Tmax (h) 
(median)[range] 
4.02 
[1.87, 5.00] 
4.06 
[2.00, 8.00] 
4.58 
[4.00, 5.18] 
4.08 
[2.92, 5.20] 
5.48 
[3.00, 6.20] 
Ctau  (µg/mL) 
0.027 [47.0] 
(0.017, 
0.043) 
0.219 [30.1] 
(0.161, 
0.298) 
0.360 [31.1] 
(0.262, 
0.495) 
0.798 [34.1] 
(0.563, 
1.131) 
0.703 [29.6] 
(0.519, 
0.953) 
CI = Confidence interval 
1One participant In the 200 mg group has been excluded from PK analysis for day 1 due to vomiting 
within 1x tmax post-dose 
2Steady State was measured at Visit 5/6 (Day 8/9 in Part 1 vs Day 7 in Part 2) [Based on FTIH study, mean 
half-life ranges between 21 h – 28 h] 
The key PK modelling and simulation data from Study 208132 is summarized in the dose 
justification in Section 4.3. 
2.3. 
Benefit/Risk Assessment 
Based upon preclinical and clinical studies (including the prior MI GSK3532795), the 
potential risks for GSK3640254 are GI intolerability (e.g., abdominal pain and diarrhea) 
and gastric toxicity (effects on parietal cell and chief cells), prolongation of the corrected 
QT interval (QT), neuropsychiatric safety, skin and subcutaneous tissue disorders, and 
treatment emergent virologic resistance.   
To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability/reversible gastric toxicity, QT prolongation, skin and subcutaneous tissue 
disorders, and neuropsychiatric safety), this clinical study will include relatively healthy 


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treatment-naïve adults living with HIV-1 who will receive clinical, ECG, and laboratory 
evaluations during their participation. 
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK3640254 may be found in the Investigator’s Brochure 
(IB) [GlaxoSmithKline Document Number 2018N379610_02]. 
 


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
Study Intervention GSK3640254   
Cardiovascular (QT prolongation) 
Non-clinically, GSK3640254 inhibited cardiac hERG/IKr 
potassium, cardiac SCN5A sodium and L-type calcium 
channel currents recorded from HEK 293 cells stably 
transfected with complementary DNA from the ion 
channels. In a single-dose safety pharmacology study in 
telemeterized dogs, increases in QT interval (up to 20 ms) 
occurred primarily in 1 dog given 17 mg/kg. Later, there 
were no GSK3640254-related effects on 
electrocardiogram (ECG) parameters in dogs given up to 
25 mg/kg/day for up to 39 weeks. 
 
In Study 207187 (MAD) the concentration-QTc analysis, a 
QTcF effect above 10 ms could be excluded up to 
GSK3640254 plasma concentrations of approximately 
2000 ng/mL (corresponding to doses approximately 
200 mg QD). Importantly, in GSK3640254 clinical trials to 
date, there have been no abnormal clinically significant 
arrhythmias, and no participants have met the trial-based 
Stopping Criteria for QTcF prolongations: values >500 ms 
or increases >60 ms from Baseline. 
Protocol exclusion criteria based on screening 
ECG parameters and cardiac medical history 
(see Section 5.2). 
 
Participants will have regular ECG monitoring 
during the course of the study (see Section 
1.3) with QTc stopping criteria (see Section 
7.1.3). 
 
As noted in Section 7.1.3, if a clinically 
significant finding is identified (including but 
not limited to changes from baseline in QT 
interval corrected using Fridericia’s formula 
[QTcF]) after enrollment, the investigator or 
qualified designee will determine if the 
participant meets QTc Stopping Criteria, and if 
any change in participant management is 
needed. This review of the ECG printed at the 
time of collection must be documented. Any 
new clinically relevant finding should be 
reported (at minimum) as an AE. 
Gastrointestinal intolerability  
Non-clinically, signs of gastrointestinal intolerability 
(sporadic vomiting and abnormal faeces beginning on Day 
1 and continuing throughout the dosing periods) occurred 
mainly in dogs at ≥1 mg/kg/day. In humans, GI 
Protocol exclusion criterion based on pre-
existing GI pathology or baseline GI 
signs/symptoms (see Section 5.2) 
 


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Mitigation Strategya,b 
intolerability (predominately abdominal pain and diarrhea) 
was seen with a structurally related compound 
GSK3532795 which was evaluated through Phase 2b 
dosing. 
 
While summarized in detail in the IB, the rates of all GI 
AEs (all Grade 1 regardless of relationship) in the MAD 
portion of Study 207187 (Phase 1 FTIH) were 33%, 0%, 
24%, and 29% in participants who received GSK3640254 
50, 100, 200, and 320 mg daily for 14 days (the only 
completed study with the greatest duration and dose of 
dosing), respectively (relative to a rate of 21% in 
participants who received placebo).  
Participants will undergo continuous 
evaluation for adverse events during their 
participation in the trial; there are clinical 
stopping criteria based upon intensity of 
treatment-emergent AEs (see Section 7.1). 
Additionally, a GI intolerability evaluation and 
monitoring plan is available to guide the 
investigator should GI AEs emerge (see 
Section 8.2.7). 
 
 
Gastric Toxicity 
Gastric toxicity effects on parietal cells and/or chief cells 
associated with changes in serum gastrin levels were 
present in preclinical species. These findings were 
reversible. 
It is unclear if gastric toxicity occurs in 
humans; and if present what the 
histopathological findings are (whether they 
correlate with AEs, biomarkers, etc). To 
explore the monitoring of gastric toxicity, a 
subset of ~7 participants in each arm from the 
208379 study will take part in the Optional 
Stomach Sub-study and will undergo EGD 
with Biopsy of the greater and lesser 
curvature (for subsequent histopathologic 
examination) along with a measurement of 
Serum Biomarkers. There is no clinical 
approach for evaluating gastric toxicity in 
Study 212483. 
 
 


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Potential Risk of Clinical Significance 
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Mitigation Strategya,b 
Neurologic/psychiatric safety 
 
Two psychiatric SAEs in previous MI GSK3532795 clinical 
program (acute psychosis, homicidal/suicidal ideation) at 
supratherapeutic doses were seen in healthy participants 
in a TQT study. 
 
From a Neurologic and Psychiatric AE summary and 
PK/PD analysis for GSK3532795 across all studies, mild 
G1 headache and G1 sleep abnormalities were the 
predominant AEs, with a trend for increasing neurologic 
and psychiatric AEs with increasing dose (based on TQT 
and P2b studies). No exposure-response relationship 
seen for select neurologic and psychiatric AEs (based on 
TQT and P2b studies) CNS penetration data for 
GSK3532795 and GSK3640254 in rats demonstrate a 
similarly low brain distribution/penetration. 
 
While summarized in the IB, the rates of all Nervous 
system and Psychiatric AEs in the MAD (Study 207187 
FTIH) ranged from 24-57% and 0-17%, respectively 
across doses (50-320 mg x 14 days) without any trend.  
 
No GSK3640254 clinical trial has observed SAEs of acute 
psychosis or homicidal/suicidal ideation. 
Protocol exclusion criterion based on any pre-
existing psychiatric condition (including results 
of psychological assessment and the eC-
SSRS tool) in participants. 
 
Continuous evaluation for adverse events 
during their participation in the trial including 
direct AE inquiry as noted in Section 1.3.  
 
Participants will also provide responses to the 
eC-SSRS throughout the study. Ultimately, in 
the event of a new onset suicidality ideation or 
behavior (SIB), as determined by the 
investigator (in consultation with psychiatry, as 
needed), the participant will discontinue from 
the trial and the Investigator will arrange for 
urgent specialist psychiatric evaluation and 
management.  
 
Guidance for the management of emergent 
psychiatric symptoms are available (see 
Section 8.2.6 ). 
 
There are clinical stopping criteria based upon 
intensity of treatment-emergent psychiatric 
AEs (see Section 7.1). 
 


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Mitigation Strategya,b 
The participant informed consent form 
includes information on the risk of depression 
and suicidal ideation and behaviour. 
Skin and subcutaneous tissue disorders 
Across clinical trials, AEs leading to discontinuation have 
included urticaria and maculopapular rash 
Participants with a history of drug or other 
allergy that, in the opinion of the investigator 
or Medical Monitor, contraindicates their 
participation are excluded. Participants will 
undergo continuous evaluation for adverse 
events during their participation in the trial 
supplemented by the use of physical exams. 
Protocol includes individual participant 
stopping criteria, including any Grade 3 or 
higher rash, or Grade 2 rash with any 
systemic signs, allergic symptoms, or if 
mucosal involvement develops. (see Section 
10.9.3). 
 
Study Intervention DTG 
Hypersensitivity reaction (HSR) and 
rash 
 
HSR has been observed uncommonly with DTG.  Rash 
was commonly reported in DTG Phase IIb/III clinical trials; 
episodes were generally mild to moderate in intensity; no 
episodes of severe rash, such as Stevens-Johnson 
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and 
erythema multiforme were reported.  
Participants with a history of drug or other 
allergy that, in the opinion of the investigator 
or Medical Monitor, contraindicates their 
participation are excluded. 
 
Guidelines for the management of HSR are 
provided in Section 10.9.2. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
Also see Section 7.1, Discontinuation of Study 
Intervention. 
Specific/detailed toxicity management 
guidance is provided for rash (Section 
10.9.3.1) 
 
The participant informed consent form (ICF) 
includes information on this risk and the 
actions participants should take in the event 
of a HSR or associated signs and symptoms. 
 
Drug induced liver injury (DILI) and 
other clinically significant liver chemistry 
elevations 
Non-clinical data suggested a possible, albeit low, risk for 
hepatobiliary toxicity with DTG.  Drug-related hepatitis is 
considered an uncommon risk for ART containing DTG 
regardless of dose or treatment population.  For 
participants with hepatitis B virus (HBV) and/or hepatitis C 
virus (HCV) co-infection, improvements in 
immunosuppression as a result of HIV virologic and 
immunologic responses to DTG- containing ART, along 
with inadequate therapy for HBV co-infected participants, 
likely contributed to significant elevations in liver 
chemistries.  A review of postmarketing data found that 
the number of cases reporting particularly severe liver 
dysfunction was found to be very low in the context of 
exposure to DTG and DTG/ABC/3TC. The reported cases 
of severe liver dysfunction (including acute hepatic failure) 
are complex with potential confounding factors but in a 
very small number of cases, drug-induced liver injury is 
Participants meeting any of the following 
criteria during the screening period are 
excluded from participating. 
• Alanine aminotransferase (ALT) 3 times 
the-upper limit of normal (ULN) or ALT 
2xULN and bilirubin 1.5x ULN  
• Infection with Hepatitis B or Hepatitis C, 
as described in the Exclusion Criteria (See 
Section 5.2) 
 
Specific/detailed liver stopping criteria and 
toxicity management guidance is provided for 
suspected DILI or other clinically significant 
liver chemistry elevations (Section 10.9.1). 
 


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Potential Risk of Clinical Significance 
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Mitigation Strategya,b 
likely and the role of DTG-containing regimens cannot be 
ruled out particularly in those involving DTG. 
 
Psychiatric disorders 
Psychiatric disorders including suicidal ideation and 
behaviours are common in people living with HIV. Events 
of suicidal ideation, attempt, behaviour and completion 
were observed in clinical studies of DTG, primarily in 
participants with a pre-existing history of depression or 
other psychiatric illness.  
Protocol exclusion criterion based on any pre-
existing psychiatric condition (including results 
of psychological assessment and the C-SSRS 
tool) in participants. 
 
Continuous evaluation for adverse events 
during their participation in the trial including 
direct AE inquiry as noted in Section 1.3.  
 
Participants will also provide responses to the 
C-SSRS throughout the study. Ultimately, in 
the event of a new onset suicidality ideation or 
behavior (SIB), as determined by the 
investigator (in consultation with psychiatry, as 
needed), the participant will discontinue from 
the trial and the Investigator will arrange for 
urgent specialist psychiatric evaluation and 
management.  
 
Guidance for the management of emergent 
psychiatric symptoms are available (see 
Section 8.2.6).  
 
There are clinical stopping criteria based upon 
intensity of treatment-emergent psychiatric 
AEs (see Section 7.1). 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
 
The participant informed consent form 
includes information on the risk of depression 
and suicidal ideation and behaviour. 
Theoretical serious drug interaction with 
dofetilide and pilsicainide 
Co-administration of DTG may increase 
dofetilide/pilsicainide plasma concentration via inhibition of 
organic cation transporter (OCT-2), resulting in potentially 
life-threatening toxicity. 
The co-administration of DTG with dofetilide 
or pilsicainide is prohibited in the study 
(Section 6.8.1). 
Renal function 
Mild elevations of creatinine have been observed with 
DTG which are related to a likely benign effect on 
creatinine secretion with inhibition of OCT-2.  DTG has 
been shown to have no significant effect on glomerular 
filtration rate (GFR) or effective renal plasma flow. 
Specific/detailed toxicity management 
guidance is provided for participants who 
develop a decline in renal function (Section 
10.9.6). 
 
Creatinine clearance is calculated in all 
participants prior to initiating therapy and 
renal function (creatinine clearance and 
serum phosphate) will be monitored at all 
subsequent study visits. 
 
Neural tube defects 
In a birth outcome surveillance study in Botswana there 
have been 7 cases of neural tube defects reported in 
3,591 deliveries (0.19%) to mothers taking dolutegravir-
containing regimens from the time of conception, 
compared with 21 cases in 19,361 deliveries (0.11%) to 
mothers taking non-dolutegravir-containing regimens from 
the time of conception (Prevalence Difference 0.09%; 
95% CI -0.03-0.30). 
1. Participants who are female at birth who 
are breastfeeding or plan to become 
pregnant or breastfeed during the study 
are excluded. 
2. Participants who become pregnant, or 
who desire to be pregnant while in the 
study, or who state they no longer are 
willing to comply with the approved 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
In the same study, no increased risk of neural tube 
defects was reported in women who started DTG during 
pregnancy. Two out of 4,448 deliveries (0.04%) to 
mothers who started dolutegravir during pregnancy had a 
neural tube defect, compared with five out of 6,748 
deliveries (0.07%) to mothers who started non-
dolutegravir-containing regimens during pregnancy. 
A causal relationship of these events to the use of 
dolutegravir has not been established. The incidence of 
neural tube defects in the general population ranges from 
0.5-1 case per 1,000 live births. As neural tube defects 
occur within the first 4 weeks of foetal development (at 
which time the neural tubes are sealed) this potential risk 
would concern women exposed to dolutegravir at the time 
of conception and in early pregnancy. 
Data analysed to date from other sources including the 
Antiretroviral Pregnancy Registry, clinical trials, and post-
marketing data are insufficient to address the risk of 
neural tube defects with dolutegravir. 
More than 1,000 outcomes from second and third 
trimester exposure in pregnant women indicate no 
evidence of increased risk of adverse birth outcomes. 
In animal reproductive toxicity studies, no adverse 
development outcomes, including neural tube defects, 
pregnancy avoidance methods, will have 
study treatment discontinued and will be 
withdrawn from the study. 
3. Participants of reproductive potential are 
reminded re: pregnancy avoidance and 
adherence to contraception requirements 
at every study visit. 
4. Pregnancy status is monitored at every 
study visit 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
were identified. Dolutegravir was shown to cross the 
placenta in animals. 
Study Intervention 3TC 
Renal Function 
3TC is eliminated by renal excretion and exposures 
increase in participants with renal dysfunction. 3TC is not 
recommended to treat participants with a creatinine 
clearance <50 mL/min. 
Specific/detailed toxicity management 
guidance is provided for participants who 
develop a decline in renal function (Section 
10.9.6). 
 
Creatinine clearance is calculated in all 
participants prior to initiating therapy and renal 
function (creatinine clearance and serum 
phosphate) will be monitored at all 
subsequent study visits. 
 
Participants with creatinine clearance <50 
mL/min are excluded from participation in this 
study. In addition, if an on-treatment estimated 
GFR of <50 mL/min is confirmed, then study 
medications will be discontinued and the 
participant withdrawn. 
 
HIV-1 Infection/Patient Population 
HIV Resistance to GSK3640254 and 
other on-study treatments 
 
There is an intrinsic risk of resistance (genotypic changes 
or decreased phenotypic susceptibility) to any 
developmental ARV (or the ARVs which are co-
administered).  
As described above, this risk will be mitigated 
using the following approaches.  


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategya,b 
 
Note: Data from Study 208132 (Phase 2a POC) showed a 
decline in HIV-1 RNA and reasonable PK profile. 
However, some participants receiving GSK3640254 had 
treatment emergent resistance mutations associated with 
maturation inhibitors observed on or after Day 11 (after 10 
days of receiving GSK3640254 monotherapy). However, 
no resistance to existing and commercially available 
classes of antiretroviral medications (e.g., reverse 
transcriptase, protease, or integrase inhibitors) was 
observed as there is no known cross-resistance between 
maturation inhibitors and other classes of ARVs.  
1) HIV-1 RNA at Week 2 will be obtained to 
demonstrate a decline relative to Day 1. 
2) All participants will have their HIV-1 RNA 
monitored at frequent intervals and have 
criteria for resistance testing based upon 
the development of Protocol Defined 
Virologic Failure (Section 7.1.1) 
a. Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired 
Immune Deficiency Syndrome [DAIDS] toxicity gradings for HIV-infected participants). Serious/severe events will be managed appropriately including, but not 
limited to, withdrawal of study intervention, and will be followed to resolution as per Sponsor’s standard medical monitoring practices.   
b. Clinical Safety Data will be routinely reviewed in GlaxoSmithKline (GSK)/ViiV Healthcare Safety Review Team meetings. This will include in-stream review of data 
from this clinical trial on a routine basis. 
 


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2.3.2. 
Benefit Assessment 
Participants in this clinical study may benefit from receiving a combination of ARVs 
containing GSK3640254. Data from the Phase 2a study does show a PK/PD (decline in 
HIV-1 RNA) relationship (described in detail in Section 4.3). Thus, GSK3640254 may 
contribute to a decline in HIV-1 RNA (and maintenance of suppression) when 
administered with DTG. A decline in HIV-1 RNA is directly associated with a reduction 
in HIV/AIDS related morbidity/mortality. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize the potential risks to participants in this 
study, the potential risks identified in association with GSK3640254 + DTG are justified 
by the anticipated benefits that may be afforded to participants with HIV-1 infection 
achieving and maintaining virologic suppression. 
3. 
OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
• To evaluate antiviral efficacy of 
GSK3640254 + DTG, relative to DTG + 
3TC at Week 24 in HIV-1-infected, ART-
naïve participants  
• Proportion of participants with plasma 
HIV-1 RNA <50 c/mL at Week 24 using 
the FDA snapshot algorithm 
Secondary 
• To evaluate the antiviral activity of 
GSK3640254 + DTG relative to DTG + 3TC 
at Week 48 
• Proportion of participants with plasma 
HIV-1 RNA <50 c/mL at Week 48 using 
the FDA snapshot algorithm 
• Absolute values and changes from 
baseline in HIV-1 RNA through Weeks 24 
and 48 
• Absolute values and changes from 
baseline in CD4+ T-cell counts through 
Weeks 24 and 48 
• To evaluate safety and tolerability of  
GSK3640254 when given in combination 
with DTG, relative to DTG + 3TC 
• 
Frequency of SAEs, Deaths and AEs 
leading to Discontinuation through 
Weeks 24 and 48 
• 
AEs of special interest (AESIs) through 
Weeks 24 and 48 


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
4 4  
 
O bjecti ves  
E n d p oi nts  
•  T o ass ess t h e d evel o p m ent of vir al 
r esist a nc e t o G S K 36 40 2 54 a n d ot h er o n-
st u dy A R T in partici p a nt s exp eri e nci ng 
vir ol o gic f ail ur e thr o u g h W eek 4 8 
•  C h a n ges i n g e noty pic a nd/ o r p h e noty pic 
pr ofil es of vir us c o m p are d to b aseli n e  
•  T o ass ess t h e st ea dy -st ate ex p osur e of 
G S K 36 4 02 54 w h en giv en i n c o m bi n atio n 
wit h D T G   
•  T h e st ea dy -st at e pl as m a P K p ar a m et ers 
of G S K 3 64 02 5 4 will b e assess e d b as ed 
o n Sp ars e P K sa m pli n g thr ou g h W eek 48   
E x pl or at or y  
C CI


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
4 5  
 
O bjecti ves  
E n d p oi nts  
4.  
S T U D Y D E SI G N  
4. 1.  
O v er all D e si g n  
St u d y 2 1 2 4 8 3 is a P hase II b, ra n d o mize d, m ultice ntre, d o u ble -bli n d, acti ve -c o ntr olle d, 
parallel gr o u p st u d y t o be c o n d ucte d i n a p pr o xi matel y 8 0 A R T -naï ve a d ults li vi n g wit h 
HI V -1.  Partici p a nts will be stratifie d by scree ni n g plas ma HI V -1 R N A, b y < 1 0 0, 0 0 0 
c/ m L or ≥1 0 0, 0 0 0 c/ m L , a n d ra n d o mize d t o o ne of t he t hree d oses of bli n de d 
G S K 3 6 4 0 2 5 4 ( 1 0 0, 1 5 0, or 2 0 0 m g) or a refere n ce ar m of bli n de d 3 T C –  eac h i n 
c o m bi nati o n wit h o pe n la bel D T G ( See Secti o n  1. 2 ).  T he st u d y will i ncl u de a Scree ni n g 
P hase (t o a ma xi m u m of 3 0 da ys) , a d o u ble-bli n d Ra n d o mize d P hase ( Da y 1 t o Wee k 2 4) 
a n d a n o pe n -l a bel Ra n d o miz e d P hase ( Wee k 2 4 t o Wee k 5 2). T he st u d y will be d o u ble-
bli n d t hr o u g h t he Wee k 2 4 pri mar y e n d p oi nt.  
A n ot her P hase 2 b st u d y , 2 0 8 3 7 9 , has bee n o n g oi n g si nce N o ve m ber 2 0 2 0. St u d y 2 0 8 3 7 9 
is a P hase 2 b d ose ra n ge fi n di n g trial w h ere HI V-1 i nfecte d treat me nt n aï v e a d ults are 
ra n d o mize d t o eit her o ne of t hree e x peri me ntal d oses of G S K 3 6 4 0 2 5 4 (als o 1 0 0, 1 5 0, a n d 
2 0 0 m g) or D T G –  i n c o m bi nati o n wit h i n vesti gat or selecte d d ual N R TI t h era p y. 
St u d y  2 0 8 3 7 9 c o ntai ns at least o ne i nteri m a nal ysis ( of efficac y a n d safet y /t olera bilit y) 
perf or me d b y a n I D M C usi n g data fr o m t he first ~ 5 0 partici pa nts w h o ha v e c o m plete d 
t heir Wee k 1 2 visit. T he pri mar y e n d p oi nt is t he pr o p orti o n of vir ol o gi c res p o n ders at 
Wee k 2 4.  
St u d y 2 1 2 4 8 3 st art e d recr uit me nt i n a d va nce of t he i nitial 2 0 8 3 7 9 I D M C r e vie w. T he  
2 0 8 3 7 9 I D M C iss ue d a n o -acti o n letter o n 0 6 -O C T -2 0 2 1, s o St u d y 2 1 2 4 8 3 c o nti n ue d  t o 
ra n d o mize partici pa nts t o all t hree e x peri me ntal ar ms.  
T his st u d y will utilize a n I n d e pe n de nt Data M o nit ori n g C o m mittee (I D M C) t o e ns ure 
e xter nal o bjecti ve me dical a n d/ or statistical re vie w of efficac y a n d safet y i n or der t o 
pr otect t he et hical i nterests a n d well -bei n g of partici pa nts a n d t o pr otect t he scie ntific 
vali dit y of t he st u d y. A n a d -h oc re vie w of data b y t he I D M C will be tri g gere d w he n t he  
n u m ber of partici p a nts e x cee ds t hres h ol ds pre -s p ecifie d i n t he I D M C c harter f or eit her: 
pr ot oc ol -defi ne d vir ol o gi c fail ure  criteria or n u m b er of safet y/t olera bilit y e ve nts. I n 
a d diti o n, t he I D M C will be tri g gere d at a ti me p oi nt pri or t o t he pri mar y e n d p oi nt. F ull 
details of t he met h o ds, ti mi n g, decisi o n criteria a n d o perati n g c haracteristics will be pre -
s pecifie d i n t he I D M C C harter. If a rate f or P D V F or safet y/t olera bilit y e ve nts tri g ger 
re vie w b y t he St u d y 2 1 2 4 8 3 I D M C, t he f oll o wi n g p ote ntial i m plicati ons ma y h ol d tr ue 
f or ori gi nall y  ra n d o mize d partici pa nts ( partici pa nts w h o are n ot yet ra n d o mize d w o ul d be 
ma na ge d as d escri be d i m me diatel y a b o ve) : 
1)  If t he 2 1 2 4 8 3 I D M C r ec o m me n ds ter mi nati o n of t he 1 0 0 m g ar m (e. g. s u b-
t hera pe utic effic ac y): St u d y 2 1 2 4 8 3 will disc o nti n ue all partici pa nts i n t he 1 0 0 m g 
e x peri me ntal ar m a n d t he PI will tra nsiti o n t he m t o t he S O C c A R T. 
C CI


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2) If the 212483 IDMC recommends termination of either 150 or 200 mg arm: Study 
212483 will re-randomize all participants on the 150 or 200 mg experimental 
arms, respectively to the remaining experimental arms. Termination of the 
experimental 150 mg dose alone is clinically unlikely (see Scenario 3 and 4 
immediately below). 
3) If the 212483 IDMC recommends termination of both 150 and 200 mg arms 
(e.g. safety/intolerability): Study 212483 will switch all participants on the 150 
and 200 mg experimental arms to the remaining experimental 100 mg arm. 
4) If the 212483 IDMC recommends termination of both 100 and 150 mg arms due 
to subtherapeutic efficacy: Study 212483 will discontinue all participants in the 
100 and 150 mg experimental arm and the PI will transition them to the SOC 
cART. 
5) If the 212483 IDMC recommends termination of both 100 and 200 mg arms due 
to subtherapeutic efficacy and safety/tolerability, respectively: Study 212483 will 
discontinue all participants in the 100 mg experimental arm and the PI will 
transition them to the SOC cART. Study 212483 will re-randomize all 
participants on the 200 mg experimental arm to the remaining experimental 
150 mg arm. 
 
Possible Implication for Originally Randomized Participants 
Possible 
Decision  
100 mg 
150 mg 
200 mg 
No doses D/C All doses continue 
100 mg D/C 
100 mg Transition to 
SOC 
150 and 200 mg doses continue 
150 mg D/C 
This is a unique and unlikely situation and would be managed as 
below  
(100 and 150 mg D/C due to subtherapeutic efficacy OR 150 and 200 
mg D/C due to safety/tolerability) 
200 mg D/C 
 100 mg Continues 
150 mg Continues 
200 mg re-
randomized to 
remaining 
experimental arms 
100 and 150 
mg D/C 
100 and 150 mg Transition to SOC 
Continues 
100 and 200 
mg D/C 
100 mg Transition to 
SOC 
150 mg Continues 
200 mg switched to 
remaining 150 mg 
arm 


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Possible Implication for Originally Randomized Participants 
150 and 200 
mg D/C 
Continues 
150 and 200 mg switched to remaining 100 
mg arm 
All doses 
D/C 
All doses Transition to SOC 
 
Study 208379 Week 24 Primary Analysis of Efficacy, Safety/Tolerability, & Resistance  
The Sponsor’s 208379 Study team will evaluate the totality of unblinded data for 
efficacy, safety/tolerability, and resistance on one, two, or three experimental arms (the 
variable number of arms reflects potential for 208379 IDMC recommendations). The 
review of this data (relative to pre-established internal Go/No-Go criteria) will result in 
the selection of an optimal continuation dose which will be used on all participants in the 
experimental arms of Study 208379 after the last participant completes their Week 48 
visit. Once the optimal continuation dose selection is made in Study 208379, all 
participants on remaining experimental arms in Study 212483 will be handled as follows: 
1) Study 212483 participants on the optimal one GSK3640254 dose arm (selected 
from study 208379): these participants will continue to receive their original 
blinded dose until the Study 212483 primary endpoint. 
2) Study 212483 participants on the non-optimal GSK3640254 dose arms (not 
selected from study 208379): participants will shift from their current dose to the 
optimal GSK3640254 dose. The blinded drug supply will be provided until the 
study 212483 Week 24 primary endpoint. 
Approximately 160 participants will be screened to achieve approximately 80 randomly 
assigned to one of 4 arms of the study interventions, approximately 20 per GSK3640254 
arm, and approximately 20 in the DTG + 3TC Reference Arm. Targets to increase 
diversity will be defined at a country level in the study recruitment plans. 
The study will include: 
• A Screening Phase to a maximum of 30 days  
• A Double-blind Randomized Phase (first participant Day 1 to last participant 
Week 24) 
• An Open-label Randomized Phase (last participant Week 24 to last participant 
Week 52) 
 
At Day 1, participants will be randomized to one of the following study treatment arms.   
All participants will receive 5 bottles of study treatment (1 with DTG tablets, 3 with 
GSK3640254 or matching placebo tablets and 1 with 3TC or matching placebo capsules) 
to maintain the study blind through last participant Week 24. Participants will take 1 
tablet/capsule from each bottle at each dose. 


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• Arm 1: Blinded GSK3640254 100 mg + Unblinded DTG 50 mg 
• Arm 2: Blinded GSK3640254 150 mg + Unblinded DTG 50 mg 
• Arm 3: Blinded GSK3640254 200 mg + Unblinded DTG 50 mg 
• Arm 4: Unblinded DTG 50 mg + Blinded 3TC 300 mg 
 
Once the study enters the open-label randomized phase, participants will take only the 
number of tablets required to make up their dose. Participants in the DTG + 3TC arm will 
switch from over-encapsulated 3TC to open-label 3TC tablets. 
4.1.1. 
Screening Period 
Assuming a screen failure rate of 50%, approximately 160 participants will be screened 
for this study to randomize approximately 80 eligible participants.  
Participants will enter a Screening period of up to 30 days. 
At the Screening visit, fasting blood samples and urine will be collected, an ECG will be 
done, and participants will be asked to provide responses to the eC-SSRS Baseline 
assessment about thoughts and feelings throughout their entire lifetime and current 
experience (within the last 2 months). 
Prohibited Medications (Section 6.8.1.2) will be reviewed for any medications the 
participant is taking that need to be stopped as much as 4 weeks prior to the first dose. 
Participants may be rescreened once (See Section 5.4). However, participants who are 
randomized into the trial and subsequently withdrawn from the study, for any reason, 
may not be rescreened.  
4.1.2. 
Treatment Period 
Visits may be conducted within a window of ± 2 days. The exception to this is the Week 
2 visits, which may be conducted between Days 11- 14.  
Any interruption in therapy during the treatment period of 3 or more consecutive days, 
for any reason, must be discussed with the ViiV Medical Monitor prior to resumption of 
therapy, if possible. If therapy was resumed without prior approval (i.e., if the PI was not 
aware at the time of the missed doses), the Investigator should contact the ViiV Medical 
Monitor upon becoming aware. 
Participants will be asked to complete a diary card that will capture key dosing times 
prior to visits that collect PK samples as well as dates of any missed doses that can be 
recalled. Site staff will perform pill counts to check compliance.  At every visit site staff 
will discuss the importance of adherence, ensuring participants understand the risk for 
developing resistance that comes with non-compliance.  
Dose administration on all arms requires participants to dose in the morning (due to study 
PK and/or post-dose ECG requirements and for consistency of daily dosing), and at/near 
the same time each day (see the SRM for guidance). 


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Study intervention administration during the double-blind phase of the study should be 
with a low-fat meal (see Section 5.3.1).  Thereafter, during the open-label phase, only 
dose administration with GSK3640254 requires participants to be dosed with a low-fat 
meal. 
All subjects will provide samples for Sparse PK at Weeks 2, 4, 8, 12, 24 and 48.  At each 
of these visits, a PK sample is drawn at the beginning of the visit with all of the other 
blood samples. 
The visit at Week 2 is to be done by all study participants (for collection of HIV-1 RNA, 
plasma for storage, pre-dose PK, a pre-dose ECG and all 3 post-dose ECGs).   
Fasting requirements: 
• Participants need to fast for a minimum of 8 hours prior to the visits at which 
lipids are collected. An overnight fast is preferred. 
4.1.2.1. 
Day 1 through Week 24  
Participants will be randomized to either: one of the three blinded, QD, oral 
GSK3640254 dose regimens (approximately 20 participants per treatment arm, each in 
combination with DTG), or to the active control Reference Arm of DTG + 3TC 
(approximately 20 participants).  
• Arm 1: Blinded GSK3640254 100 mg + unblinded DTG 50 mg 
• Arm 2: Blinded GSK3640254 150 mg + unblinded DTG 50 mg 
• Arm 3: Blinded GSK3640254 200 mg + unblinded DTG 50 mg 
• Arm 4: Unblinded DTG 50 mg + blinded 3TC 300 mg 
On Day 1, there are several pre-dosing assessments and procedures, then ECGs are also 
required 2, 4 and 6 hours post-dose. ECGs are also required 2, 4 and 6 hours post-dose at 
Week 2. 
Participants will be seen in-clinic for study visits approximately every 4 weeks. At these 
clinic visits, blood and urine will be collected, ECG(s) will be done at some visits, and 
participants will be asked to provide responses to the eC-SSRS questions about their 
thoughts since the last visit (See Section 1.3).  
4.1.2.2. 
Week 24 through 52 
Participants will be seen in-clinic for study visits approximately every 4 weeks (See 
Section 1.3).  
4.1.2.2.1. Potential cART Reimbursement after Last Dose of Study Treatment 
Sponsor recognizes that the clinical goal is for all participants to achieve and maintain 
virologic suppression. When a participant is discontinued from the trial early, whether 


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they are a Virologic Non-Responder at Week 24 or they are withdrawn early for any 
other reason, there may be situations where sites may be reimbursed for up to a 6-week 
supply of Investigator selected/prescribed antiretroviral medication to facilitate the 
transition of participants to non-study cART. Any brief duration of reimbursement longer 
than 6 weeks, expected to be in individual and rare circumstances, may be considered 
with Sponsor.  
Specific direction will be provided by GSK/ViiV, who will determine for which 
country(ies) this is not a viable option, e.g., where reimbursement is not allowed by local 
regulations, or where acquisition of cART can be obtained without delay.   
4.1.3. 
Follow-up 
After the last dose, when a participant withdraws early (at any point prior to the end of 
the study, including Virologic Non-responders at Week 24), participants will be required 
to be seen in-clinic for a follow-up visit between 2 to 4 weeks after their Early 
Withdrawal visit. These data comprise an essential evaluation that needs to be done 
before discharging any participant from the study. 
Beyond this follow-up visit (outside of the study), all AEs, SAEs and clinically relevant 
vitals, ECG findings, and lab abnormalities will be followed towards acceptable clinical 
resolution. 
Participants who are withdrawn for reasons of safety should continue to be followed even 
beyond the study final, follow-up visit (outside of the study) to assess the outcome of the 
safety event that triggered discontinuation of study intervention (as determined by the 
Investigator).  
An in-clinic Follow-Up visit will be conducted 2-4 weeks after the last dose of study 
medication for participants with ongoing AEs, serious adverse events (SAEs) regardless 
of attributability, and any laboratory abnormalities that are considered to be AEs or 
potentially harmful to the participant, at the last on-study visit (Week 52). Assessments at 
the Follow-up visit should reflect any ongoing complaints (e.g., blood draws to follow a 
laboratory abnormality). 
Any participant who continues to access to study treatment after their Week 52 visit and 
who subsequently discontinues study treatment for any reason will be asked to attend a 
discontinuation/withdrawal visit and a follow-up visit. They will undergo the same 
procedures and assessments as for the Early Withdrawal and follow-up visits required for 
participants who discontinue or withdraw during the main study (see Section 1.3). 
Discontinuation/withdrawal visits during continued access will be captured on distinct 
eCRF pages to those from the main study.      
4.1.4. 
Study Completion  
For study status purposes, a participant is considered to have completed the study if they 
completed the Week 52 visit. The Follow-Up visit is not required for successful 
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• To provide continued access to an investigational drug to participants deriving 
therapeutic benefit, participants who have successfully completed 52 weeks of 
treatment may be given the opportunity to continue to receive their study 
treatment. During the blinded randomized phase: that could be non-optimal 
GSK3640254 + DTG, optimal GSK3640254 + DTG, or 3TC + DTG).  
• During the open label randomized phase:  
• Any participant who received 3TC + DTG beyond their individual 
Week 52 visit will discontinue from the study and be transferred to locally 
available standard of care treatment.  
• Any participant who received GSK3640254 + DTG beyond their 
individual Week 52 visit will be switched to a single optimal dose of 
GSK3640254 once it is determined from the ongoing Study 208379. After 
this occurs, participants who continue to receive GSK3640254 + DTG 
beyond their individualized Week 52 will have the option to continue on 
open label optimal dose GSK3640254 + DTG until either they or their 
healthcare provider decide to discontinue study treatment or until 
GSK3640254 + DTG is receives local marketing authorization and is 
commercially available). 
• Continued access to GSK3640254 + DTG in Study 212483 may occur, as 
described above, provided all of the following conditions are met: 
• There is evidence of continued clinical benefit for the participant, and  
• There are no comparable alternative treatment options available, and  
• Such provision of GSK3640254 + DTG is permitted under local laws and 
regulations. 
Continued access to an investigational drug will cease if the participant no longer derives 
clinical benefit from receipt of GSK3640254 + DTG; the participant meets a protocol-
defined reason for discontinuation; or the development of GSK3640254 + DTG is 
discontinued.  
Importantly, study 212483 may be terminated early by the CMO at least if either of the 
two situations below occur:  
a) This study 212483 IDMC recommends discontinuing all remaining experimental arms,  
b) Results from study 208379 primary analysis prompt a development decision (e.g. 
termination) for GSK3640254. 
4.2. 
Scientific Rationale for Study Design 
Based on available GSK3640254 data, including in vitro virology, PK, antiviral 
activity/resistance, and safety/tolerability data from completed clinical trials, doses 100 
mg, 150 mg and 200 mg QD are anticipated to provide adequate antiviral 
activity/efficacy and be well-tolerated (in combination with DTG). As described earlier, 
these are the same three doses used in the ongoing Phase 2b dose-range finding trial, 
Study 208379, in HIV-1 infected treatment naïve adults. The primary endpoint will assess 
efficacy by determining the proportion of virologic responders (participants with plasma 


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HIV-1 RNA <50 c/mL at Week 24). HIV-1 RNA is highly predictive of meaningful 
clinical benefit [U.S. Food and Drug Administration, Center for Drug Evaluation and 
Research, 2015].   
The reference arm (DTG + 3TC) chosen for this study is an accepted regimen for 
initiation of antiretroviral therapy in treatment guidelines [European AIDS Clinical 
Society (EACS) Guidelines, 2020; Panel on Antiretroviral Guidelines for Adults and 
Adolescents, 2021] and, as such, is considered appropriate for this trial. 
4.2.1. 
Participant Input into Design  
Community experts participated in review of the protocol study design and entry criteria. 
Based on feedback received, text was added to align with our company position to clarify 
that receipt of a SARS-CoV-2 vaccine that has received emergency, conditional, or 
standard market authorization is allowed. 
4.3. 
Justification for Dose 
The planned doses of GSK3640254 for this Phase 2b study (100 mg, 150 mg, and 200 mg 
QD administered with food) were selected based on population PK and exposure-
response (E-R) modelling and clinical trial simulations of antiviral effect as described in 
this section. The doses were targeted to achieve a minimum of 75% of maximum effect 
predicted at day 8 and to maintain steady-state C above the 3-times protein binding-
adjusted EC90 (3xPBAEC90) target of 0.11 µg/mL (in-vitro EC90 value for in-vitro 
virus containing R361K/V362I/L363M substitutions) in 95% of the participants.  
A population pharmacokinetic model was developed using the single dose (1 – 400 mg) 
and multiple dose (50-320 mg QD for 14 days) data from healthy participants from the 
FTIH study 207187, as well as the multiple dose data in participants living with HIV-1 
(10 mg – 200 mg QD for 7-10 days from study 208132). All doses were administered 
with a moderate-fat meal. The pharmacokinetics of GSK3640254 (given with food) was 
described by a two-compartment model with sequential zero-order absorption (in the 
depot compartment) followed by first order absorption (from depot to the central 
compartment) and first order elimination. Inter-individual variability was estimated on 
the apparent oral clearance (CL/F), apparent volume of distribution of the central 
compartment (V2/F), intercompartmental clearance (Q/F), absorption rate constant (Ka), 
and duration of the zero-order process (D1). The CL/F and V2/F were scaled using fixed 
allometric coefficients of 0.75 and 1, respectively. Weight was found to be a significant 
covariate on Ka. In addition, ‘STUDY’ (i.e. 207187 vs. 208132, as a surrogate for subject 
type and GSK3640254 salt differences) was also found to be significant covariates on 
bioavailability (F was ~27% lower in the FTIH study compared to that from the PoC). 
Evaluation of the post-hoc individual estimates of Cmax, AUC and C indicated that 
model-estimated PK parameters were comparable to the observed values. 
The objective of the E-R analysis was to characterize the relationship between antiviral 
activity and exposure of GSK3640254 in participants living with HIV-1, and to 
determine the effect of key covariates (including baseline EC50, baseline HIV-1 RNA, 
baseline CD4 and CD8 T-cell counts) on GSK3640254 antiviral activity. The E-R 


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analysis was conducted using the data from the Phase 2a study 208132 (up to day 8/9 
[Visit 5] in Part 1 and up to day 8 [Visit 6] in Part 2. All doses were administered with a 
moderate-fat meal. The decline in HIV-1 RNA over 7 or 10 days (and the treatment 
emergent genotypic and phenotypic changes) in treatment naïve adults living with HIV-1 
is described in Section 2.2.4. 
The E-R was assessed via an inhibitory Emax model using the observed average steady-
state C and maximum viral load decline from baseline. None of the screened covariates 
were found to be significant and therefore were not included in the full covariate model. 
The population PK model of GSK3640254 was integrated with the E-R model and short-
term clinical trials simulations were conducted (500 trials with 60 participants/ dose level 
mrgsolve_0.8.9 package in R version 3.2.5) by sampling from the multivariate normal 
distribution and covariance matrix to include both uncertainty in parameter estimates and 
inter-subject variability. It was assumed that the bioavailability of GSK3640254 in Phase 
2b will be similar to that from study 208132 (Phase 2a). For each individual, the 
anticipated response (maximum viral load decline) and percent of maximum effect was 
estimated. Simulations were then summarized by computing the median percent of 
maximum effect for each dose across the trials. The results of the simulations 
summarized in Table 4 indicate that doses ≥100 mg QD administered with food are 
predicted to result in a median percent of maximum effect at day 8 of at least 75%. In 
addition, a 300 mg QD dose is not predicted to provide a significant increase in predicted 
% of maximum effect compared to the 200 mg dose.   
Table 4 
Predicted Median Percent of Maximum Effect [90% PI] at Day 8 for 
GSK3640254 Doses Ranging from 75 mg to 300 mg QD administered 
with food (500 trials with n=60 participants per dose level) 
Dose (mg) 
Median [5%, 95%] Percent of Maximum Effect 
75 
70.4 [47.5, 95.4] 
100 
78.0 [54.5, 98.1] 
125 
83.1 [61.4, 99.6] 
150 
86.4 [66.6, 101] 
200 
90.4 [73.1, 102] 
300 
94.2 [80.1, 103] 
PI = Prediction Interval 
 


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Figure 1 depicts the predicted decline in viral load versus C at Day 8 and boxplot 
summary of predicted C by proposed dose levels. 
Figure 1 
Simulated Predicted Decline in HIV-1 RNA versus Predicted C at 
Day 8 
Top panel – Dashed and solid blue lines are 5th, 95th and median of simulated data, respectively. Shaded area is the 
90% prediction interval of simulated data. Bottom panel – the middle bar inside the boxes represents the median; 
the ends of the boxes are the 25th and 75th percentiles; the whiskers are the 5th and 95th percentiles of simulated 
C. The red dashed line in both panels represents the 3xPBAEC90 (determined in-vitro based on virus with 
R361K/V362I/L363M substitutions). 
 
Table 5 presents the model-predicted steady-state GSK3640254 PK parameters at the 
planned doses following QD administration with food. As expected, the predicted PK 
parameter values for the maximum proposed dose of 200 mg QD administered with food 
fall within the observed 95% CI of the geometric mean PK parameters from the PoC 
study 208132 (Table 3 in Section 2.2.4).  The associated inhibitory quotient (IQ) for each 
dose was calculated by dividing C median [5th – 95th percentiles] by the 3xPBAEC90 
(Table 5).  
The results show that all proposed doses are predicted to result in C values 
>3xPBAEC90 in more than 95% of the participants (i.e. C 5th percentile for the 100 mg 
dose >0.11 g/mL) (Table 5). In addition, the planned doses provide a median IQ ranging 
from 4 – 8. Taking into account the variability in parameter estimates, the predicted IQ 
over the proposed doses ranges from 1.4 to 18.2.  By comparison, for GSK3532795, a 
previous generation MI, the median IQ in phase 2b (calculated as C/1xPBAEC90 based 


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on in-vitro 370 virus) for the 180 mg QD dose (maximum tested dose) was 
approximately 1.5. Therefore, assuming a biologically plausible correlate between Day 8 
antiviral response and Week 24 efficacy, when GSK3640254 is combined with DTG, the 
response rate at week 24 is likely to be similar or better than GSK3532795 180 mg QD 
(i.e. >82.4% for week 24 snapshot HIV-1 RNA <40c/mL).  
Table 5 
Predicted Steady-State PK Parameters Median [90% PI] Following 
Once a Day Dosing of GSK3640254 with Food and Associated IQ 
Dose 
(mg) 
Median [5th – 95th Percentiles] 1 
Cmax (g/mL) 
AUC(0-24) (g.h/mL) 
C (g/mL) 
IQ (Fold Above 
3xPBAEC90)2 
100 
1.11 [0.652-1.9] 
15 [8.2-27] 
0.442 [0.153-0.999] 
4 [1.4 - 9.1] 
150 
1.67 [0.978-2.85] 
23 [12-41] 
0.663 [0.23-1.5] 
6 [2.1 - 13.6] 
200 
2.22 [1.3-3.8] 
30 [16-54] 
0.883 [0.307-2] 
8 [2.8 - 18.2] 
PI = Prediction Interval 
1All simulations included uncertainty and inter-subject variability in parameter estimates. 
2 3xPBAEC90 = 0.11 g/mL based on in-vitro virus containing R361K/V362I/L363M 
substitutions. 
 
Calculated Fold Coverage for Selected Doses 
Predicted GSK3640254 safety coverage based on NOAEL and LOAEL exposure in the 
non-clinical chronic toxicity studies in rat and dog for the at the planned doses given once 
daily with food are presented in Table 6.  
Table 6 
Predicted Safety Cover Following Once a Day Dosing of 
GSK3640254 with Food 
Dose (mg) 
Fold cover dog NOAEL:human 
AUC(0-24) 1 
Fold cover rat LOAEL:human 
AUC(0-24) 2 
Fold cover dog 
LOAEL:human AUC(0-24)3 
100 
0.56  
1.26  
3.1 
150 
0.36  
0.82  
2.0 
200 
0.28 
0.63  
1.6 
1 Based on dog NOAEL mean AUC of 8.37 from non-clinical chronic studies and the model-predicted median AUC 
(Table 5). 
2 Based on rat LOAEL mean AUC of 18.9 µg.h/mL  from non-clinical chronic studies and the model-predicted 
median AUC (Table 5).  
3 Based on dog LOAEL mean AUC of 46.4 µg.h/mL  from non-clinical chronic studies and the model-predicted 
median AUC (Table 5).  
 
At the highest planned dose of 200 mg QD, the model-based predicted exposure 
corresponds to 0.3-fold the NOAEL (AUC = 8.37 ug.hr/mL) in dogs, 0.6-fold the 
LOAEL in rats (AUC = 18.9 ug.hr/mL) and 1.6-fold the LOAEL in dogs (AUC = 46.6 
ug.hr/mL) from chronic toxicity studies (See Section 2.2.2). All microscopic findings in 
the stomach of rats and dogs and changes in serum gastrin were shown to be reversible. 
Potential effects in the stomach of humans during clinical trials are being investigated in 
a gastric substudy in study 208379, with appropriate clinical monitoring for GI 
intolerability in study 212483. 


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With regard to potential for QT prolongation, in the concentration-QTc analysis using the 
Multiple Ascending Dose data collected in the FTIH study 207187, a QTcF effect above 
10 ms could be excluded up to GSK3640254 mean plasma concentrations of 
approximately 2000 ng/mL, which corresponds to doses of approximately 200 mg. As 
described in Section 2, there is a cardiovascular risk mitigation strategy for QT 
prolongation. 
Evaluated and anticipated Drug Interactions Between GSK3640254 and DTG 
In this Phase IIb study, GSK3640254 will be combined with DTG.  
DDI risk with DTG 
A Phase 1, two-way drug interaction study with GSK3640254 and DTG showed no effect 
on plasma GSK3640254 PK. GSK3640254 200 mg QD increased plasma DTG AUC(0-
τ), Cmax and Cτ by 17%, 9%, and 24%, respectively. These increases were not 
considered clinically meaningful. 
In summary, based on the lack of observed or predicted clinically meaningful drug 
interactions, GSK3640254 can be administered with DTG without dose adjustments.  
Assessment of the Change in Formulation and Effect of Food 
The recently completed Phase 2a clinical trial (208132) utilized capsules; this Phase 2b 
will use tablets. Study 213567 was a relative bioavailability and food effect study 
performed to compare the exposures between the GSK3640254 tablet and capsule in the 
presence of moderate fat meal and to investigate the effect of food on the PK of the 
GSK3640254 tablet. As shown in Table 7, the tablet provided similar exposures to the 
capsule when both were given with food.  
Table 7 
Assessment of Relative Bioavailability: Preliminary Statistical 
Comparison of Plasma GSK3640254 PK Parameters Based on 
Nominal Time (Study 213567) 
PK Parameter 
Ratio of GLS Means for Test vs. Reference [90%CI] (%Ref) 
AUC(0-) h*g/mL  
99.8 [92.6, 108] 
AUC(0-t) h*g/mL 
100 [93.2, 108] 
Cmaxg/mL 
109 [98.8, 121] 
1. 
Ref: Treatment A;  Test: Treatment B 
Treatment A: GSK3640254 200 mg (capsules) administered under moderate fat conditions. 
Treatment B: GSK3640254 200 mg (tablets) administered under moderate fat conditions. 
 
The summary of the statistical analysis for the assessment of food effect presented in 
Table 8 shows that GSK3640254 AUC(0-) and Cmax values following administration 
of the tablet with a moderate fat meal are 345% to 484% higher relative to administration 
in a fasted state, respectively. In addition, GSK3640254 AUC(0-) and Cmax following 
administration of the tablet with a high fat meal is 306% to 365% higher relative to 
administration in fasted state, respectively.  


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Table 8 
Assessment of Food Effect: Preliminary Statistical Comparison of 
Plasma GSK3640254 PK Parameters Based on Nominal Time (Study 
213567) 
PK Parameter 
Test vs Ref 
Ratio of GLS Means for Test vs. Reference [90%CI] (%Ref) 
AUC(0-) h*g/mL  
C vs D 
345 [288, 413] 
E vs D 
306 [256, 366] 
AUC(0-t) h*g/mL 
C vs D 
378 [318, 449] 
E vs D 
335 [282, 399] 
Cmaxg/mL 
C vs D 
484 [391, 599] 
E vs D 
365 [295, 451] 
Treatment C: GSK3640254 200 mg (tablets) administered under moderate fat conditions (test). 
Treatment D: GSK3640254 200 mg (tablets) administered under fasted conditions (ref). 
Treatment E: GSK3640254 200 mg (tablets) administered under high fat conditions (test). 
In summary, the results from the RBA and food effect study indicate that no dose 
adjustments are required due to the change in formulation based on:  
• The similarity in PK parameters between the tablet to used in this Phase 2b study 
and the capsule used in the Phase 2a in the presence of a moderate fat meal. 
• The dose predictions are based on modelling of the data from studies in which 
GSK3640254 was administered with food. 
In conclusion, 212483 is anticipated to study a range of exposures which should provide 
therapeutic benefit (virologic suppression from antiviral activity) while being well 
tolerated in combination with DTG. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last Week 52 visit of the last participant 
in the study. 
A participant is considered to have completed the study if the participant has completed 
all phases of the study up to and including the Week 52 visit. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety. Therefore, adherence to the criteria as specified in the protocol is 
essential. 
 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare Investigational Product (IP) or 
other study treatment that may impact participant eligibility is provided in the current IB 


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GlaxoSmithKline Document Number 2018N379610_02 for GSK3640254, and in the 
current IB GlaxoSmithKline Document Number RM2007/00683/14 for DTG/3TC.  
Participants are allowed to rescreen for this study one time with the exception of 
clinically irreversible findings in Screening; examples include but are not limited to: liver 
cirrhosis, CDC Stage 3 disease, drug allergy/sensitivity, significant psychiatric disorder, 
or cardiac arrythmias.  
A single repeat test (retest) per laboratory analyte is allowed during a single Screening 
period to determine eligibility.  
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participants must be 18 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Treatment-naïve, defined as no ARVs (in combination or monotherapy) received 
after a known diagnosis of HIV-1 infection  
NOTE: Use of PrEP (prior to known HIV-1 infection) is allowed and still meets 
inclusion. PrEP is used by individuals who are not infected with HIV-1 but who are 
at high risk for acquiring the virus.  PrEP alone is not sufficient to treat HIV and the 
use of PrEP is stopped if/when a diagnosis of HIV is made. 
3. Documented HIV infection and Screening plasma HIV-1 RNA  1000 c/mL;   
4. Screening CD4+ T-cell count 250 cells/mm3 . 
Weight  
5. Body weight 50.0 kg (110 lbs.) for men and 45.0 kg (99 lbs) for women and body 
mass index (BMI) > 18.5 kg/m2.  Calculations will utilize sex assigned at birth. 
Sex 
Sex and Contraceptive/Barrier Requirements 
6. Male and female  
a. Participants who are male at birth: There are no contraceptive requirements for 
participants who are male at birth 
b. Participants who are female at birth:  
Contraceptive use by participants who are female at birth should be consistent with 
local regulations regarding the methods of contraception for those participating in 
clinical studies. 


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• A participant who is female at birth is eligible to participate if they are not pregnant 
or breastfeeding, and one of the following conditions applies: 
o Is not a participant of childbearing potential (PONCBP) as defined in Section 
10.4. 
OR 
o Is a POCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, as described in 
Section 10.4 during the study intervention period and until after the last dose 
of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
o If a hormonal method is selected, the participant is required to be 
clinically stable on it for at least one month prior to starting treatment 
in the study. 
• A POCBP must have a negative highly sensitive serum pregnancy test at 
Screening and a negative urine pregnancy test at Day 1 before starting study 
intervention. 
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), 
a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
• Additional requirements for pregnancy testing during and after study intervention 
are located in Section 8.2.5 Pregnancy Testing. 
• The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a participant with an 
early undetected pregnancy 
Informed Consent 
7. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
Other 
8. For participants enrolled in France: a participant will be eligible for inclusion in 
this study only if either affiliated to or a beneficiary of a social security category. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 
3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic 
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2. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or 
penile intraepithelial neoplasia;  
Note: Other localized malignancies require agreement between the investigator 
and the Medical Monitor for inclusion. 
3. Presence of primary HIV infection, evidenced by acute retroviral syndrome (e.g., 
fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) documented 
viremia without antibody production and/or evidence of recent (within 3 months) 
documented seroconversion;  
4. Known history of liver cirrhosis with or without viral hepatitis co-infection; 
5. Unstable liver disease (as defined by any of the following: presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or 
persistent jaundice or cirrhosis), known biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver 
disease per investigator assessment) 
6. History of ongoing or clinically relevant hepatitis within the previous 6 months; 
7. History of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation;  
8. Any history of significant underlying psychiatric disorder, in the opinion of the 
Investigator or Medical Monitor, including but not limited to schizophrenia, bipolar 
disorder with or without psychotic symptoms, other psychotic disorders, or 
schizotypal (personality) disorder; or a clinical assessment of suicidality based on 
the responses on the eC-SSRS. 
9. Any history of major depressive disorder with or without suicidal features, or anxiety 
disorders, that required medical intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient 
treatment;   
Note: Participants with other conditions such as adjustment disorder or dysthymia 
that have required shorter term medical therapy (<6 months) without inpatient 
treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the Medical Monitor. 
10. Any pre-existing physical or other psychiatric condition (including alcohol or drug 
abuse), which, in the opinion of the Investigator or Medical Monitor (with or without 
psychiatric evaluation), could interfere with the participant’s ability to comply with 
the dosing schedule and protocol evaluations or which might compromise the safety 
of the participant;  
11. A pre-existing condition, in the opinion of the Investigator or Medical Monitor, that 
could interfere with normal gastrointestinal anatomy or motility (e.g., 
gastroesophageal reflux disease [GERD], gastric ulcers, gastritis, inflammatory 
bowel disease), hepatic and/or renal function, or with the absorption, metabolism, 
and/or excretion of the study interventions or render the participant unable to take 
oral study treatment; 


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12. Myocardial infarction, acute coronary syndrome, unstable angina, stroke, transient 
ischemic attack, or intermittent claudication in the past 3 months; 
13. Familial or personal history of long QT syndrome or sudden cardiac death; 
14. Medical history, current or historical, of significant cardiac arrhythmias or ECG 
findings which, in the opinion of the Investigator or Medical Monitor, will interfere 
with the safety of the participant;  
Note: Examples of ECG findings include symptomatic bradycardia, non-sustained 
or sustained atrial arrhythmias, non-sustained ventricular tachycardia (VT) or 
sustained VT, second degree atrioventricular block (AVB) Mobitz Type II, or 
third degree AVB. 
Prior/Concomitant Therapy 
15. Active treatment for a viral infection other than HIV-1, such as Hepatitis B, with an 
agent that is active against HIV-1 (were known to be infected with HIV-1 after 
treatment for Hepatitis B was completed); 
16. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;  
17. Treatment with any of the following agents within 28 days of Screening: radiation 
therapy, cytotoxic chemotherapeutic agents, any systemic immune suppressant;  
18. Participants receiving any protocol-prohibited medication and who are unwilling or 
unable to switch to an alternate medication;   
19. Participants who require concomitant medications known to be associated with a 
prolonged QTc (see list from https://www.crediblemeds.org). 
Prior/Concurrent Clinical Study Experience 
20. Exposure to an experimental drug, human blood product, monoclonal antibody, or 
vaccine (which does not have emergency, conditional, or standard market 
authorization) within 28 days prior to the first dose of study treatment; 
Note: Consult with the Medical Monitor if clarification is needed. Receipt of a 
SARS-CoV-2 vaccine that has received emergency, conditional, or standard 
market authorization is allowed if the PI determines that the benefit-risk profile 
for that individual study participant is favourable.  The use of other 
investigational COVID vaccines that have not received emergency, conditional, 
or standard market authorization and are still only used in clinical trials will not 
be allowed at this time. 
21. Current enrollment or past participation within the last 30 days before signing of 
consent in any other clinical study involving an investigational study intervention 
(including an investigational COVID vaccine) or any other type of medical research. 


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Diagnostic assessments 
22. Historical evidence (prior to study screening period) of the presence of resistance-
associated mutations gag A364V or A364A/V. Historical evidence of the presence of 
resistance to the integrase inhibitor class or to lamivudine. 
23. Creatinine Clearance <50 mL/min;  
24. ALT ≥ 3x ULN or ALT ≥ 2x ULN and total bilirubin ≥ 1.5x ULN (upper limit of 
normal) 
25. Evidence of Hepatitis B virus (HBV) infection based on the results of testing for 
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), 
Hepatitis B surface antibody (anti-HBs) and reflex HBV DNA as follows: 
a. Participants positive for HBsAg are excluded; 
b. Participants negative for anti-HBs but positive for anti-HBc (negative 
HBsAg status) and positive for HBV DNA on reflex testing are excluded 
Note: Participants positive for anti-HBc (negative HBsAg status) and positive for 
anti-HBs (past and/or current evidence) are immune to HBV and are not 
excluded.  
See SRM for further details. 
26. Positive Hepatitis C antibody test result at Screening AND positive on reflex to 
Hepatitis C RNA; 
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  
27. Known or suspected active COVID-19 infection OR contact with an individual with 
known COVID-19, within 14 days of study enrollment (WHO definitions Section 
10.11.5.2.1). Note, this study does not require a negative molecular test for SARS-
CoV-2 for entry into the study. 
28. Untreated syphilis infection [positive rapid plasma reagin (RPR) at Screening] 
without documentation of treatment.   
Note: Participants with a known syphilis infection can be Screened for the study 
no sooner than 14 days after the last dose of treatment for the syphilis infections.  
Participants who are assessed to have syphilis by the Screening tests can be 
treated within the Screening period, though the start of study treatment can be no 
sooner than 30 days after the last dose of treatment for the syphilis infection.   
29. Presence of moderate-to-severe hepatic impairment (Class B or C) as determined by 
Child-Pugh classification (see Section 10.7);  
30. Any acute laboratory abnormality at Screening, which, in the opinion of the 
investigator or Medical Monitor, would preclude participation in the study of an 
investigational compound; 
31. Urine Drug Screen positive (showing presence of): Amphetamines, Barbiturates, 
Cocaine, MDMA, or Phencyclidine, or non-prescribed opiates, oxycodone, 
benzodiazepines, methadone, methamphetamines or tricyclic antidepressants; 


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Notes: 
If the urine drug screen shows the presence of opiates, oxycodone, 
benzodiazepines, methadone, methamphetamines or tricyclic antidepressants that 
are prescribed, the participant can be considered for the trial at the discretion of 
the Investigator recognizing at the time of enrolment: no studies on relevant drug 
interaction or GSK3640254 absorption-distribution-metabolism-elimination 
(ADME) will have been completed.  
A positive result for THC is not exclusionary, though the PI should assess usage 
and only refer for the treatment phase those participants who seem appropriate for 
the trial, i.e., whose use of marijuana would not interfere with the participant’s 
ability to comply with the required daily dosing schedule and protocol 
evaluations, or that might compromise the safety of the participant. 
32. Any clinically relevant Grade 4 laboratory abnormality at Screen, including results 
for creatine phosphokinase (CPK), ALT, and lipid abnormalities that lack a 
compelling explanation from the Investigator;        
Note:  Grade 4 CPK, ALT and lipid abnormalities that are explained by the 
Investigator, and with assent from the Medical Monitor, will not exclude the 
participant. 
33. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 28 days;  
34. Exposure to more than 4 new investigational drugs or vaccines (exclusive of a 
SARS-CoV-2 potential indication) within 12 months prior to the first dosing day;  
35. ECG Heart Rate <50 bpm or >100 bpm, or QTcF >450 msec; 
Notes: 
• A heart rate of <50 or >110 is exclusionary and cannot be rechecked to 
determine eligibility.  
• A heart rate from 101 - 110 bpm can be rechecked by a single repeat ECG or 
by vitals within 30 minutes to verify eligibility. 
• The QT interval is corrected for heart rate according to Fridericia’s formula 
(QTcF). It is either machine read or manually over-read by the Investigator. 
QTcF is used to determine eligibility and discontinuation for a participant in 
this study.  
• The Investigator’s or Medical Monitor’s over-read can supersede that of the 
machine at any time. 
36. FOR PORTUGAL ONLY: HIV-2 infection (either determined by prior testing, 
medical history, or obtained locally during the Screening window) 
Exclusion Criteria 37 and 38 FOR FRANCE ONLY: 
37. Persons deprived of their liberty by a judicial or administrative decision; 
38. Adults subject to legal protection or unable to express their consent will not be 
included in the study 


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Other Exclusions 
To assess any potential impact on participant eligibility with regard to safety, the 
Investigator must refer to the IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions, 
contraindications, AEs, drug interactions, and other significant data pertaining to the 
study interventions. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Study intervention administration during the double-blind phase of the study should be 
with a low-fat meal.  Thereafter, during the open-label phase, dose administration with 
GSK3640254 requires participants to take their  dose with a low-fat meal (may include 
but not limited to 400-500 calories, with 25% calories from fat) [FDA, 2019].   
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• It is suggested that alcohol consumption should be limited throughout study 
participation to the following: An average weekly intake of <14 drinks for 
participants assigned as male at birth or <7 drinks for participants assigned as females 
at birth. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. 
• Only clinically minor to moderate use (as determined by the PI) of tobacco products 
will be allowed during study participation.  
• Participants should refrain from the use of marijuana. 
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 24 hours before each clinic visit 
to reduce the chances of seeing a high CPK result in the study lab results.  
• 
See Section 10.9.5 for follow up assessments for elevated CPK. 
5.3.4. 
Counsel regarding safe sex practices 
All participants should be counselled on safer sexual practices including the use and 
benefit/risk of effective barrier methods and on the risk of HIV transmission to an 
uninfected partner. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 


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Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened an additional time if, in the opinion of the Investigator, a current 
clinical outlook of the participant seems favorable for study inclusion (and if the 
participant never received study medication in this trial).  Rescreened participants will be 
assigned a new participant number and will sign a new ICF(s). 
As noted in Section 5, clinically irreversible findings found during screening would result 
in the individual not being screened a second time; examples include but are not limited 
to: liver cirrhosis, CDC Stage 3 disease, drug allergy or sensitivity, significant psychiatric 
disorder, cardiac arrythmias, or established, archived drug resistance.   
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 


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6.1. 
Study Intervention(s) Administered 
 
GSK3640254 
GSK3640254 
Placebo 
DTG 
3TC 
3TC Placebo 3TCa 
Intervention 
Name 
GSK3640254  Placebo to 
match 
GSK3640254  
Tivicay  
(The clinical 
label will 
state 
Dolutegravir 
50mg to 
match the 
SPC) 
3TC  
(The clinical 
label will state 
Lamivudine 
300mg) 
3TC Placebo  
(The clinical 
label will state 
Placebo to 
match 
Lamivudine 
300mg) 
3TC  
(The clinical 
label will state 
Lamivudine 
300mg) 
Type  
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation 
Tablet 
Tablet 
Tablet 
Capsule 
Capsule 
Tablet 
Unit Dose 
Strength(s) 
25 mg, 100 mg N/A 
50mg 
300mg 
N/A 
300mg 
Dosage Level(s) 
Variable 
depending on 
dose 
Variable 
depending on 
dose 
One tablet 
per day 
One capsule 
per day 
One capsule 
per day 
One tablet per 
day 
Route of 
Administration 
Oral 
Oral  
Oral 
Oral 
Oral  
Oral 
Use 
Experimental 
Placebo 
Background 
Comparator 
Placebo 
Comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Packaging and 
Labeling 
32 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
32 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
30 tablets 
per HDPE 
bottle, 
labelled per 
country 
requirement 
32 capsules 
per HDPE 
bottle, labelled 
per country 
requirement 
32 capsules 
per HDPE 
bottle, labelled 
per country 
requirement 
30 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
a. 
 3TC (Lamivudine 300mg) tablets for the Open Label phase will not be over-encapsulated, the existing 
commercial pack presentation (with a clinical label) will be supplied. 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 


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4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual. 
• Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.   
• A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK and ViiV Healthcare. 
• IP accountability will be evaluated using pill counts.  This assessment will be 
conducted during each clinic visit through study completion or early withdrawal. IP 
accountability records must be maintained throughout the course of the study. 
• Please refer to Appendix 11 in Section 10.11 for study management information 
during the COVID-19 pandemic. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This study will use an IVRS/IWRS. 
 
• All participants will be centrally randomized using an Interactive Voice/Web 
Response System (IVRS/IWRS).  Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log-in information & directions for the 
IWRS will be provided to each site 
• Study interventions will be dispensed at the study visits summarized in the SOA. 
• Returned study intervention should not be re-dispensed to any other participant. 
 
To minimize bias, all treatment arms will be blinded to the research participants and all 
study personnel during the study through Week 24. The Sponsor study team will also 
remain blinded until the database lock for the Week 24 analysis. 
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 and ViiV Healthcare policy. 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted.  Participant safety must always be the 
first consideration in making such a determination.  If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention of the participant.  If a participant’s intervention assignment is unblinded 
GSK must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and case report form, 
as applicable. 


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For the first 24 weeks of the study a participant will be withdrawn if the participant’s 
intervention code is unblinded by the investigator or treating physician. The primary 
reason for discontinuation (the event or condition which led to the unblinding) will be 
recorded in the CRF. 
Additionally, there may be modifications to study arm recruitment and/or study arm 
continuation and/or design in 212483 based on the outcome of the 208379 IDMC review, 
the 208379 Week 24 primary endpoint, and the potential 212483 IDMC review. Further 
details on the implications of these three analyses on the experimental dosing arms of 
study 212483 are described in Section 4.1. 
6.4. 
Study Intervention Compliance 
• When participants are dosed at the site, the date and time of each dose administered in 
the clinic will be recorded in the source documents.   
• When participants self-administer study intervention(s) at home, compliance with 
study interventions will be assessed by direct questioning and review of the diary card 
during the site visits and documented in the source documents and relevant form. 
Deviation(s) from the prescribed dosage regimen should be recorded. 
• A record of the number of study interventions dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and 
compliance records.  
6.5. 
Dose Modification 
No dose modifications are allowed in this protocol, including for a decline in Creatinine 
Clearance.   
Additionally, there may be modifications to study arm recruitment and/or study arm 
continuation and/or design in 212483 based on the 208379 Week 24 primary endpoint, 
and the 212483 IDMC review. Further details on the implications of these two analyses 
on the experimental dosing arms of study 212483 are described in Section 4.1. These 
constitute changes among the three established experimental doses (not modifying the 
established experimental doses). 
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
The investigator is responsible for ensuring that consideration has been given to the 
poststudy care of the participant’s medical condition, whether or not ViiV is providing 
specific post-study treatment. 
• To provide continued access to an investigational drug to participants deriving 
therapeutic benefit, participants who have successfully completed 52 weeks of 
treatment may be given the opportunity to continue to receive their study 
treatment. During the blinded randomized phase: that could be non-optimal 
GSK3640254 + DTG, optimal GSK3640254 + DTG, or 3TC + DTG).  


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• During the open label randomized phase:  
• Any participant who received 3TC + DTG beyond their individual 
Week 52 visit will discontinue from the study and be transferred to locally 
available standard of care treatment.  
• Any participant who received GSK3640254 + DTG beyond their 
individual Week 52 visit will be switched to a single optimal dose of 
GSK3640254 once it is determined from the ongoing Study 208379. After 
this occurs, participants who continue to receive GSK3640254 + DTG 
beyond their individualized Week 52 will have the option to continue on 
open label optimal dose GSK3640254 + DTG until either they or their 
healthcare provider decide to discontinue study treatment or until 
GSK3640254 + DTG is receives local marketing authorization and is 
commercially available). 
• Continued access to GSK3640254 + DTG in Study 212483 may occur, as 
described above, provided all of the following conditions are met: 
• There is evidence of continued clinical benefit for the participant, and  
• There are no comparable alternative treatment options available, and  
• Such provision of GSK3640254 + DTG is permitted under local laws and 
regulations. 
Continued access to an investigational drug will cease if the participant no longer derives 
clinical benefit from receipt of GSK3640254 + DTG; the participant meets a protocol-
defined reason for discontinuation; or the development of GSK3640254 + DTG is 
discontinued.  
Participants who meet the criteria outlined above and who consent to continued access to 
study treatment beyond their individual Week 52 will be required to attend continued 
access visits approximately every 12 weeks for safety and efficacy follow-up, as per the 
SOA (see Section 1.3). Should a participant with continued access discontinue study 
treatment for any reason, this should be reported to the Sponsor together with the reason 
for discontinuation. 
6.7. 
Treatment of Overdose 
Any tablet intake exceeding the randomized daily number of tablets will be considered an 
overdose.  
Sponsor 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 until study 
intervention can no longer be detected systemically (at least 5 days). 


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3. Obtain a plasma sample for PK analysis within 7 days 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 eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
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.  Concomitant medications (prescription and non-
prescription) should be administered only as medically necessary during the study.   
Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the 
discretion of the participant and their physician.  All concomitant medications, blood 
products, and vaccines taken during the study will be recorded in the eCRF with dates of 
administration. 
Because non-HIV vaccines (e.g. Influenza vaccine or SARS-CoV-2 vaccine) may cause a 
temporary increase in the level of HIV-1 plasma RNA, it is highly recommended that a 
vaccine, if necessary, be given during or immediately after a scheduled visit after all 
laboratory tests have been drawn when possible.  This approach will minimize the risk of 
non-specific increases in the level of plasma HIV-1 RNA at the next scheduled 
assessment if possible. 
DTG should be administered with the following considerations: 
• 
2 hours before or 6 hours after taking antacid or laxative products or sucralfate 
containing polyvalent cations (e.g. aluminium and magnesium) or calcium 
supplements.  Proton pump inhibitors and H2-antagonists may be used in place of 
antacids with no scheduling restrictions.  
• 
Concurrent administration with multivitamins is acceptable.  Iron supplements can 
be taken with study treatment provided that all are taken together with a meal. 
• 
Under fasted conditions, DTG should be given 2 hours prior to OR 6 hours after iron 
supplements. 


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Metformin concentrations may be increased by DTG.  A dose adjustment of metformin 
should be considered when starting and stopping co-administration of DTG with 
metformin, to maintain glycemic control. 
Clinical monitoring is recommended for participants taking methadone, as methadone 
maintenance therapy may need to be adjusted in some participants. 
Non-protocol defined treatments or medical interventions (e.g., physical therapy, 
radiotherapy, surgical procedures) are permitted during the study for appropriate medical 
management of the participant.  
6.8.1. 
Prohibited Medications and Non-Drug Therapies 
6.8.1.1. 
Prohibited Medications: All Participants 
The following, general concomitant medications or therapies are not permitted at any 
time during the study: 
• 
HIV immunotherapeutic vaccines are not permitted at any time during the study.  
• 
Other experimental agents (which do not have emergency, conditional, or standard 
market authorization), antiretroviral drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy may not be administered. Approval 
for potential co-enrolment of a study participant in a study not involving an 
experimental agent (e.g., a questionnaire, research method, health monitoring etc), 
must be obtained from the Sponsor before co-enrolment). 
• 
Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited (a list of examples is provided in the SRM) This includes 
topical agents with substantial systemic exposure and systemic effects.  Use of 
topical imiquimod is permitted.    
• 
Acetaminophen (paracetamol) cannot be used if a participant has an acute viral 
hepatitis [James, 2009]. 
6.8.1.2. 
Medications that need to be stopped in Screening 
The following medications need to be stopped at least 4 weeks prior to the first dose: 
• 
Carbamazepine 
• 
Oxcarbamazepine 
• 
Phenobarbital 
• 
Phenytoin 
• 
Rifampicin or rifapentine 
• 
St. John’s wort (Hypericum perforatum) 
• 
Any other strong CYP3A Inducers (e.g., dexamethasone, rifapentine, rifabutine, etc) 
• 
Fampridine 


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The following medications need to be stopped at least 2 weeks prior to the first dose: 
• 
Dofetilide and pilsicainide 
• Any substrate of organic cation transporter 2 (OCT2), with a narrow therapeutic 
window should not be administered concurrently with DTG containing products (see 
prescribing information [TIVICAY, 2020 and DOVATO, 2020]).  
6.8.1.3. 
On Treatment Prohibited Medications: GSK3640254  
The following medications may significantly interact with GSK3640254 and are not 
permitted during the double-blind phase and thereafter not permitted with GSK3640254: 
• Strong CYP3A inhibitor (Clarithromycin, telithromycin, nefazodone, itraconazole, 
ketoconazole etc);  
• Strong CYP3A inducer (e.g. phenobarbital, dexamethasone, carbamazepine, 
phenytoin, rifampin, rifapentine, rifabutine, St John’s wort, etc); 
• Substrate of OATP1B3 (e.g. telmisartan, valsartan, olmesartan, rifampin, ezetimibe, 
statins such as atorvastatin, rosuvastatin, pitavastatin). 
 
6.8.1.4. 
On Treatment Prohibited Medications: When dosing with DTG in any 
arm 
• 
The following medications or their equivalents may cause decreased concentrations 
of DTG. Therefore, they may not be administered concurrently in participants on the 
DTG arm.  
• 
Carbamazepine 
• 
Oxcarbamazepine 
• 
Phenobarbital 
• 
Phenytoin 
• 
Rifampicin and rifapentine 
• 
St. John’s wort (Hypericum perforatum) 
• 
Fampridine 
• Dofetilide and pilsicainide are prohibited as DTG may inhibit their renal tubular 
secretion resulting in increased dofetilide/pilsicainide concentrations and potential for 
toxicity. 
• 
Any substrate of organic cation transporter 2 (OCT2), with a narrow therapeutic 
window should not be administered concurrently with DTG containing products (see 
prescribing information [TIVICAY, 2020 and DOVATO, 2020]).  
 
For information on concurrent therapies and interactions suspected to be relevant to 
3TC, please consult the local prescribing information. 


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
7 3  
 
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L  
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 
U p o n st u d y disc o nti n uati o n, c A R T s h o ul d be start e d, as selecte d/ pres cri be d/ pr o vi de d b y 
t heir p h ysici a n. 
I n rare i nsta nces, it ma y be necessar y f or a partici pa nt t o per ma ne ntl y disc o nti n ue st u d y 
i nter ve nti o n. If st u d y i nter ve nti o n is per ma ne ntl y disc o nti n ue d,  t he partici p a nt will 
perf or m a n earl y wit h dra wal visit.  See t he S O A f or data t o be c ollecte d at t he ti me of 
disc o nti n uati o n of st u d y i nter ve nti o n  a n d f oll o w -u p a n d f or a n y f urt her e val uati o ns t hat 
nee d t o be c o m plet e d.  
Partici pa nts m ust be disc o nti n ue d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
•  
C o nfir me d or S us pecte d H y p erse nsiti vit y Reacti o n;  
•  
C o nfir me d Vir ol o gi c Fail ures  as defi ne d i n Secti o n 7. 1. 1 ; 
•  
 Vir ol o gic N o n -Res p o n d er at Wee k 2 4, defi ne d as partici pa nts w h o ha v e eit her:  
o  
HI V -1 R N A ≥2 0 0 c/ m L at Wee k 2 4, or  
o  
HI V -1 R N A ≥5 0 c/ m L o n re peat testi n g of Wee k 2 4 res ults a n d pri or t o 
Wee k 2 8 (see Fi g ure 2 ); 
•  
Partici pa nt re q uires s u bstit uti o n or d ose m o dificati o n of G S K 3 6 4 0 2 5 4, D T G or 
3 T C ;  
•  
Treat me nt e mer ge nt r esista nce t o a n y c o m p o ne nt of t he  st u d y me di cati o ns. F or 
partici pa nts recei vi n g G S K 3 6 4 0 2 5 4, t he ge n ot y pic e mer ge n ce of a n A 3 6 4 V or 
A 3 6 4 A/ V re q uir es disc o nti n uati o n ;  
•  
F or partici pa nts recei vi n g G S K 3 6 4 0 2 5 4, a P h e n o Se nse Ga g c F CI C 5 0 > 5 0 ( o n -
treat me nt 
Da y 1
;  
•  
Li ver t o xicit y w h ere st o p pi n g criteria  s pecifie d i n Secti o n 7. 1. 2  are met;  
•  
Aller gi c reacti o n or Ras h criteria as descri b e d i n Secti o n 1 0. 9. 2  a n d Secti o n  
1 0. 9. 3 , res pecti vel y, are met a n d n o c o m pelli n g alter nate ca use is i de ntifie d;  
•  
Re nal t o xicit y  is met a n d n o c o m pelli n g alter nate ca use is i de ntified  (a n esti mate d 
G F R of < 5 0 m L/ mi n o n c o nfir me d meas ure me nt as defi ne d i n Secti o n 1 0. 9. 6 ); 
•  
C o nfir me d Pr o xi mal Re nal T u b ule D ysf u ncti o n ( P R T D)  ( See Secti o n 1 0. 9. 7 ); 
•  
Pre g n a nc y (i ntr a uteri ne), re gar dl ess of ter mi nati o n stat us of pre g na n c y  ( See 
Secti o n 8. 2. 5 ); 
•  
Dia g n osis of He patitis B or C viral i nfecti o n;  
•  
A n y cli nicall y si g nifica nt A E dee me d t o re q uire disc o nti n uati o n of t he I P;  
C CI
C CI


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C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
7 4  
 
•  
M o derate t o se v ere (as cli nicall y deter mi ne d b y t h e i n vesti gat or) C O VI D -1 9 
i nfecti o n (s us pect, pr o b a ble, or c o nfir me d usi n g t he m ost rece nt v ersi o n of t he 
W H O case defi niti o n) ; 
•  
A Gra d e 4 or relate d Gra de 3 A E: t he I n vesti gat or will disc o nti n ue t he partici pa nt 
fr o m t he st u d y. If t he A E, i n t he o pi ni o n of t he i n vesti gat or, ma y be re pres e ntati ve 
of gastric t o xicit y (e. g. o bsti pati o n, diarr hea, d ys p ha gi a/ o d y n o p h a gia, GI 
blee di n g, m u c ositis/st o matitis, or na usea), t he I n v esti gat or m a y c o nsi der 
perf or mi n g a n e val uati o n/ ma na ge me nt pla n i nc or p orati n g ele me nts i n t he GI 
I nt olera bilit y E v al uati o n a n d Ma na ge m e nt ta ble ( See Secti o n 8. 2. 7 ); 
•  
A n y Gra d e 3 or hi g her Ps yc hiatric A E. T h e I n vesti gat or will disc o nti n ue t h e 
partici pa nt  fr o m t he st u d y a n d arra n ge f or e mer ge nc y ps yc hiatric 
e val uati o n/ ma na ge me nt; t he pa nel f or dr u gs of a b use will be teste d;  
•  
Ne w o nset s uici dal i de ati o n, as cli nicall y di a g n ose d b y t he I n vesti gat or (i n 
c o ns ultati o n wit h ps yc hiatr y, if n ee de d). T he I n v esti gat or will disc o nti n ue t he 
partici pa nt  fr o m t he st u d y a n d arra n ge f or ur ge nt s pecialist ps yc hi atric 
e val uati o n/ ma na ge me nt ;   
•  
•  
Partici pa nts w h o re q uir e c o nc o mita nt me dicati o ns k n o w n t o be ass ociate d wit h a 
pr ol o n ge d Q Tc;  
•  
A tri plicate set of o n -tr eat me nt E C Gs s h o w t he a vera ge Q Tc F > 5 0 0 msec or 
i ncreas e fr o m bas eli ne Q TcF  > 6 0 msec ( See Secti o n 7. 1. 3 ). 
7. 1. 1.  
Pr ot o c ol -D efi n e d Vir ol o gi c F ail ur e  
Vir ol o gic fail ure m ust be c o nfir me d b y a re peat a n d c o nsec uti ve plas ma HI V -1 R N A 
meas ure me nt b et wee n t w o a n d f o ur wee ks after t h e i nitial s us pecte d vir ol o gic fail ure 
sa m ple.  
Partici pa nts  s h o ul d recei ve f ull d ose of st u d y treat me nts acr oss all plas ma s a m pli n g ti mes 
use d f or deter mi ni n g vir ol o gic fail ure.  
F or t he p ur p os es of cli nic al ma na ge me nt i n t his st u d y, pr ot o c ol -defi ne d vir ol o gic fail ure 
(P D V F) is defi ne d as a n y of t he f oll o wi n g:  
Vir ol o gic N o n -res p o nse  
•  Decrease fr o m Baseli ne ( Da y 1) i n plas ma HI V -1 R N A of ˂ 1. 0 l o g 1 0 c/ m L u nless 
plas ma HI V -1 R N A is < 2 0 0 c/ m L b y Wee k 1 2;  
•  C o nfir me d plas ma HI V -1 R N A le vels ≥2 0 0 c/ m L at or after Wee k 2 4 ( See Fi g ure 
2  a n d Ta ble 9 );  
•  Plas ma HI V -1 R N A ≥5 0 c/ m L o n re peat testi n g of Wee k 2 4 res ults a n d pri or t o 
Wee k 2 8 (see  Fi g ure 2 ). 
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Virologic Rebound  
• Confirmed plasma HIV-1 RNA ≥200 c/mL after confirmed consecutive plasma 
HIV-1 RNA <50 c/mL (see Table 9). 
Participants who meet the definition of virologic failure must be immediately 
discontinued from the study.  
7.1.1.1. 
Managing Suspected Virologic Failure/Endpoint Cases 
Inadequate adherence is a common cause for virologic failure and should be explored as a 
first step in management of study participants (e.g., at the first indication of inadequate 
virologic response or rebound).  
All cases that meet a criterion for suspected virologic failure must be confirmed by a 
second measurement performed at least 2 weeks but not more than 4 weeks (as 
specified below) apart from the date of the original sample, unless one of the 
extenuating circumstances outlined below applies.  
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. Please refer to Appendix 11 in Section 10.11 for study 
management information during the COVID-19 pandemic.  
Upon notification that a participant’s HIV-1 RNA plasma level qualifies him/her as a 
suspected virologic failure, the Investigator should query the participant regarding 
intercurrent illness, recent immunization, or interruption of therapy. 
The following guidelines should be followed for scheduling confirmatory plasma HIV-1 
RNA testing in an effort to avoid false-positive results:  
• 
Confirmatory testing should be scheduled 2 to <4 weeks following resolution of 
any intercurrent illness, during which time the participant should receive full dose 
of all IP.  
• 
Confirmatory testing should be scheduled 2 to <4 weeks following any 
immunization, during which time the participant should receive full dose(s) of all 
IP.  
• 
If therapy is interrupted due to non-compliance, or other reasons, confirmatory 
testing should be scheduled 2 to <4 weeks following resumption of full dose of all 
IP.  
• 
The participant should have received full doses of IP for at least 2 weeks at the 
time confirmatory plasma HIV-1 RNA testing is done.  
Sites should contact the study medical monitor to discuss individual participants, 
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7.1.1.2. 
Managing Confirmed Virologic Failure/Endpoint Cases 
A participant who meets confirmed virologic failure must be immediately discontinued 
from the study. Once a participant has been confirmed as meeting the protocol definition 
of confirmed virologic failure, a sample from the suspected virologic failure visit, and a 
sample from the Day 1 visit (if not sent previously), will be sent for genotypic and 
phenotypic resistance testing and the result made known to the Investigator when 
available.   
If the confirmed HIV-1 RNA level is ≥50 and <200 c/mL, and the decision is taken to 
withdraw the participant, resistance testing will not be done and the participant should be 
transitioned off study intervention immediately. For all other confirmed virologic failure 
cases where HIV-1 RNA ≥200 resistance testing will be triggered. 
If a participant is withdrawn early from participation in the study, the Investigator must 
make every effort to perform the evaluations outlined in the Schedule of Activities. These 
data will be recorded, as they comprise an essential evaluation that needs to be done 
before discharging any participant from the study. 
7.1.1.3. 
Virologic Management 
See the decision tree in Figure 2. 
Participants in any arm who are Virologic Responders (HIV-1 RNA <50 c/mL) within 
the Week 24 Snapshot Window will continue in the study beyond Week 24. 
Participants in any arm who are Virologic Non-Responders (HIV-1 RNA ≥ 50 c/mL on 
confirmatory testing as shown in the Figure below) must be discontinued from the study 
immediately. These participants will perform the Early Withdrawal visit, and then be 
seen in clinic once more at a Final Follow-Up visit if needed. 


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Figure 2 
Assessment by HIV-1 RNA at Week 24 
 
Refer to Table 9 for management by HIV-1 RNA after Week 24. 
For the purposes of clinical management in this study, Investigators will continuously 
assess HIV-1 RNA throughout the Treatment Phase of the trial (from Day 1, at any visit 
either scheduled or unscheduled) using information found in this section and in Table 9 
(after Week 24).  
 
Table 9 
Assessment by HIV-1 RNA after Week 24 
Current HIV-1 RNA <50 
c/mL 
Regardless of previous HIV-1 RNA result, proceed with the next visit, per SOA in 
Section 1.3. 
Current HIV-1 RNA ≥50 
c/mL but <200 c/mL 
If previous HIV-1 RNA result was <50 c/mL, perform a scheduled or unscheduled 
visit to reassess HIV-1 RNAa in a time frame consistent with Section 7.1.1. 
If previous HIV-1 RNA result was ≥50 c/mL, discuss results with the ViiV medical 
monitorb,c  Participant has met criteria for additional HIV-1 RNA testing or possible 
withdrawal. 
If the participant is withdrawn under the above criteria, they will have met 
“Precautionary Virologic Withdrawal Criteria (PVW)” 
If the 2 previous consecutive HIV-1 RNA results were ≥50 c/mL and <200 c/mL, the 
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Current HIV-1 RNA ≥200 
c/mL 
If previous HIV-1 RNA result was <50 c/mL, perform a scheduled or unscheduled 
visit to reassess HIV-1 RNAa in a time frame consistent with Section 7.1.1. 
Participant has met “Suspected Virologic Withdrawal Criteria (SVW)”.  
• 
If the repeat HIV-1 RNA is ≥ 200 c/mL, the participant has met PDVF 
criteriad  
• 
If the repeat HIV-1 RNA is 50-199 c/mL, then discuss results with the ViiV 
medical monitor. 
 
If previous HIV-1 RNA result was ≥50 c/mL, the participant has met PDVF criteriad 
a. 
Investigators should not schedule reassessment blood draws in the presence of factors that could be associated 
with virologic blips, such as intercurrent infection, treatment interruption due to toxicity management or non-
compliance, or vaccination. Participants should have received full doses of study intervention for at least 2 weeks 
at the time of plasma HIV-1 RNA reassessment. 
b. 
In case of withdrawal, a sample from the initial visit will be used for resistance testing. If resistance testing will not 
be done, withdrawing participants should be transitioned off study intervention as soon as possible.  
c. 
The medical monitor and investigator should consider intercurrent illness, recent immunization, interruption of 
therapy or other non-virologic reasons associated with transient elevated HIV-1 RNA measurements 50 and 
<200 c/mL. If no non-virologic reasons are identified to explain the lack of virologic suppression, the participant 
must be withdrawn.  If the Investigator and the medical monitor agree that the participant is experiencing a slow 
re-suppression due to one of the above issues, then a retest HIV-1 RNA measurement is required in in a time 
frame consistent with Section 7.1.1 . If the HIV-1 RNA remains 50 c/mL on a second retest (the third consecutive 
HIV-1 RNA assessment), the participant must be withdrawn. 
d. 
Participants with confirmed HIV-1 RNA results in the range 200 c/mL to <500 c/mL, should be transitioned off 
study intervention and withdrawn from study immediately  
7.1.2. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). Refer to Appendix 6 in Section 10.6. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm or  
• in the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, if the investigator believes that it is in the best interest of the 
participant.  
• Liver Safety Required Actions and Follow up Assessments Section can be found 
in Section 10.6. 
7.1.2.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 


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7.1.3. 
Columbia-Suicide Severity Rating Scale 
Emergence of any positive (abnormal) response on the C-SSRS, confirmed by the 
Investigator, during the treatment phase of the study will be cause for immediate clinical 
assessment of suicidality (by the Investigator or a consulting psychiatrist). Emergence of 
new onset suicidal ideation or a Grade 3 or higher psychiatric AE will result in immediate 
discontinuation and urgent specialist psychiatric evaluation and management. 
7.1.4. 
QTc Stopping Criteria 
The same QTcF correction formula must be used for each participant to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the participant has been enrolled. 
The Baseline QTcF should be based on averaged QTcF values of triplicate ECGs 
obtained over a brief recording period from the Day 1 pre-dose ECG (see Section 8.2.3). 
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
Investigator or qualified designee will determine if the participant can continue in the 
study and if any change in participant management is needed. This review of the ECG 
printed at the time of collection must be documented. Any new clinically relevant finding 
should be reported as an AE. The Investigator’s or Medical Monitor’s over-read can 
supersede that of the machine at any time. If so, it must be noted in the chart. 
A randomized participant that develops an on-treatment single ECG QTcF >500 msec or 
an increase from baseline QTcF >60 msec should have two repeat unscheduled ECG’s 
within 10 minutes apart. Using these three ECGs, if the average QTcF shows either of the 
following, the participant will be withdrawn from the study: 
• >500 msec, or 
• An increase from baseline QTcF >60 msec 
• 
ViiV Healthcare encourages PI’s to consult with a local cardiologist for assistance in 
interpretation of an EKG showing a prolonged QTcF (> 500 msec or increase > 60 
msec). Finally, this participant should have 1) a complete, unscheduled chemistry 
panel, 2) an unscheduled GSK3640254 PK sample, and 3) repeated unscheduled 
ECGs until their QTc measurement returns to their original averaged QTcF value at 
Day 1 pre-dose.  
See the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.5. 
Temporary Discontinuation 
Participants may not have any temporary interruptions to their study intervention. 
Withdrawal of study intervention requires withdrawal from study. 


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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/withdrawal visit should be conducted, as shown in the SoA. See 
SoA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed, followed by the Study 
Completion eCRF for the Intervention Period. 
• An early discontinuation/withdrawal visit should also be conducted if a 
participant who has been entered into the Continued Access Phase discontinues or 
is withdrawn from study treatment. The reason will be captured on a separate 
Continued Access Phase-related Completion  eCRF page – different to that for 
discontinuation from the main study. 
• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
7.3. 
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.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• Please refer to Appendix 11 in Section 10.11 for study management information 
during the COVID-19 pandemic.  
• Protocol waivers or exemptions are not allowed.  
• Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
• Laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel (with the exception of HIV-1 
resistance assays) 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
• Plasma for quantitative HIV-1 RNA will be generated at time points listed in the 
SOA (see Section 1.3). 
• An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 40 c/mL 
will be used. However, the primary and secondary endpoints will define 
responders as HIV-1 RNA <50 c/mL. 
• Details concerning the handling, labeling and shipping of these samples will be 
supplied separately. 
8.1.1. 
Lymphocyte Subsets by Flow Cytometry 
• Blood samples will be obtained from each participant for the analysis of 
lymphocyte subsets (CD4 and CD8) by flow cytometry at the timepoints listed in 
the SOA (Section 1.3).  
• Details concerning the handling, labeling and shipping of these samples will be 
supplied separately. 


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8.1.2. 
Disease Progression 
• HIV-associated conditions will be recorded as per the SoA (Section 1.3).  
• CDC-classification will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection in Adults (See Section 10.10).  
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.  
• A targeted physical examination will include, at a minimum, assessments of the 
skin, lungs, heart, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• Investigators should pay special attention to any signs of rash. 
• Height and weight will also be measured and recorded.  Height will be captured 
only at Screening; Weight will be captured at each visit to accurately calculate 
Creatinine Clearance (CrCL) and also allow for careful monitoring of weight 
throughout the study. For guidance on weight measurement see Section 8.2.1.1. 
8.2.1.1. 
Weight Measurement 
Adapted from WHO STEPS Surveillance Manual [WHO, 2017]. 
Equipment 
To measure weight, you will need a weighing scale, (such as a SECA scale or the Tanita 
HS301 Solar Scale). Alternatively, a BMI scale measuring both height and weight (e. g. 
Growth Management Scale) can be used. 
Ensure the scale has been regularly calibrated according to the manufacturer instructions 
and that calibration documentations are filed and available to the study CRA as required. 
We recommend using the same scale across visits for individual study participants. 
We recommend having the same study staff performing the measurement across visits for 
individual study participants. 
We recommend that the time of day a participant’s weight is measured is consistent for 
every participant at the site within the study. (ex. If measured at 10 a.m. at initial 
measurement, attempt to have the participant measured at 10 a.m. at subsequent visits). 


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Set up requirements 
Make sure the scales are placed on a firm, flat surface. Do not place the scales on: 
• 
carpet 
• 
a sloping surface 
• 
a rough, uneven surface. 
Set up scales  
Follow the steps below before measuring the weight of a participant: 
1. 
Make sure the scale is on a firm, flat surface. 
2. 
Turn on the scale and wait until the display shows 0.0. 
Procedures 
Follow the steps below to measure the weight of a participant: 
1. 
Ask the participant to remove their footwear (shoes, slippers, sandals, etc). They 
should also take off any heavy belts and remove all objects out of their pockets 
(example:  mobile phones, wallets, coins). 
2. 
Ask the participant to step onto scale with one foot on each side of the scale. 
3. 
Ask the participant to: 
• 
stand still 
• 
face forward 
• 
place arms on the side and 
• 
wait until asked to step off. 
4. 
Record the weight in kilograms to one decimal place in the eCRF. 
8.2.2. 
Vital Signs 
• 
Vital signs will be collected as indicated in the SOA (Section 1.3). 
• 
Vital signs will be measured in a semi-supine position after 5 minutes rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones) 
and will include temperature, pulse rate (heart rate), respiratory rate, and systolic 
and diastolic blood pressure.  
o Blood pressure and pulse measurements will be done with a completely 
automated device. Manual techniques will be used only if an automated 
device is not available. 
o Three readings of blood pressure and pulse will be taken. The first reading 
should be rejected. The second and third readings should be recorded in the 
eCRF where the average of the 2 readings will be calculated. 


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8.2.3. 
Cardiac Monitoring with Electrocardiograms 
• 
See Table 11 in Section 8.4. 
• 
Triplicate and Single 12-lead ECGs will be obtained as outlined in the SOA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTcF intervals. Refer to Section 7.1.3 for 
QTcF withdrawal criteria and additional QTcF readings that may be necessary. 
• 
At each time point at which triplicate ECGs are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 
2 minutes apart. The full set of triplicates should be completed in less than 4 
minutes. 
• 
Participant should remain still while the tracing is being recorded.  Site staff 
should review the tracing to look for movement artefact and redo the ECG, if 
necessary. 
• 
The high-quality ECG should be transmitted to the central vendor.  If there is an 
issue with electronic transmission (via analog or LAN), sites will upload the 
ECG tracing to a site for vendor access. 
• 
The central vendor will not be providing over-reads on any of the ECGs. The 
Investigator (or designee) should review the Screening output to determine if any 
exclusion criteria have been met. Subsequent ECGs should be assessed by the 
Investigator (or designee) for any new issue or parameter results that meet QTcF 
stopping criteria (See Section 7.1.3). In addition, review of such an ECG with a 
Cardiologist is encouraged.  
8.2.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 in Section 10.2 for the list of clinical laboratory tests to be 
performed and to the SoA (Section 1.3) for the timing and frequency. All 
protocol required laboratory assessments must be performed by central 
laboratory services. Please refer to Appendix 11 in Section 10.11 for study 
management information during the COVID-19 pandemic. Laboratory 
assessments must be conducted in accordance with the Laboratory Manual, and 
SoA (Section 1.3).  Details for the preparation and shipment of samples will be 
provided by PPD central lab and are detailed in the laboratory manual.  
Reference ranges for all safety parameters will be provided to the site by PPD 
central lab. 
• 
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 eCRF.  Please refer to 
Appendix 11 in Section 10.11 for study management information during the 
COVID-19 pandemic. 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed and 
Section 1.3 for the timing and frequency.  


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• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents.  
• 
Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor.  
• 
If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified and 
the Sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).  
• 
Refer to the SRM for processing and handling of samples to avoid duplicate 
and/or additional blood draws. 
8.2.5. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• Participants of childbearing potential must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test at Day 1 to be eligible for the 
start of administration of IP.  
• Pregnancy testing (urine and/or serum as required by local regulations) will be 
conducted at Screening, Day 1, and at monthly intervals during study intervention 
period, as outlined in the SOA (Section 1.3). 
8.2.6. 
Suicidal Ideation and Behaviour Risk Monitoring 
The reason for the use of the electronic version of the Columbia Suicidality Severity 
Rating Scale (eC-SSRS) assessment in this study is two-fold: 
1. Participants with HIV infection occasionally may present with symptoms of 
depression and/or other relevant psychiatric diagnoses that increase the risk for 
suicidality (suicidal ideation or behavior).  In addition, there have been some 
reports of depression, suicidal ideation and behavior (particularly in participants 
with a pre-existing history of depression or psychiatric illness) in some 
participants being treated with INIs, including DTG.  
2. GSK3640254 is not a CNS active drug nor is it being developed for a neurologic 
or psychiatric condition. However, the risk of suicidal ideation was identified with 
the previous generation MI GSK3532795 at supratherapeutic doses.  
Therefore, the use of the eC-SSRS is appropriate to monitor participants for potential risk 
of suicidality before and during treatment.  At the Screening visit, participants will 


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complete the baseline eC-SSRS lifetime assessment.  At all other visits, participants will 
complete the eC-SSRS based on changes from the last visit. Participants can complete the 
eC-SSRS 7 days from each visit post-randomization. 
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behaviour (SIB) or any other unusual changes in behaviour. It is recommended that 
the investigator promptly refer participants for psychiatric evaluation and management 
who experience signs of SIB if encountered during the screening period.  
If randomized and on-treatment, participants presenting with new onset/treatment 
emergent depression (e.g. Grade 3-4) should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop because discontinuation of study medication and urgent 
specialist psychiatric evaluation and management are required. Independent of 
psychiatric symptoms, an on-treatment eC-SSRS will be performed at all study visits. 
Ultimately, in the event of a new onset suicidality as clinically diagnosed by the 
Investigator (in consultation with psychiatry, if needed), the participant will discontinue 
from the trial and the PI will arrange for urgent specialist psychiatric evaluation and 
management.  
Assessment of treatment-emergent suicidality will be clinically diagnosed but monitored 
during this study using the eC-SSRS. The definitions of behavioural suicidal events used 
in this scale are based on those used in the Columbia Suicide History Form [Posner, 
2007].  Questions are asked on suicidal behaviour, suicidal ideation, and intensity of 
ideation.  Screening visit questions will be in relation to lifetime experiences and current 
experiences (within the past 2 months); all subsequent questioning is in relation to the last 
assessment. 
• 
Additionally, the investigator will collect information using the Possible 
Suicidality-Related AE (PSRAE) eCRF form in addition to the AE (non-serious 
or SAE) eCRF form on any participant that experiences a possible suicidality-
related AE while participating in this study.  This may include, but is not limited 
to, an event that involves suicidal ideation, a preparatory act toward imminent 
suicidal behaviour, a suicide attempt, or a completed suicide.  The investigator 
will exercise his or her medical and scientific judgment in deciding whether an 
event is possibly suicide-related. PSRAE forms should be completed and 
reported to GSK/ViiV Healthcare/Syneos Health within 1 week of the 
investigator diagnosing a possible suicidality-related AE.  
• 
In addition to new onset suicidality, emergent non-suicidal Psychiatric AEs will 
be evaluated and managed in the following manner: 
• 
Any Grade 1 or 2 Psychiatric AE: A Grade 1 or 2 Psychiatric AE may result 
in additional unscheduled visits (in-clinic or at home) as clinically indicated. 
This may include a more in-depth assessment of AE through interview, 
additional unscheduled clinical labs, and/or imaging. Psychiatric consultation 
may be required at the discretion of the PI. Any pharmacotherapy should be 
discussed with the Medical Monitor.  


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• 
Any Grade 3 or 4 Psychiatric AE: As described in Section 7.1, a Grade 3 or 4 
Psychiatric AE will result in discontinuation from the trial and emergency 
psychiatric evaluation. A urine sample should be submitted for the Drugs of 
Abuse panel. 
8.2.7. 
GI Intolerability Evaluation & Monitoring Plan (with Stopping 
Criteria) 
Pre-clinical toxicology studies in rats and dogs have suggested a potential for GI related 
toxicity with GSK3640254. Prior clinical trials have not evaluated for the presence of 
gastric toxicity in humans. Thus, it is unclear if any of the GI AEs observed in any 
clinical trial were representative of, associated with, or resulted from gastric toxicity (if 
present). Thus, in a clinically conservative fashion, this section provides general guidance 
to the Investigator on the evaluation and management of primarily upper gastrointestinal 
symptoms (Table 10). The Investigator may contact the Medical Monitor to discuss 
evaluation and management (including discontinuation of a participant) of any GI 
symptoms throughout the trial. 
Table 10 
GI Intolerability Evaluation and Management 
HISTORY  
For symptoms of all grades, a thorough history (and 
differentiation of acute and chronic manifestations) forms the 
foundation of proper evaluation and management. The 
following are potential manifestations of some GI clinical 
syndromes that may occur (possibly in combination) during 
the clinical trial.  
Abdominal Pain 
The Investigator should obtain information on chronology, 
location, intensity/character, aggravating and alleviating factors, 
and associated symptoms in the context of the participants 
relevant past medical history [Millham, 2016]. With chronic 
symptoms, factors suggestive of an organic process include: 
fever, night sweats, loss of appetite, weight loss, and nocturnal 
awakening [Yarze, 2016]. The historical and physical 
examination should be efficient and lead to an accurate diagnosis 
soon after presentation. 
Nausea and 
Vomiting 
The Investigator should attempt to identify the etiology of these 
symptoms (and whether it is intraperitoneal, extraperitoneal, 
medication related, infection related, or due to a metabolic 
disorder [Hasler, 2012].  


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HISTORY  
For symptoms of all grades, a thorough history (and 
differentiation of acute and chronic manifestations) forms the 
foundation of proper evaluation and management. The 
following are potential manifestations of some GI clinical 
syndromes that may occur (possibly in combination) during 
the clinical trial.  
Dyspepsia 
The Investigator should identify the presence of red flags 
(odynophagia, unexplained weight loss, recurrent vomiting, GI 
bleeding, jaundice, palpable mass or adenopathy, or family 
history of GI malignancy). Symptoms of dyspepsia could include 
early satiety, bloating, or belching. Additionally, atypical 
symptoms of dyspepsia could include: pharyngitis, asthma, 
bronchitis, hoarseness, chest pain, or abdominal pain.  
Diarrhea 
Similar to other GI symptoms, important historical assessment 
includes duration, onset, pattern, epidemiology (e.g. travel and 
diet), aggravating or iatrogenic factors, alleviating factors, stool 
appearance, presence of other symptoms (e.g. abdominal pain), or 
weight loss. The differential can be narrowed if there are clear 
watery, inflammatory, or fatty manifestations [Schiller, 2016]. 
Other Clinical 
Syndromes 
Additional diagnostic criteria for other GI disorders potentially 
encountered in the clinical trial are available. [Stanghellini, 2016 
and Lacy, 2016] 
PHYSICAL 
EXAMINATION 
Physical examination should complement elements obtained 
from the history [Hasler, 2012]. The exam elements may 
include: auscultation for bowel sounds (up to 2 minutes if 
necessary) and palpation (including assessment for rebound, 
guarding, and muscular rigidity) [Millham, 2016]. Acutely, 
the investigator may assess for signs of intravascular volume 
depletion (e.g., orthostasis) and/or aspiration of vomitus as 
appropriate. Abdominal tenderness and guarding may 
indicate inflammation. The presence of fecal blood can 
indicate mucosal damage (e.g., from an ulcer). Complete 
evaluation of dyspepsia should include an oral examination 
(poor dentition or pharyngeal erythema) and lungs for 
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HISTORY  
For symptoms of all grades, a thorough history (and 
differentiation of acute and chronic manifestations) forms the 
foundation of proper evaluation and management. The 
following are potential manifestations of some GI clinical 
syndromes that may occur (possibly in combination) during 
the clinical trial.  
DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT 
A major goal in the diagnostic evaluation of a participant with 
upper GI symptoms is to quickly arrive at a final diagnosis 
without exposing the participant to unnecessary (invasive) 
testing; Investigators should exercise good clinical judgment 
in this regard [Soll, 2009]. A major goal of therapy is directed 
at correcting the underlying identifiable medical or surgical 
abnormalities (e.g perforation or infarction) [Malagelada, 
2016]. Consultation (e.g., gastroenterologist) is recommended 
as clinically indicated. Emergent action should be taken as 
necessary: correction of hypovolemia or electrolyte 
abnormalities. 
Grade 1 symptoms Participants may be treated symptomatically. If participants 
develop dyspepsia alone, generally only limited and direct 
diagnostic testing should be performed. If the participant has 
dyspepsia, they should limit alcohol, caffeine, chocolate, tobacco, 
and eating directly before bedtime.  
Grade 2 
symptomsa 
Diagnostic testing may include but is not limited to the following 
(as clinically indicated): 
Serum chemistries (for evaluation of fluid and 
acid/base/metabolic status) and assessment of white blood cells 
(with differential) and hemoglobin if not recently performed. 
Amylase and Lipase may also be appropriate. 
Polymerase chain reaction (PCR) for viruses (e.g., 
Cytomegalovirus [CMV]) 


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HISTORY  
For symptoms of all grades, a thorough history (and 
differentiation of acute and chronic manifestations) forms the 
foundation of proper evaluation and management. The 
following are potential manifestations of some GI clinical 
syndromes that may occur (possibly in combination) during 
the clinical trial.  
Grade 3 
symptomsa 
Diagnostic testing may include but is not limited to the following 
(as clinically indicated): 
• 
The testing outlined above in Grade 2 
• 
A barium swallow  
• 
CT scan to identify gastrointestinal inflammation  
• 
Upper endoscopy with biopsy as indicated (eg, mucosal 
injury or the presence of red flags). 
Generally, use of imaging should be appropriate and timely. 
Management should be targeted at addressing the underlying 
pathology. 
Grade 4 
symptomsa  
Diagnostic testing may include but is not limited to the following 
(as clinically indicated): 
• 
The testing outlined above in Grade 2 and Grade 3 
• 
An acute abdominal series 
• 
Focused Assessment with Sonography in Trauma (FAST) 
Ultrasound 
Initial management can include correction of hemodynamic and 
electrolyte abnormalities as clinically indicated. After 
stabilization, management should be targeted at addressing the 
underlying pathology. 
a Grade 4 or related Grade 3 AE: The Investigator will discontinue the participant from the study 
(see Section 7.1). If the AE, in the opinion of the investigator, may be representative of gastric 
toxicity (e.g. obstipation, diarrhea, dysphagia/odynophagia, GI bleeding, mucositis/stomatitis, or 
nausea), the Investigator may consider performing an evaluation/management plan incorporating 
elements of the above GI Intolerability Evaluation and Management table. 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 


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The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7).  
Please refer to Appendix 11 in Section 10.11 for study management information during 
the COVID-19 pandemic. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signing of the informed consent form (ICF)  until 
the follow-up visit at the time points specified in the SoA (Section 1.3).  
• All AEs will be collected from the start of intervention until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
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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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in participants will be collected after the start of study 
intervention and until 35 days after the last dose. Details of pregnancies in partners of 
participants do not need to be collected in this study. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK/ViiV Healthcare/Syneos Health within 24 
hours of learning of the female participant pregnancy. While pregnancy itself is not 
considered to be an AE or SAE, any pregnancy complication or elective termination 
of a pregnancy for medical reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to GSK/ViiV Healthcare/Syneos Health.  
• GSK’s central safety department will forward this information to the Antiretroviral 
Pregnancy Registry. The international registry is jointly sponsored by manufacturers 
and licensees of antiretroviral products. Additional information and a list of 
participating manufacturers/licensees are available from http://www.apregistry.com/. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 


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• Any participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 , 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.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes (HIV-
Associated Conditions) 
The events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(Section 10.10) will be recorded on the HIV-Associated Conditions eCRF page if they 
occur.  However, these individual events or outcomes, as well as any sign, symptom, 
diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these 
events or outcomes are not reported to GSK as AEs and SAEs even though such event or 
outcome may meet the definition of an AE or SAE, unless the following conditions 
apply: 
• 
The investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (Section 10.3.2), or 
• 
The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, or 
• 
Death occurring for any reason during a study, including death due to a disease-
related event, will always be reported promptly. 
• 
Lymphomas and invasive cervical carcinomas are excluded from this exemption; 
they must be reported as SAEs even if they are considered to be HIV-related. 
If any of the above conditions is met then record the Disease Related Event on either the 
AE or SAE page (according to severity) in addition to the HIV Associated Conditions 
eCRF page.  If it is categorized as an SAE, report promptly (Section 10.3.5) to GSK/ViiV 
Healthcare/Syneos Health. 
Additionally, the PI should designate on the eCRF whether or not the AE or SAE meets 
any aspect of being an AIDS defining condition. 


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8.3.8. 
Adverse Events of Special Interest  
• 
AEs of special interest (AESIs) include those related to GI intolerability/gastric 
toxicity, neuropsychiatric safety, QT prolongation and skin and subcutaneous 
disorders. See Section 8.2.3, Section 8.2.6, Section 8.2.7 and Section 10.9.3 for 
further details. 
8.4. 
Pharmacokinetics 
All participants will provide samples for PK analysis. 
 
Participants will be expected to complete a dosing card with the date and time of IP 
administration of the last three doses prior to the scheduled clinic visits at which PK is 
collected (Weeks 2, 4, 8, 12, 24, and 48). These dates and times will be recorded in the 
eCRF. Additionally, dosing information on the clinic day, including whether or not the 
dose was administered with food, and the actual date and time of the PK samples must be 
recorded in the eCRF.  
 
The pre-dose samples must be collected within the window of 20-28 hours after the most 
recent dose taken. 
 
• Blood samples will be collected for measurement of plasma concentrations 
(including but not limited to GSK3640254) at the visits outlined in the SoA and as 
detailed in Table 11). 
• Samples may be collected at additional time points during the study if warranted 
and agreed upon between the investigator and Sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (e.g., 
to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided 
by Sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Genetic analyses will not be performed on these plasma samples.  
• Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Table 11 
Pharmacokinetic Sampling Schedule, Cardiac Monitoring with ECGs 
and Related Activities 
 
Time  
(Event) 
Window for blood draw 
Time  
(Relative to 
Dosing) 
Hour: Min 
Morning pre-dose work:  
 
 


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Time  
(Event) 
Window for blood draw 
Time  
(Relative to 
Dosing) 
Hour: Min 
Week 2 (Days 
11-14) 
20-28 hrs after the dose was taken the day 
prior: ECGs, vitals and full blood draw 
(including the pre-dose PK collection)a 
Eat Meal  
DOSEb: Administer study treatment and start the clock. 
00:00 
2 hr ECG 
02:00 
4 hr ECG 
04:00 
6 hr ECG 
06:00 
Week 4 
20-28 hrs after the dose was taken the day 
prior:  Draw lab kit (including the pre-dose PK 
collection)a 
 
 
Eat meal. Administer doseb 
00:00 
Week 8 
20-28 hrs after the dose was taken the day 
prior:  Draw lab kit (including the pre-dose PK 
collection)a 
 
00:00 
Eat meal. Administer doseb 
00:00 
Week 12 
20-28 hrs after the dose was taken the day 
prior:  Draw lab kit (including the pre-dose PK 
collection)a 
 
 
Eat meal. Administer doseb 
00:00 
ECG 2-6 hrs post dose 
02:00 - 06:00 
 
1 PK blood sample 2-6 hours post-dosec 
± 15 minutes 
02:00 - 06:00 
Week 24 
20-28 hrs after the dose was taken the day 
prior:  Draw lab kit (including the pre-dose PK 
collection).a   
 
 
Eat meal. Administer doseb 
00:00 
ECG 2-6 hrs post dose 
02:00 - 06:00 


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Time  
(Event) 
Window for blood draw 
Time  
(Relative to 
Dosing) 
Hour: Min 
 
1 PK blood sample 2-6 hours post-dosec 
± 15 minutes 
02:00 - 06:00 
Week 48  
20-28 hrs after the dose was taken the day 
prior:  Draw lab kit (including the pre-dose PK 
collection). 
 
 
Eat meal. Administer doseb 
00:00 
ECG 2-6 hrs post dose  
02:00 - 06:00 
a) The pre-dose, full morning blood draw and ECG should be done in the standard required sequence of 
assessments: ECG – Vitals – Blood Draw (all within 15 minutes to ensure that the PK sample from the blood draw 
approximates that of the ECG). 
b) At visits with PK collections, aim to dose the participant near the same time that they have typically been dosing. 
Best Practice is to plan for approximately 30-45 minutes in which to get these pre-dose assessments and 
procedures done and the meal consumed by the participant. 
c) 
Each post-dose blood draw should be drawn relative to the time the dose was given; never base the interval for 
the next blood draw on the time of the previous blood draw  
 
8.5. 
Genetics and/or Pharmacogenomics 
A 6 mL blood sample for deoxyribonucleic acid (DNA) isolation will be collected on 
Day 1 (or at any time later) from participants who have consented to participate in the 
genetics analysis component of the study. Participation is optional. Participants who do 
not wish to take part in the genetic research may still participate in the main study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Section 10.5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the laboratory 
manual and the SRM. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.6.1. 
Viral Genotyping and Phenotyping Analyses 
Some of the plasma samples collected in this study will be used to test for the incidence 
of treatment emergent genotypic and phenotypic resistance to reverse transcriptase 
inhibitors, integrase inhibitors, protease inhibitors and the study intervention, 
GSK3640254 maturation inhibitor.   


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• Development of virologic failure in any participant will trigger shipment for 
resistance testing of the sample collected at the time point of interest, 
accompanied by the Day 1 sample for the same following 5 assays: PhenoSense 
GT, GeneSeq Integrase, PhenoSense Integrase, PhenoSense Gag assays for 
GSK3640254, and Gag genotype (using a Next Generation Sequencing platform).     
The resistance assays will be performed at Monogram Biosciences. 
Details of the analyses to be performed will be specified in the SAP. 
8.7. 
Immunogenicity Assessments 
Not Applicable. 
8.8. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The study is designed to investigate the efficacy, safety, tolerability and resistance of 
three doses (100 mg, 150 mg, and 200 mg) of GSK3640254 + DTG, relative to DTG + 
3TC for 24 weeks. Although no formal statistical analysis will be carried out in this 
study, Bayesian analyses will still be conducted to evaluate the probability that the Week 
24 response rate, defined as the proportion of participants with plasma HIV-1 RNA 
<50 c/mL as calculated by the FDA snapshot algorithm, of the optimal dose of 
GSK3640254 has comparable efficacy to the reference treatment using a 12% margin. A 
positive sign of efficacy will be achieved if any GSK3640254 dose has a high posterior 
probability (e.g., ≥75%) of being within the 12% margin. 
The effectiveness of the components of DTG + 3TC have been assessed in numerous 
previous studies with DTG + 3TC, including GEMINI-1 and GEMINI-2. Historical data 
from these studies suggests that the Week 24 response rate for treatment naïve 
participants treated with DTG + 3TC is 90~92%.  In Bayesian model of the final analysis, 
the noninformative prior Beta (1,1) will be utilized for the reference arm to calculate the 
posterior distributions of response rates of plasma HIV-1 RNA <50 c/mL for the optimal 
dose and the reference treatment.  
9.2. 
Sample Size Determination 
Approximately 160 participants will be screened to achieve approximately 80 randomly 
assigned to study intervention for an estimated total of 20 evaluable participants per 
GSK3640254 + DTG and DTG + 3TC arm. However, as a result of the potential impact 
of the parallel Phase 2b trial, Study 208379, the enrolment of Study 212483 may be 
adaptive resulting in no more than 30 participants originally randomized to any treatment 
arm. 
The planned sample size of approximately 20 participants per active arm and 
approximately 20 participants assigned to the reference arm is based on the primary 
efficacy endpoint of FDA Snapshot response rate at Week 24 (proportion of participants 
with plasma HIV-1 RNA <50 c/mL). Since the analysis will be conducted using Bayesian 
methodology, the sample size was determined using robust simulation rather than a 
closed form equation.   
Considering the small sample size of the study, response rate 90% (N=18) is used for the 
reference arm, and a response rate of 78% on the optimal dose, the probability of 
declaring positive sign of efficacy is approximately 27.5%. Given the stage of this phase 
2b study and the relatively small sample size of each arm, this is considered acceptable. 
Conversely, assuming a response rate of 90% on the optimal dose, the probability of 
declaring a positive sign of efficacy would be 78.4%.  
Selected probabilities of declaring a positive efficacy sign (defined as the optimal dose 
having a posterior probability of being within a 12% non-inferiority margin compared to 


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the reference treatment of at least 75%) are presented as the first row in Table 12 in 
Section 9.2.1. 
9.2.1. 
Sample Size Sensitivity 
As described in Section 4, a recommendation from the Study 208379 IDMC Week 12 
analysis could result in one or two arms in this trial (212483) to be discontinued. If either 
or both of these arms were in fact 150 and/or 200 mg, these participants may be re-
randomized to existing experimental arms. The decision will also stop the enrollment on 
these dropped arms. Subsequently, the remaining study arms may enroll 20-30 patients in 
each arm. The Bayesian analysis described in Section 9.1 will solely evaluate participants 
who originally received the blinded GSK3640254 optimal dose or blinded 3TC from Day 
1 of the study. Any participant who changed arms (or doses) will not be included in the 
Bayesian analysis. 
Simulations were conducted using various numbers of participants on the optimal 
GSK3640254 dose and the same number of participants for the reference arm in the range 
of [30,40]. In simulation, noninformative prior Beta(1,1) is utilized in the Bayesian model 
for both the optimal dose and reference arms to ensure the balanced design and apply the 
fair comparison between two arms.    
Under the same decision rule, the number of participants greater than 20 (N>20) resulted 
in modest increases in the probability of correctly declaring a positive efficacy sign at 
high response rates (> 80%) and minimal change in the probability of incorrectly 
declaring positive efficacy at relatively low response rates (≤80%).  Table 12 along with 
Figure 3 shows the response rates with the various sample sizes explored. 
Table 12 
Simulated power under various realistic response rates of optimal 
GSK3640254 dose with different sample size N 
N  
Per Arm 
Response Rate of optimal dose of GSK3640254 
78% 
80% 
83% 
85% 
88% 
90% 
92% 
94% 
95% 
20 
0.275 
0.336 
0.452 
0.55 
0.696 
0.784 
0.851 
0.912 
0.94 
24 
0.278 
0.341 
0.467 
0.546 
0.708 
0.797 
0.861 
0.926 
0.951 
30 
0.255 
0.329 
0.461 
0.578 
0.731 
0.814 
0.914 
0.966 
0.982 
 


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Figure 3 
Probability of a Positive Efficacy Sign at Various Sample Sizes 
Scenarios 
Note: N is number of participants on optimal dose given various randomization situations, and the 
same number for reference arm.  
9.3. 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
 
 Population 
Description 
Enrolled 
All participants who sign the ICF 
Randomized 
All participants who are randomized to receive study intervention 
Safety 
All randomized participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received. 
9.3.1. 
Intent-to-Treat Exposed Population (ITT-E) 
The ITT-E population consists of all randomized participants who received at least one 
dose of study intervention.  Participants will be analyzed according to the randomized 
treatment regardless of what treatment was actually received. Unless stated otherwise, the 
ITT-E population will be the primary population for efficacy analyses. 


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9.3.2. 
Per Protocol Population (PP) 
This population will consist of participants in the ITT-E population with the exception of 
participants with significant protocol violations as defined in the SAP of this study. The 
PP population will be a secondary population for efficacy purposes. 
 
9.3.3. 
Pharmacokinetic Population 
The pharmacokinetic (PK) population will include all participants who receive 
GSK3640254, undergo sparse PK sampling during the study, and provide evaluable 
GSK3640254 plasma concentration data, demographic and baseline characteristics, 
and/or information on concomitant medications. Participants in this population will be 
included in the Population PK analysis. A population PK analysis will be done under a 
separate Population-PK Reporting and Analysis Plan.  
9.3.4. 
Safety Population 
The Safety Population consists of all randomized participants who were exposed to study 
intervention with the exception of any participants with documented evidence of not 
having consumed any amount of study intervention. Participants will be analyzed 
according to the actual treatments received. The safety population will be the primary 
population for safety analyses.  
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to Database Release (DBR) and will 
include a more technical and detailed description of the statistical analyses. This section 
is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1. 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary efficacy statistical analysis will be based on the proportion of 
participants in the ITT-E population with plasma HIV-1 RNA <50 c/mL at 
Week 24  using the FDA Snapshot algorithm. The posterior probability of 
response rate of the optimal GSK3640254 dose within 12% margin of the 
reference arm will be produced. Besides, Bayesian posterior mean of 
response rate and associated 95% credible interval, frequentist point 
estimate and 95% confidence intervals will be derived and displayed. Full 
details of the planned Bayesian analyses will be provided in the SAP. 
Secondary 
Secondary statistical analyses will be based on the proportion of participants 
in the ITT-E population with plasma HIV-1 RNA <50 c/mL at Weeks 48 using 
the FDA Snapshot algorithm. Full details will be provided in the SAP. 
Exploratory 
Will be described in the SAP 


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9.4.2. 
Safety Analysis 
The study is designed to select a dose for further evaluation on the basis of tolerability 
and virological efficacy in conjunction with immunological response, safety and 
pharmacokinetic measures. Measures of safety and tolerability will be used to compare 
the doses in a pre-specified manner will be detailed in the statistical analysis plan of the 
study. Exposure to study medication, measured by the number of weeks on study 
intervention, will be summarized by treatment arm. The proportion of participants 
reporting adverse events (AEs) will be tabulated for each treatment arm. The following 
summaries of AEs will be provided:  
• Incidence and severity of All AEs;  
• Incidence and severity of treatment related AEs;  
• Incidence and severity of AEs leading to withdrawal from study;  
• Incidence of SAEs  
Laboratory data, vital signs and ECG data (absolute values and change from baseline) 
will be summarized by visit and treatment group. More detailed safety analyses will be 
described in the statistical analysis plan and will be performed on the Safety Population. 
9.4.3. 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic 
Analyses 
If data permits, the pharmacokinetics of GSK3640254 in combination with DTG will be 
determined using a non-linear mixed effects modeling approach.  Population 
pharmacokinetic parameters will be estimated.  Dependent on the final structural 
pharmacokinetic model, additional pharmacokinetic parameters may also be estimated.  
Sources of variability in pharmacokinetic parameters will be investigated during 
population modeling.  Demographic parameters including, but not limited to age, sex, 
race, body weight, body mass index, concomitant medications, relevant laboratory 
parameters, and any additional parameters, will be evaluated as potential predictors of 
inter- and intra-participant variability for pharmacokinetic parameters.  Population 
pharmacokinetic modeling will be performed using the non-linear mixed effects software 
NONMEM. The individual post-hoc PK parameters will be estimated and documented 
for the purposes of any subsequent exposure response 
(Pharmacokinetic/Pharmacodynamic) analyses. Further details of population 
pharmacokinetic analyses will be described in the Modeling Analysis Plan (MAP).   
9.4.3.1. 
Pharmacokinetic/Pharmacodynamic Analyses 
Exploratory analyses will be performed to examine the relationship(s) between plasma 
concentrations of GSK3640254 in combination with DTG and pharmacodynamic 
endpoints.  A population pharmacokinetic/pharmacodynamic modeling approach may be 
further applied to model the data using the nonlinear mixed effect modeling software, 
NONMEM.  Further details of population pharmacokinetic/pharmacodynamic analyses 
will be described in the MAP.   


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9.5. 
Other Analysis 
The overall proportion of study intervention taken relative to the planned amount will be 
estimated via pill counts and summarized by treatment arm for each IP.  
Data from C-SSRS assessments will be summarised by visit. 
Pharmacokinetic, analyses will be described in the SAP. The population PK analysis and 
pharmacodynamic analyses will be presented separately from the main clinical study 
report (CSR).  
Additionally, special statistical and data analysis considerations may be warranted in the 
event that the COVID-19 or related epidemics or natural disasters may affect the study 
and data integrity.  To the extent possible, these will be described in the main study SAP; 
alternatively, a separate SAP focusing on modified data handling rules (e.g., changes to 
analysis populations, visit windows and endpoints) and analyses (e.g., sensitivity analyses 
to assess impact of and account for missing data) may be prepared, taking in to account 
applicable regulatory guidance and industry best practices for handling such situations 
[FDA, 2020; EMA, 2020a; EMA, 2020b]. 
9.6. 
Interim Analysis 
At least two interim analyses will be performed throughout the course of the study: 
• The primary analysis will be conducted to evaluate the efficacy, safety and 
tolerability of optimal dose of GSK3640254 + DTG when all participants have 
completed their Week 24 visit  
• At least one IDMC interim analysis at one timepoint prior to the Week 24 primary 
endpoint will be necessary as described in Section 9.6.1. 
Finally, a secondary and End of Study analysis will be conducted to characterise the 
long-term safety, tolerability and durability of antiviral response of the optimal dose of 
GSK3640254 + DTG when all participants have completed their Week 48 visit. 
Further data cuts and analyses may be conducted as necessary to support regulatory 
submissions and/or publications. No adjustment for multiplicity caused by repeated 
analysis on the primary endpoint will be made as the interim analysis will be secondary. 
Type I error rate will not be inflated for the treatment comparison at the final analysis as 
non-inferiority will not be assessed at the interim. 
The ITT-E population will be the primary efficacy population and the safety population 
will be the primary safety population for any interim analysis. The actual dosage for 
participants randomized to a GSK3640254 arm and whether they are blinded to 
GSK3640254 or 3TC in combination with unblinded DTG will remain blinded to the 
study team until Week 24 database lock.  


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9.6.1. 
Independent Data Monitoring Committee 
This study will utilize an Independent Data Monitoring Committee (IDMC) to ensure 
external objective medical and/or statistical review of efficacy and safety in order to 
protect the ethical interests and well-being of participants and to protect the scientific 
validity of the study. An ad-hoc review of data by the IDMC will be triggered when the 
number of participants exceeds thresholds pre-specified in the IDMC charter for either: 
protocol-defined virologic failure criteria or number of safety/tolerability events. In 
addition, the IDMC will be triggered at least at one timepoint prior to the Week 24 
primary endpoint (independent of an event based trigger). Full details of the methods, 
timing, decision criteria and operating characteristics will be pre-specified in the IDMC 
Charter.  


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
o 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC 
o 
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), ), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
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 and answer all questions 
regarding the study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
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 their legally 
authorized representative.  
• Participants who are rescreened are required to sign a new ICF(s). 
GSK and ViiV Healthcare (alone or working with others) may use participant’s coded 
study data and samples and other information to carry out this study; understand the 
results of this study; learn more about GSK3640254 or about the study disease; publish 
the results of these research efforts; work with government agencies or insurers to have 
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. 
Committees Structure 
10.1.5.1. 
Safety Data Review by Safety Review Teamand IDMC 
• Participant safety will be continuously monitored by the Sponsor’s internal safety 
review committee, which includes safety signal detection at any time during the 
study 
• In addition, an independent safety review by an IDMC for this study will occur 
prior to the Week 24 primary endpoint (see Section 9.6.1) 
• Case unblinding may be performed for above reviews, if necessary. 
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 
ViiV Healthcare/GSK site or other mutually-agreeable location. 
• ViiV Healthcare/GSK will also provide all investigators who participated in the 
study with a summary of the study results and will tell the investigators what 
treatment their patients received.  The investigator(s) is/are encouraged to share 
the summary results with the study participants, as appropriate. 
• Under the framework of the SHARE initiative, ViiV Healthcare/GSK intends to 
make anonymized participant-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
• ViiV Healthcare/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 ViiV Healthcare/GSK Policy. 
• ViiV Healthcare/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 


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• 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.  
• Guidance on completion of CRFs will be provided in the eCRF Completion 
Guidelines. 
• Quality tolerance limits (QTLs) will be pre-defined in the QTL Plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the 
study data management plan or equivalent CRO document. 
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the 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.  


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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 the 
Source Data Acknowledgment or CRO equivalent document. 
• 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 participant Screening that is registered into the IVRS/IWRS is considered the 
first act of recruitment and will be the study start date. 
Study/Site Termination 
ViiV Healthcare, 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 ViiV Healthcare. Study sites 
will be closed upon study completion.  A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit 
has been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 


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For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 13 will be performed by the central laboratory. The total blood 
volume in this study is approximately 720 mL. 
Please refer to Appendix 11 in Section 10.11 for study management information during 
the COVID-19 pandemic. 
• 
Protocol-specific requirements for inclusion or exclusion of participant are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 13 
Protocol-Required Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
Amylase, Lipase 
 
Creatinine 
Sodium, 
Bicarbonate, 
and Chloride 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
eGFR or 
Creatinine 
Clearance3 
 
Glucose (can be 
nonfasting; 
though fasting on 
days when 
fasting lipids are 
collected) 
Calcium, 
Magnesium, 
and 
Phosphate 
Creatinine 
Phosphokinase  
(CPK) 
Fasting Lipid 
Panel 
(Cholesterol, 
Triglycerides, 
High density 
lipoprotein 
[HDL], low 
density 
lipoprotein 
[LDL]) 
Alkaline 
phosphatase2 


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Laboratory 
Assessments 
Parameters 
Routine 
Urinalysis 
• Albumin 
• Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
Testing 
• Highly sensitive serum/urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for participants of childbearing potential) 
Other Tests 
• Follicle-stimulating hormone and estradiol  
• Urine Drug Screen (to include at minimum: amphetamines, barbiturates, 
cocaine, MDMA, phencyclidine, opiates, oxycodone, cannabinoids, 
benzodiazepines, methadone, methamphetamines and tricyclic 
antidepressants) 
• HIV-1 RNA 
• CD4+ and CD8+ T-lymphocyte counts, CD4+/CD8+ T-cell count ratio 
• Hepatitis B: hepatitis B virus surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), and hepatitis B core antibody (with reflex to HBV DNA) 
• Hepatitis C: hepatitis C virus antibody (HCVAb) with reflex to HCV RNA, if 
positive 
• Serum albumin 
• PT/INR 
• rapid plasma reagin (RPR)  
• Gamma glutamyl transferase [GGT] and glutamate dehydrogenase 
[GLDH] 
• International normalized ratio (INR) 
NOTES : 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Section 10.6. 
2. 
If alkaline phosphatase is elevated, consider fractionating. 
3. 
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI-creatinine) [Levey, 2009]. In addition, GFR will be estimated by the 
central laboratory using the CKD-EPI-cystatin C [Inker, 2012] at Screening/Day 1 and when indicated by renal 
toxicity criteria 
 
MCV = mean corpuscular volume, MCH = mean corpuscular haemoglobin, RBC = red blood cells, WBC = white 
blood cells, BUN = Blood urea nitrogen, PT/INR = prothrombin time/international normalized ratio 


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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected 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. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE.  
 


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Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
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An SAE is defined as any serious adverse event that, at any dose: 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias,  
convulsions, or development of intervention dependency or intervention 
abuse. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 


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10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to ViiV Healthcare/GSK/Syneos Health in lieu of completion of 
the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by ViiV Healthcare/GSK/Syneos Health. 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 ViiV Healthcare/GSK/Syneos 
Health. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the DAIDS Grading Table, Version 2.1, March 2017 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf and assign it 
to 1 of the following categories:  
• 
Grade 1 (Mild) 
• 
Grade 2 (Moderate) 
• 
Grade 3 (Severe) 
• 
Grade 4 (Potentially Life Threatening) 
• 
Grade 5 (Death) 
Where a DAIDS toxicity scale is not available for a particular event or parameter, then 
the investigator will instead make an assessment of intensity using their clinical 
judgement based on the DAIDS scale.  
• 
Note: An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE. 
 


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


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10.3.5. 
Reporting of SAE to GSK/ViiV Healthcare/Syneos Health 
SAE Reporting to ViiV Healthcare/GSK/Syneos Health via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to ViiV Healthcare/GSK/Syneos Health 
will be the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The Investigator will capture the SAE Causality in the participant’s source notes in 
a timely manner and the investigator or an appropriately delegated team member 
will enter the causality into the eCRF.  Clinical research associates (CRAs) will 
monitor the subject source documentation to confirm that SAE causality is being 
documented by the Investigator in a timely manner.. 
• 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 ViiV Healthcare/GSK/Syneos Health via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Participants of Childbearing Potential (POCBP) 
Participants who are female at birth in the following categories are considered POCBP 
(fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in participants who are female 
at birth 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 Participants who are female at birth on HRT and whose menopausal status is 
in doubt will be required to use one of the non-estrogen hormonal highly 
effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study entry. 
• 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
10.4.2. 
Contraception Guidance: 
The list does not apply to participants of childbearing potential with same sex partners or 
for participants of childbearing potential who are and will continue to be abstinent from 


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penile-vaginal intercourse on a long term and persistent basis, when this is their preferred 
and usual lifestyle.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Methods of contraception are categorized by their effectiveness and user dependency: 1) 
highly effective methods (failure rate of <1% per year when used consistently and 
correctly) that have a low user dependency, 2) highly effective methods that are user 
dependent, and 3) effective methods that are not highly effective (failure rate of ≥1% per 
year when used consistently and correctly, e.g., condoms, cervical cap, diapraghm, 
sponge).   
GSK3640254 and DTG are not genotoxic. 
There are no contraceptive requirements for participants who are male at birth based on 
data for GSK3640254 and the most recent data for DTG.  
GSK3640254 has an “unlikely” risk for teratogenicity/fetotoxicity and would allow the 
use of contraceptive methods both highly effective and effective.  However, DTG has a 
“possible” risk for teratogenicity/fetotoxicity and appropriate methods of contraception 
are thus limited to only those methods that are considered to be highly effective.  Because 
there is a DTG component in all 4 treatments arms over the course of the study, POCBP 
will need to adhere to the following highly effective methods of contraception: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
If a hormonal method is selected, the POCBP is required to be clinically stable on it for at least one month prior to 
starting treatment in the study. 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the participant 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 Failure rate of <1% per year when used consistently and 
correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
• oral 
• intravaginal 
• transdermal 
• injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
• oral 
• injectable 
• Sexual abstinence 


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
If a hormonal method is selected, the POCBP is required to be clinically stable on it for at least one month prior to 
starting treatment in the study. 
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 participants 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. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 


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


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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments  
Liver Chemistry Stopping Criteria - Liver Stopping Event 
If Baseline ALT ≤ 1.5x ULN 
ALT-absolute ALT ≥ 5X ULN  
ALT Increase 
NONE for this study. 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
Symptomatic3 ALT  3xULN with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity 
If Baseline ALT > 1.5x ULN 
ALT-absolute ALT ≥ 5x ULN OR > 500 U/L (whichever occurs first) 
ALT Increase 
ALT ≥ 3x baseline but < 5x ULN persists for ≥ 2 weeks (with bilirubin <2x ULN 
and no signs or symptoms of acute hepatitis or hypersensitivity)  
Bilirubin1, 2 
ALT ≥ 3x baseline OR > 300 U/L (whichever occurs first) and bilirubin ≥ 2x 
ULN 
Cannot 
Monitor 
ALT ≥ 3x baseline but < 5x ULN and cannot be monitored every 1-2 weeks 
Symptomatic3 ALT ≥ 3x baseline and symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity) 


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Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment. 
• Report the event to the medical monitor 
within 24 hours. 
• Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2. 
• Perform liver event follow up assessments.  
• Monitor the participant until liver chemistries 
resolve, stabilise, or return to within 
baseline (see MONITORING below). 
 
 
MONITORING: 
• Make every reasonable attempt to have 
participants return to clinic within 24 hours 
for repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
at the central laboratory as described to the 
right.  
• A specialist or hepatology consultation is 
recommended. 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline. 
 
• Viral hepatitis serology, including: 
• 
Hepatitis A immunoglobulin M 
(IgM) antibody; 
• 
HBsAg and hepatitis B core 
antibody; 
• 
Hepatitis C RNA; 
• 
Hepatitis E IgM antibody. 
• Cytomegalovirus IgM antibody. 
• Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain 
heterophile antibody or monospot 
testing). 
• Syphilis screening. 
• Drugs of abuse screen, including alcohol. 
Record alcohol use on the liver event 
CRF 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).  The site must 
contact the medical monitor when this 
test is required.  
• Blood sample for pharmacokinetic (PK) 
analysis, obtained within 60 hours of last 
dose4. 
• Serum CPK and lactate dehydrogenase 
(LDH). 
• Gamma glutamyl transferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin 
• International normalized ratio (INR) 
• Fractionate bilirubin, if total bilirubin 
1.5xULN. 


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• Obtain complete blood count with 
differential to assess eosinophilia. 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash as relevant 
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 eCRF. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant 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) 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. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).   
4. 
PK sample may not be required for participants known to be receiving non-ViiV comparator treatments.  Record 
the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood 
sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.   


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Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT ≥3x baseline and <5x baseline 
and bilirubin <2x ULN without 
symptoms believed to be related to 
liver injury or hypersensitivity 
• Notify the medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety.  
• Participant can continue study treatment   
• Participant must return every 2 weeks for repeat 
liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until resolution or 
stabilisation (ALT <5×ULN on 2 consecutive 
evaluations)  
• If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above. 
Asymptomatic Liver Enzyme Elevations 
For asymptomatic participants who have ALT≥3X ULN, following discussions with 
medical monitor, ALT and other specific lab tests can be repeated in an unscheduled 
visit. This may include liver panel tests included in study protocol, even though 
participant did not meet any liver monitoring or liver stopping criteria above. 
 


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10.7. 
Appendix 7: Child-Pugh Classification 
A participant is classified with mild hepatic impairment (Class A) if their overall sum of 
scores is 5-6 points, moderate hepatic impairment (Class B) if their overall sum of scores 
is 7-9 points, and severe hepatic impairment (Class C) if their overall sum of scores is 10-
15 based on the Child-Pugh system [Pugh, 1973] scoring described in the following 
Table (Table 14).  For participants requiring anticoagulation therapy, discussion with the 
study medical monitor will be required. 
Table 14 
Child-Pugh System 
Finding  
Points Scored for Each Observed Finding  
 
1 
2 
3 
Encephalopathy Grade1  
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Serum bilirubin, SI units (μmol/L),  
Serum bilirubin, conventional units (mg/dL)  
<34 
<2 
34 to 52 
2 to 3 
>52 
>3 
Serum albumin, SI units (g/L)  
Serum albumin, conventional units (mg/dL)  
>35 
>3.5 
28 to 35 
2.8 to 3.5 
<28 
<2.8 
 Prothrombin Time (seconds prolonged) or 
INR  
<4 
<1.7 
4 to 6 
1.7 to 2.3 
>6 
>2.3 
1. 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity 
[Pugh, 1973; Lucey, 1997] 
 
 


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10.8. 
Appendix 8: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Corrected Version 
2.1, July 2017 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term. 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional Table below should be used to grade the severity of an AE that is not 
specifically identified in the grading Table.  In addition, all deaths related to an AE are to 
be classified as Grade 5. 
PARAMETER 
GRADE 
1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Clinical adverse 
event  NOT 
identified 
elsewhere in 
the 
grading Table 
Mild symptoms 
causing no or 
minimal 
interference 
with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Moderate symptoms
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated 
Severe symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
with 
intervention 
or 
hospitalization 
indicated 
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1. [July 2017] is available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 


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10.9. 
Appendix 9: Toxicity Management 
Adverse events that occur during the trial should be evaluated by the investigator and 
graded according to the DAIDS toxicity scales (see Section 10.8).  Additional 
information regarding detecting, documenting and reporting AEs and SAEs are available 
in Section 10.3.5. 
Grade 1 or Grade 2 Toxicity/Adverse Event 
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study 
treatment at the discretion of the investigator.  Participants who choose to withdraw from 
the study due to a Grade 1 or 2 AE should have study withdrawal and follow-up 
evaluations completed. 
Grade 3 Toxicity/Adverse Event 
Participants who develop a Grade 3 AE or toxicity should be managed as follows:  
If the investigator has compelling evidence that the Grade 3 AE or toxicity has not been 
caused by study treatment, dosing may continue after discussion with the medical 
monitor. 
Participants who develop a Grade 3 AE that the investigator considers related or possibly 
related to the study interventions should have study treatment discontinued. 
Should the same Grade 3 AE recur within 28 days in the same participant, study 
treatment should be permanently discontinued, and the participant withdrawn from study.  
Participants experiencing Grade 3 AEs requiring permanent discontinuation of study 
treatment should be followed weekly until resolution of the AE and have withdrawal 
study evaluations completed.  A Follow-up visit should be performed 4 weeks after the 
last dose of study intervention.  
Participants with asymptomatic Grade 3 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue study intervention if the investigator has compelling evidence that 
the toxicity is not related to study treatment. 
Exceptions are noted for lipid abnormalities (for example, isolated Grade 3 lipid 
abnormalities do not require withdrawal of IP) and rash in Section 10.9.7. 


T M F -1 4 4 3 5 4 6 1  
C O N FI D E N TI A L  
 
 
 
2 1 2 4 8 3  
 
1 3 0  
 
Gr a de 4 T o xicit y/ A d verse E ve nt  
Partici pa nts w h o de vel o p a Gra d e 4 A E or t o xicit y s h o ul d ha ve st u d y tr eat me nt 
disc o nti n ue d.  H o we ver, f or Gra de 4 t o xicities o nl y ( n ot A Es), if t he i n vesti gat or h as 
c o m pelli n g e vi d e nce t hat t he t o xicit y is n ot ca usall y rel ate d t o t he st u d y i nter ve nti o ns, 
d osi n g ma y c o nti n ue after disc ussi o n wit h a n d asse n t fr o m t he me dical m o nit or.  
Partici pa nts s h o ul d be rec hec k e d eac h wee k u ntil t he t o xicit y ret ur ns t o Gra de 2.  
Partici pa nts e x perie nci n g Gra de 4 A Es re q uiri n g p er ma ne nt disc o nti n uati o n of st u d y 
treat me nt s h o ul d be f oll o we d wee kl y u ntil res ol uti o n of t he A E a n d e nc o ura ge d t o 
c o m plete t he wit h dra w al a n d f oll o w -u p st u d y e val uati o ns as n ote d a b o ve.  
S p e cifi c T o xi citi e s/ A d v er s e E v e nt M a n a g e m e nt  
Ge neral g ui d eli nes f or t h e ma na ge m e nt of s pecifi c t o xicities t hat are c o nsi dere d t o be 
relate d or p ossi bl y rel ate d t o st u d y treat me nt are pr o vi de d bel o w.  
Partici pa nts w h o per ma n e ntl y disc o nti n ue st u d y tr eat me nt f or reas o ns of t o xicit y s h o ul d 
be f oll o we d w ee kl y u ntil res ol uti o n of t he A E a n d e nc o ura ge d t o c o m plete t he 
wit h dra wal a n d F oll o w -u p st u d y e v al uati o ns (see Secti o n 1. 3 ). 
1 0. 9. 1.  
Li v er C h e mi str y St o p pi n g a n d F oll o w -u p Crit eri a  
Li ver c he mistr y t hres h ol d st o p pi n g criteri a ha ve b ee n desi g ne d t o ass ure partici pa nt  
safet y a n d t o e v al uate li v er e ve nt aeti ol o g y d uri n g a d mi nistrati o n of st u d y i nter ve nti o n 
a n d t he f oll o w -u p peri o d. F or a c o m plete listi n g of st o p pi n g a n d f oll o w -u p criteria refer 
t o Secti o n 7. 1. 2  a n d Secti o n 1 0. 6 . 
1 0. 9. 2.  
H y p er s e n siti vit y R e a cti o n  
H y p erse nsiti vit y reacti o ns ha ve bee n re p or t e d wit h i nte grase i n hi bit ors, i ncl u di n g D T G, 
a n d were c haracteriz e d b y ras h, c o nstit uti o nal fi n di n gs, a n d s o meti mes, or ga n 
d ysf u n cti o n, i ncl u di n g li ver i nj ur y. Disc o nti n ue D T G a n d ot her s us pect a ge nts 
i m me diatel y if si g ns or s y m pt o ms of h y perse nsiti vit y reacti o ns de vel o p (i n cl u di n g, b ut 
n ot li mite d t o, se vere ras h or ras h acc o m pa nie d b y fe ver, ge neral malaise, fati g u e, m uscle 
or j oi nt ac hes, blisters, oral lesi o ns, c o nj u ncti vitis, facial oe d e ma, he p atitis, e osi n o p hilia, 
a n gi o e de ma). Cli nical stat us i ncl u di n g li ver a mi n otra nsferases s h o ul d be m o nit ore d a n d 
a p pr o priate t h era p y i nitiate d. Dela y i n st o p pi n g tr eat me nt wit h D T G or ot her s us pect 
a ge nts after t he o nset of h y perse nsiti vit y ma y res ult i n a life -t hreate ni n g reacti o n. 
C CI


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Participants may continue study intervention for Grade 1 or 2 allergic reactions at the 
discretion of the Investigator.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop.  Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed.  
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study intervention should permanently discontinue study treatment 
and the participant should be withdrawn from the study.  Participants should be treated as 
clinically appropriate and followed until resolution of the AE. 
10.9.3. 
Rash & Skin Reactions 
10.9.3.1. 
Rash 
Mild to moderate rash is an expected adverse reaction for DTG-containing ART.  
Episodes generally occur within the first ten weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within two to three weeks.  
No instances of serious skin reaction, including SJS, TEN and erythema multiforme, have 
been reported for DTG in clinical trials.  For further characterisation of HSR and rash 
observed with DTG-containing ART, please see the current version of the IB 
[GlaxoSmithKline Document Number RM2007/00683/14]. 
Skin and Subcutaneous disorders have also been reported across clinical trials with 
GSK3640254. 
Grade 1 Rash: Participants with an isolated Grade 1 rash may continue study intervention 
at the Investigator’s discretion.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops. 
Grade 2 Rash: Participants may continue study intervention for an isolated Grade 2 rash.  
However, study intervention (and all other concurrent medication(s) suspected in the 
Investigators causality assessment) should be permanently discontinued for any Grade 2 
rash that is associated with any systemic signs, allergic symptoms, or if mucosal 
involvement develops. 
Grade 3 Rash: Participants should permanently discontinue study intervention (and all 
other concurrent medication(s) suspected in the Investigators causality assessment) for an 
isolated Grade 3 rash, except where the aetiology has been definitively diagnosed as NOT 
attributable to study intervention (see below).  Participants should be treated as clinically 
appropriate and followed until resolution of the AE.  Every effort should be made to 
collect as much information as possible about the evolution of the event and any 
relationship with potentially related medical events (e.g., viral infection) or start of 
concomitant medication. 
Grade 4 Rash: Participants should permanently discontinue study intervention (and all 
other concurrent medication(s) suspected in the Investigators causality assessment). 
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the AE.  Every effort should be made to collect as much information as possible about the 
evolution of the event and any relationship with potentially related medical events (e.g., 
viral infection) or start of concomitant medication. 
The rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
gradings, Section 10.8). 
10.9.4. 
Hypertriglyceridemia/Hypercholesterolemia 
Samples for lipid measurements must be obtained in a fasted state according to the 
Schedule of Activities (Section 1.3).  Participants who experience asymptomatic 
triglyceride or cholesterol elevations may continue to receive study intervention. 
10.9.5. 
Creatine Phosphokinase (CPK) Elevation 
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 4 
weeks to ensure the result is transient or due to exercise and will not require a change in 
study treatment.  A history regarding use of drugs known to cause increase of CPK (such 
as statins), physical activity or exercise preceding the CPK evaluation should be obtained.  
Grade 4 elevations in CPK should have a repeat assessment after the participant has 
abstained from exercise for >24 hours.  For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the study interventions, study treatment should 
be discontinued, and the participant withdrawn from the study. 
10.9.6. 
Decline in Renal Function 
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (μMol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis and urine albumin/creatinine 
and urine protein/creatinine ratios, serum cystatin C and an estimated GFR using the 
CKD-EPI cystatin C method [Inker, 2012] should also be done at this confirmatory visit 
(refer to the SRM for details on the collection and processing of these urine samples).  If 
the creatinine increase is confirmed, the investigator should contact the Medical Monitor 
to discuss additional follow-up and medical management. 
Participants who experience progression to an estimated GFR (using the CKD-EPI 
method) [Levey, 2009] of <50 mL/min must return for a confirmatory assessment within 
2 weeks.  A urinalysis and urine albumin/creatinine and urine protein/creatinine ratios, 
serum cystatin C and an estimated GFR using the CKD-EPI cystatin C method [Inker, 
2012] should be done at this confirmatory visit (refer to the SRM for details on the 
collection and processing of these urine samples). 
If an estimated GFR of <50 mL/min is confirmed, then study medications should be 
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10.9.7. 
Proximal Renal Tube Dysfunction 
PRTD is defined as: 
• 
Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum 
phosphate <2.0 mg/dL; 
• 
Either of the above accompanied by any two of the following: 
o Glycosuria (≥250 mg/dL) in a non-diabetic; 
o Low serum potassium (<3 mEq/L); 
o Low serum bicarbonate (<19 mEq/L). 
Participants meeting criteria for PRTD must return for a confirmatory assessment within 
2 weeks of diagnosis. A urinalysis should also be performed at the time of the 
confirmatory assessment.  If PRTD is confirmed, participants must be withdrawn from 
the study. 
10.9.8. 
Proteinuria 
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, >300 mg/g, or 
>34 mg/mmol) that represents a change from Baseline and no associated increase in 
creatinine, should have a repeat spot urine albumin/creatinine ratio performed within 2-4 
weeks.  If confirmed, then consideration should be given to additional evaluation after 
consultation with the study medical monitor. Additional evaluation may include a 24-
hour urine protein and creatinine measurement and nephrology referral. 
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g, or 
>34 mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 
confirmed, the study medical monitor should be contacted immediately.  Agreement on 
further management should be agreed between the investigator and medical monitor. 
Refer to the SRM for details on the collection and processing of urine samples. 


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10.10. 
Appendix 10: CDC Classification for HIV-1 Infection (2014) 
• 
Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-
lymphocyte percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-
lymphocyte percentage should only be considered if the count is missing. 
• HIV infection, stage 0 
• 
Indicates early HIV infection, inferred from a negative or indeterminate HIV test 
result within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages. 
• 
HIV infection, stage 1 
• 
Laboratory confirmation of HIV infection with no AIDS-defining condition, and 
o CD4+ T-lymphocyte count of ≥500 cells/L, or 
o CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%. 
• HIV infection, stage 2 
• 
Laboratory confirmation of HIV infection with no AIDS-defining condition, and 
o CD4+ T-lymphocyte count of 200 to 499 cells/L, or 
o CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%. 
• HIV infection, stage 3 (AIDS) 
• 
Laboratory confirmation of HIV infection, and 
o CD4+ T-lymphocyte count of <200 cells/L, or 
o CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or 
o Documentation of an AIDS-defining condition (see below). 
• 
Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte count 
of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes of >14%.  
• 
HIV infection, stage unknown 
• 
Laboratory confirmation of HIV infection, and 
o No information on CD4+ T-lymphocyte count or percentage, and 
o No information on presence of AIDS-defining conditions. 
• Stage-3-defining opportunistic illnesses in HIV infection 
• 
Candidiasis of bronchi, trachea, or lungs  
• 
Candidiasis of oesophagus  
• 
Cervical cancer, invasive 
• 
Coccidioidomycosis, disseminated or extrapulmonary  


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• 
Cryptococcosis, extrapulmonary  
• 
Cryptosporidiosis, chronic intestinal (>1 month's duration) 
• 
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month 
• 
Cytomegalovirus retinitis (with loss of vision) 
• 
Encephalopathy, HIV-related  
• 
Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, or 
oesophagitis (onset at age >1 month) 
• 
Histoplasmosis, disseminated or extrapulmonary  
• 
Isosporiasis, chronic intestinal (>1 month's duration)  
• 
Kaposi's sarcoma  
• 
Lymphoma, Burkitt's (or equivalent term)  
• 
Lymphoma, immunoblastic (or equivalent term)  
• 
Lymphoma, primary, of brain  
• 
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary  
• 
Mycobacterium tuberculosis of any site, pulmonary, disseminated or extrapulmonary  
• 
Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary 
• 
Pneumocystis jirovecii pneumonia  
• 
Pneumonia, recurrent 
• 
Progressive multifocal leukoencephalopathy  
• 
Salmonella septicaemia, recurrent  
• 
Toxoplasmosis of brain, onset at age >1 month  
• 
Wasting syndrome attributed to HIV. 


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10.11. 
Appendix 11: COVID-19 Pandemic and Clinical Trial 
Continuity 
The COVID-19 pandemic may impact the conduct of clinical studies. Significant 
logistical challenges may arise from quarantines, variable restrictions on site resource and 
operations, site closures, travel limitations and the inability of an individual participant to 
attend clinic visit, interruptions to the supply chain for the investigational product, or 
other considerations if site personnel or study participants become infected with COVID-
19. These challenges may lead to difficulties in meeting protocol-specified procedures, 
including dispensation of the investigational product to the participant or adhering to 
protocol-mandated visits and laboratory/diagnostic testing.   
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy. 
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database. 
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect participant safety, welfare and rights, and to ensure data integrity 
and the integrity of the clinical trial, as a result of COVID-19 only. These measures may 
be implemented in accordance with any requirements and expectations set out by local 
Independent Review Boards/Independent Ethics Committees and National Competent 
Authorities, as necessary. 
This appendix does not apply for participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19.  
10.11.1. 
Changes to Study Visits and Study Procedures 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up however when not possible, for the duration of 
these special circumstances, the following measures may be implemented for enrolled 
participants: 
• When site staff resources are limited due to COVID-19, abbreviated study visits 
may proceed without conducting all protocol-specified additional assessments 
(e.g. lab tests, questionnaires, etc.). If laboratory testing will be missed for more 
than one consecutive visit, medical monitor pre-notification is required, and all 
efforts should be made to find alternative approaches for lab testing.  
• Consider alternative travel options for participants, if possible.  
• When central laboratory testing is not possible at a particular visit, tests for 
management of participant safety, including HIV-1 RNA may be performed at an 
appropriately authorised/accredited local laboratory (or other relevant clinical 
facility), if this can be done within local restrictions on physical distancing. The 


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site should proactively inform the Sponsor about such instances. Local laboratory 
results done as per routine follow-up, including HIV-1 RNA, may be used to 
inform safety and participant management decisions.  Results should be retained 
in source records and added to the eCRF. 
o If labs are collected on site and cannot be processed (either via central lab 
shipping, or local labs), freeze (and maintain at correct temperature for 
later processing) those samples that are sent frozen. Please safely discard 
ambient samples per site standards. 
• When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including AEs/SAEs, from the participant 
through alternative means, e.g. by telephone contact or video app such a Skype, 
FaceTime, Zoom, etc., where allowed.  
o The assessment should include inquiries to determine if the participant has 
been impacted by COVID-19 (extent of travel restriction, have they been 
in contact with any known positive cases [See Section 10.11.5.2 for WHO 
definition of “contact” -  it is important to understand who among our 
participants could be at risk], assess for COVID-19 as part of the AE/SAE 
assessment, and inquire about any possibility that the participant has plans 
to be on an experimental agent for COVID-19 See Section 10.11.4)  
o Other protocol assessments and procedures as specified in the Schedule of 
Activities should be completed where possible (e.g. answer questions, 
update concomitant medications, emphasize adherence, plan/schedule 
participants return for next scheduled visit). This information should be 
placed in source records and entered into the eCRF when next possible.  
o The eC-SSRS assessment is already planned to be done via telephone in 
this study, whether the participant is on site for an in-clinic visit or at 
home and doing a virtual visit.  When the participant is unable to be in the 
clinic for a required on-site visit, the eC-SSRS is still able to be performed 
at home, preferably prior to virtual contact by the site. Plans for addressing 
any positive results and referring for care remain no matter from which 
location the eC-SSRS is phoned in.  
• Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation.  
• Where applicable country and local regulations and infrastructure for home 
healthcare allow, home healthcare may take place at a location other than the 
clinical trial site to perform study assessments, which may include collection of 
blood and urine samples, measurement of vital signs and weight, and performance 
of ECGs.  It is the responsibility of the investigator to inform GSK/ViiV 
Healthcare/Syneos Health when this occurs and to document in source notes.  
• It may become necessary for the Sponsor to broadly incorporate the use of home 
healthcare staff to perform visits in the participant’s home. This possibility is also 
discussed in the ICF. 
• There may be cases where the current principal investigator (PI) of a site is 
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temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the sponsor. 
• There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations. 
10.11.2. 
Changes to Informed Consent 
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 
the investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.   
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval. 
Any updated informed consent form or other participant-facing materials should be 
provided to participants by e-mail, mail or courier before re-consent is obtained. Any 
consent obtained this way should be documented in source records and confirmed by way 
of normal consent procedure at the earliest opportunity when participants attend their 
next on-site study visit. 
The changes to the protocol, including COVID-19 related changes may be implemented 
before an ICF including COVID-19 related updates will be signed. 
10.11.3. 
Direct-To-Patient (DTP) Shipment of Study IP  
If a participant is unable to attend a study visit or to come to the site to pick-up 
investigational product (IP) due to site restrictions, or due to an inability to travel to the 
site (for personal precaution/sequestration, or government mandated travel restrictions, 
etc.), sites can consider DTP shipments of drug, from the site, to the participant, to ensure 
access to medicines.  All other options, including alternative travel options for 
participants, should be considered before reverting to DTP shipments. 
• If the study site is considering DTP shipment of IP, the site must first verify if 
DTP IP dispensing by investigators/hospital pharmacies is locally permitted and 
whether it requires regulatory and/or local ethics pre-approval, or post-hoc 
notification. 
• The study participant will express his/her agreement for DTP shipment and the 
sharing of their personal information with any third-party couriers (as applicable), 
in accordance with local requirements.  This agreement will be documented 
within the main ICF.   


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• DTP IP should be supplied only in a quantity that is sufficient to cover the interval 
to the next scheduled dispensation visit. There is a risk that accompanies 
dispensing more than a single 3-bottles set of blinded GSK3640254.  Please see 
the SRM for details about the limitations with dispensation. 
• GSK/ViiV Healthcare suggest the use of Marken in most countries for DTP 
shipments.  Otherwise, ensure local courier vendors, or vendors of hospital 
pharmacies, can ensure proper in-transit temperature monitoring, have enough 
shipper boxes and temperature loggers and can document storage conditions 
during IP transportation. 
• Where temperature monitoring is not available, oral protocol study treatments can 
be shipped at ambient temperatures with couriers that can provide shipper boxes 
capable of maintaining the shipment temperature storage requirements as 
described in the study guides. The risk of going outside of the excursion ranges 
listed in the study guide should be evaluated and documented. Proper 
documentation of the shipment should be maintained. In all cases IP 
accountability must be maintained, and all DTP dispensing documentation should 
be reflected in source records and dispensing logs per GCP. 
• Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IP directly to participants. 
• Remember that any courier deliveries can be affected by limitations of 
movements imposed by governments in relation to COVID-19.  
• Local courier vendors should be equipped to reduce risks of COVID-19 
contamination during transportation. 
10.11.4. 
COVID-19 Therapeutic Agents 
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study medical monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate. 
The protocol does not allow for concurrent enrolment in other interventional studies. 
10.11.5. 
COVID-19 Specific Data Capture 
10.11.5.1. Capturing COVID-19 Specific Protocol Deviations 
Please refer to the SRM for specific details on capturing protocol deviations as a result of 
COVID-19. 
10.11.5.2. Capturing COVID-19 Specific AEs and SAEs 
ViiV Healthcare are monitoring the evolving situation with respect to COVID-19 
carefully and the impact this may have on ongoing or planned clinical trials.  It is 
important for the study team to describe COVID-19 related adverse events/serious 
adverse events and their impact on study data and outcomes. Standardization of case 
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Please use the following guidance:  
1. 
AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual study 
procedures and timelines.  
2. 
When an in-person clinic visit is not possible, please conduct a remote telehealth 
visit to assess for, and document any AEs/SAEs. 
3. 
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to evolve; 
the most recent definitions should be consulted for each case (WHO). When 
reporting both serious and non- serious adverse events (related to COVID-19 
infection), investigators should use the following Verbatim terms:  
a) Suspected COVID-19 infection; or  
b) Probable COVID-19 infection; or  
c) Confirmed COVID-19 infection  
 
4. 
Sites should contact the study Medical Monitor for questions related to definitions 
and reporting, and decisions around impact to study intervention continuation in 
the setting of clinically defined mild COVID-19 infection.  
5. 
A new COVID-19 infection Case Report Form is included in the eCRF to collect 
additional details about the reported COVID-19 AE or SAE data. It is important 
that the correct information is collected from each participant reporting a COVID-
19 AE or SAE.  Therefore, please use the CRF templates to help you collect this 
information for all COVID-19 related AEs/SAEs. 
10.11.5.2.1. 
WHO Case Definition (July 15, 2022 Version or later):  
Please see the WHO Case Definition for Suspected, Probable, or Confirmed case of 
SARS-CoV-2 infection: https://www.who.int/publications/i/item/WHO-2019-nCoV-
Surveillance_Case_Definition-2022.1 or the current applicable version at the time of a 
potential COVID case. 
COVID-19 Contact: 
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case:  
1. 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes;  
2. 
Direct physical contact with a probable or confirmed case;  
3. 
Direct care for a patient with probable or confirmed COVID-19 disease 
without using proper personal protective equipment; OR  
4. 
Other situations as indicated by local risk assessments.  


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Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation. 


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10.12. 
Appendix 12: Abbreviations and Trademarks 
3TC 
Lamivudine 
ABC 
Abacavir 
ADME 
absorption-distribution-metabolism-elimination 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine aminotransferase 
anti-HBc 
Hepatitis B core antibody 
AST 
Aspartate aminotransferase 
ART 
Anti-retroviral therapy 
ARV 
Anti-retroviral 
AUC(0-) 
Area under the curve (Area under the plasma drug concentration-time curve 
from pre-dose to the end of the dosing interval at steady state)  
AUC(0-24) 
Area under the plasma concentration time curve from zero to 24 
AVB  
Atrioventricular block 
β-HCG 
Human chorionic gonadotropin 
BDC 
Bile-Duct-Cannulated 
BMI 
Body mass index 
BMS 
Bristol-Myers Squibb 
bpm 
Beats per minute 
cART 
Combination anti-retroviral therapy 
c/mL 
Copies per millilitre 
C0 
Concentration, pre-dose 
C24 
Concentration, 24 hours post-dose 
CAp24 
Capsid protein 24 
CD4 
Cluster of designation 4 
CD8 
Cluster of designation 8 
CDC 
Center for Disease Control and Prevention 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
CIB 
Clinical Investigator's Brochure  
CIOMS 
Council for International Organizations of Medical Sciences 
CKD EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMO 
Chief Medical Officer 
CMV 
Cytomegalovirus 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CrCl 
Creatinine Clearance 
CRF 
Case report form 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 


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Ct 
Concentration at end of dosing interval 
CV 
Cardiovascular 
CVb 
Between-participant coefficient of variation 
DAIDS 
Division of AIDS 
DBR 
Database Release 
DDI 
Drug-Drug Interaction 
DNA 
Deoxyribonucleic acid 
DTG 
Dolutegravir 
DTG/ABC/3TC Triumeq 
EC50 
Effective concentration 
EC90 
Effective concentration 
EGD 
Esophagogastroduodenoscopy 
ECG 
Electrocardiogram  
Emax 
Effect, at the maximum 
EMEA 
European Medicines Agency 
FACTS 
Fixed and Adaptive Clinical Trial Simulation 
FAST 
Focused Assessment with Sonography in Trauma 
FDA 
Food and Drug Administration  
FDC 
Fixed Dose Combination 
FSH 
Follicle Stimulating Hormone 
FTIH 
First-time-in-human 
Gag 
Group-specific antigen 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance  
GERD 
Gastroesophageal reflux disease 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline  
h or hr 
hour 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HCV Ab 
Hepatitis C antibody 
HDPE 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1 
Human immunodeficiency virus-1 
HRT 
Hormonal replacement therapy 
HSR 
Hypersensitivity Reaction 
ICF 
Informed consent form  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee  
INI 
Integrase Inhibitor 
INR 
International normalized ration 
IQ 
Inhibitory quotient 
IRB 
Institutional Review Board  


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INSTI 
Integrase Strand Transfer Inhibitor 
IP/IMP 
Investigational Product/Investigational Medicinal Product 
IRT 
Interactive Response Technology 
iSRC 
Internal Safety Review Committee 
ITT 
Intent to treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS/IWRS 
Interactive Voice/Web Response System 
kDa 
Kilodalton 
kg 
Kilogram 
lbs 
Pounds 
LDL 
Low density lipoprotein 
LOAEL 
Lowest observed adverse effect level 
LLOD 
Lower limit of detection 
LOC 
Local Operating Company 
MAD 
Multiple ascending dose 
MAP 
Modeling Analysis Plan 
MedRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Maturation inhibitors 
MOA 
Mechanisms of action 
MSDS 
Material Safety Data Sheet  
ms, msec 
Milliseconds 
NOAEL 
No-observed-adverse-effect-level 
NIMP 
Non-investigational Medicinal Product 
nM 
nanomolar 
NPO 
nil per os (Nothing by mouth) 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
NNRTI 
Non- Nucleoside Reverse Transcriptase Inhibitor 
OCT2 
Organic Cation Transporter 2  
PBAEC90 
Protein binding adjusted concentration 
PBO 
Placebo 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic  
PDVF 
Protocol-Defined Virologic Failure 
PI 
Principal Investigator  
PK 
Pharmacokinetic  
POC 
Proof of Concept 
PRSAE 
Possible Suicidality-Related AE 
PGX 
Pharmacogenetics 
POCBP 
Participant of Childbearing Potential  
PP 
Per protocol 
PPI 
Proton pump inhibitor 
PPL 
Physician Product Lead 
PRTD 
Proximal Renal Tubule Dysfunction 


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PSRAE 
Possible Suicidality-Related AE 
PT/INR 
Prothrombin time/International normalized ratio 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
QTL 
Quality Tolerance Limit 
R 
Accumulation ratio 
RBC 
Red blood cells 
RNA 
Ribonucleic Acid 
RPR 
Rapid Plasma Reagin 
SAD 
Single ascending dose 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis Software 
SD 
Standard deviation  
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SI 
Sub-Investigator 
SOA 
Schedule of activities 
SOC 
System Organ Class 
SP1 
Spacer peptide 1 
SRDP 
Study Results Dissemination Plan 
SRM 
Study Reference Manual  
SRT 
Safety Review Team 
STR 
Single tablet regimen 
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2 
Apparent terminal phase half-life  
tlag 
Absorption lag time 
tmax 
Time of occurrence of Cmax  
TN 
Treatment naïve 
ULN 
Upper limit of normal  
VH 
ViiV Healthcare 
VLD 
Viral load drop 
VSLC 
ViiV Safety and Labelling Committee 
VT 
Ventricular Tachycardia 
WBC 
White blood cells 
Wk 
Week 
 


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Trademark Information 
Trademarks of the ViiV Healthcare 
group of companies 
 
Trademarks not owned by the ViiV 
Healthcare group of companies 
 
DOVATO 
 
GenoSure 
EPZICOM 
 
Leica Aperio AT2DX  
TIVICAY 
 
Monogram Biosciences 
 
 
NONMEM 
 
 
PhenoSense 
 
 
 


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10.13. 
Appendix 13: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 02: 02-SEP-2021 
Study 212483 is undergoing a substantial amendment to reduce the sample size from 
approximately 120 participants to approximately 80 participants. This reduction of 40 
participants will occur equally among the 3 experimental arms. Thus, the number of 
participants will be as follows (each arm in combination with open-label DTG backbone 
as originally described): 
Arm 
Original Number 
Participants 
Amended Number of 
Participants 
GSK3640254 100 mg 
30 
20 
GSK3640254 150 mg 
30 
20 
GSK3640254 200 mg 
30 
20 
3TC 
30 
20 
Total 
120 
80 
The justification of this reduction in sample size is as follows:  
1. The Sponsor is conducting an additional Phase 2b study (Study 208379 that began 
screening in November 2020) – also in Treatment Naïve adults – investigating 
GSK3640254 (at the same 3 doses) in combination with open-label nucleoside 
reverse transcriptase inhibitors (NRTI) backbone. Since the trial began screening in 
November 2020, approximately ~89% of sites world-wide have been activated. The 
Sponsor anticipated screening would complete by 18 May 2021. However, as of 01 
July 2021, approximately 59 (of 150 total) have randomized. The reasons for slower 
than anticipated recruitment is based upon the multi-factorial impact of the global 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. 
Qualitative feedback from Investigators shows the incidence of known newly 
diagnosed HIV-1 infection has decreased. Moreover, physicians and newly infected 
patients have a strong desire to immediately start antiretroviral therapy, so they are 
less likely to participate in this Phase 2b study, which has a screening period of 
approximately 42 days. Based on this, a substantial amendment is being submitted to 
reduce the sample size from 30 per arm to 20 participants per arm in this study. 
2. Note, of approximately 109 participants initially screened in 208379, a screening 
Phenosense GT result is available for 22 participants. Of the 22 participants, there is 
ample diversity in HIV-1 sub-type as follows: Sub-type B (13 participants), Sub-
type C (2 participants), and 1 participant in each of the following Sub-types: 
Complex, AG, G, B/G, F1, AE, A1. Thus, a smaller sample size in this study, with 


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the same sample population and similar geographic recruitment area would not limit 
diversity in HIV-1 sub-type. Preserving the diversity of HIV-1 sub-type still allows 
the Sponsor to evaluate the broad spectrum of efficacy of GSK3640254 (note: Gag 
polymorphisms, varying by sub-type, impacted prior developmental Maturation 
Inhibitors). 
3. The Sponsor does not have formal statistical testing in this trial (212483). Note, 
Section 9 has been updated to describe modifications to the Statistical Considerations. 
The Sponsor finds the changes Type I error rate and Power to be clinically 
acceptable.  
4. A reduction in sample size does not limit the ability to make clinical inferences on the 
efficacy, safety/tolerability, and resistance of an optimal dose GSK3640254 (for 
subsequent clinical development) – resulting in maintenance of clinical integrity and 
unchanged risk benefit ratio to study participants.  
Justification for the removal of the Internal Sequestered Team 
In order to improve the clinical and scientific rigor and independence, the Sponsor will 
conduct a planned interim analysis with an IDMC instead of a Sequestered Team. The 
timing of the interim analyses (either by time of event trigger) will be specified in the 
IDMC charter.  
Overall Rationale for the Amendment:  
This is a global protocol amendment.  An update was made to the number of study 
participants from total 120 to 80; revised text to include changes made in the IDMC 
Charter to account for the reduced number of participants, revisions to the interim 
analysis, and the removal of the internal sequestered team; other updates were made 
throughout to correct errors and for clarity and consistency. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Schema Figure Footnotes 1 and 
3 were updated to reflect the 
changes in the IDMC reviews 
for Study 208379 and this study 
and to reflect the removal of the 
Sequestered internal analysis 
team. 
Updated to incorporate changes made 
in this protocol amendment  
1.1 Synopsis  
 
2.1 Study 
Rationale 
4.1 Overall Design,  
6.3 Measures to 
Minimize Bias 
10.1.5.1 Safety 
Data Review by 
Safety Team and 
IDMC 
Protocol Summary, 
4.1 Overall Design, 
9.6 Interim 
Analysis,  
9.6.1 Independent 
Data Monitoring 
Committee  
9.6.2 Sequestered 
Sponsor Team 
Analysis  
Mention of the internal 
Sequestered team was 
removed  
 
Updates on the IDMC interim 
analysis. 
Section 9. 6.2 was deleted 
since the internal Sequestered 
Team was removed from the 
IDMC charter  
In order to improve the clinical and 
scientific rigor and independence, the 
Sponsor will conduct a planned interim 
analysis with an IDMC instead of a 
Sequestered Team to be consistent 
with the modified IDMC Charter. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis  
4.1 Overall Design,  
4.1.1 Screening 
Period 
4.1.2.2 Week 24 
through Week 52 
9.2 Sample Size 
Determination 
9.2.1 Sample Size 
Sensitivity 
9.2.1 Sample Size 
Sensitivity Table 3 
and Figure 2 
Updated to reduce study 
sample size from 120 to 80 total 
participants; 
All treatment arms were 
reduced from 30 to 20 
participants;  
The 50% Screen failure rate 
was thus revised from 240 to 
160 participants. 
 
 
The decision rule was updated 
due to a change in sample size   
 
Update Table and Figure to 
reflect the new sample size 
Reduction in sample size was done to 
improve enrolment goals so they can 
be met in a timely manner.  The study 
is not powered, and the reduction does 
not limit the ability to make clinical 
inferences on the efficacy, 
safety/tolerability, and resistance of an 
optimal dose GSK3640254 (for 
subsequent clinical development).   
1.3  
Schedule of 
Activities 
Added  15-minute window for 
each ECG measurement for 
clarity. 
Added assessment windows around 
the time ECG data is collected in the 
schedule of activities for clarity. 
1.3 
Schedule of 
Activities  
 
8.2.6 Suicidal 
Ideation and 
Behaviour Risk 
Monitoring 
 
Updated to mention about 
window period of  7 days for 
completing eC-SSRS for each 
visit post-randomization. 
The visit to collect the baseline 
e-C-SSRS lifetime experience 
and current experience (within 
the past 2 months) was clarified 
to be at the Screening visit. 
Text added for clarity. 
4.1 Overall Design 
9.2.1 Sample Size 
Sensitivity  
Revisions to Study 208379 
relating to the IDMC interim 
analysis.  The interim analysis 
time-point was moved from 
Week 16 to Week 12 
The total number of participants in 
208379 was reduced in a protocol 
amendment and to account for changes 
in the IDMC Charter (i.e., updated 
timepoints for interim analysis). 


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Section # and 
Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
Added that all participants will 
receive 5 bottles (4 with tablets 
and 1 with capsules) to maintain 
the study blind through Week 
24. 
Text added for clarity. 
4.1.2, 8.4 Table 11 
Week 2 sample collection 
window reduced from 9-14 days 
to 11-14 days. 
Window reduced to better assess HIV-1 
viral load in all participants. 
5.1 Inclusion 
Criteria 
Inclusion criterion 4 was 
updated to decrease the 
screening CD4+ T-cell count 
from≥300 cells/mm3 to 
≥250 cells/mm3. 
To improve future recruitment based on 
recent experience in other internal 
studies based on the same treatment 
naïve participants. 
5.2 Exclusion 
Criteria 
Exclusion Criteria 28 was 
updated to when study 
treatment can start after 
treatment for syphilis infection. 
Text was modified for clarity. 
5.2 Exclusion 
Criteria 
Exclusion 22 was updated to 
include: Historical evidence of 
the presence of resistance to 
the integrase inhibitor class or 
to lamivudine. 
New text added. 
5.2 Exclusion 
Criteria 
Country specific exclusion 
criteria were added (Exclusion 
criteria 37 and 38) 
France specific request 
5.3.3 Activity 
Removed the following text: 
Participants may engage in light 
recreational activities during 
studies (e.g., watching 
television, reading). 
Text was deleted as it was not correct 
for this study. The prior sentence in this 
section was correct. 
8.2.3 Cardiac 
Monitoring with 
Electrocardiograms 
Removed text that ERT may 
provide a cardiologist over-read 
of ECGs 
Revised for clarity 
8.2.4 Clinical 
Laboratory 
Assessments 
Q2 Solutions was changed to 
PPD central lab. 
Study changed the central lab vendor. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
9.2 Sample Size 
Determination 
The probability of declaring 
positive sign of efficacy was 
modified to approximately 
27.5%.  
The probability of declaring a 
positive sign of efficacy would 
be 78.4%. 
Changes to same size determination 
were modified due to the lower sample 
size. 
9.6 Interim 
Analysis 
Added the potential for 
additional data cuts and 
analysis. 
Clarification to add that additional data 
cuts or analysis could be required for 
regulatory submissions or publications. 
10.2 Clinical 
Laboratory Tests 
Added the approximate total 
study blood volume (720 mL) 
Text added 
10.2 Clinical 
Laboratory Tests, 
Table 13 
Added a new footnote 3 with 
reference to Glomerular 
filtration rate (GFR) 
Deleted acronym definitions that 
are not used in this protocol 
Correction to the footnotes 
10.3.5 Reporting of 
SAE to GSK/ViiV 
Healthcare/Syneos 
Health 
Revised text to state SAE 
causality will be documented in 
the source documents in a 
timely manner prior to the entry 
into the eCRF. CRAs will 
monitor source documentation 
to confirm that SAE causality is 
being documented in a timely 
manner. 
GSK Process change. 
10.11.4 COVID-10 
Therapeutic 
Agents 
Updated COVID-19 agents from 
‘experimental’ to ‘therapeutic’. 
COVID-19 vaccines have been 
approved for use. 
 
 


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Amendment 01: 19-MAR-2021 
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. 
Overall Rationale for the Amendment:  
This is a global protocol amendment.  An update was made to the study entry criteria and 
minor updates were made throughout to correct errors and for clarity and consistency. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
Study Acronym added. 
To include the study acronym 
(DYNAMIC). 
2.3.2 Benefit 
Assessment 
Removed the word ‘preliminary’  
from ‘Data from the Phase 2a 
study does show a PK/PD 
(decline in HIV-1 RNA) 
relationship (described in detail in 
Section 4.3).’ 
To correct an error. 
5.1 Inclusion 
Criteria 
Inclusion criterion 4 was updated 
to decrease the screening CD4+ 
T-cell count from≥350 cells/mm3 
to ≥300 cells/mm3. 
 
To improve future recruitment based on 
recent experience in the sister study in 
the Phase 2b program in a similar 
population. 
7.1.3 
Columbia-
Suicide 
Severity Rating 
Scale 
Section added. 
For clarity and consistency. 
8.3.7 Disease-
Related Events 
and/or 
Disease-related 
Outcomes 
(HIV- 
Associated 
Conditions) 
Text updated.  
 
For clarity and consistency. 
10.6 Appendix 
6: Liver Safety: 
Required 
Actions and 
Follow-up 
Assessments 
and Section 7.1 
Discontinuation 
of Study 
Intervention 
Text updated. 
To clarify that study drug must be 
stopped immediately when ALT ≥ 5X 
ULN and that restart is not permitted. 
10.9.2 
Hypersensitivity 
Reaction 
Text updated. 
For clarity and consistency. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
10.9.3 Rash & 
Skin Reactions 
and 2.3.1 Risk 
Assessment 
Text updated 
To clarify that study drug should be 
permanently discontinued for any Grade 
2 rash that is associated with any 
systemic signs, allergic symptoms, or if 
mucosal involvement develops. 
 


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P P D

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  212483
Official Title of Study: A Phase IIb, Randomized, Double-blind, Parallel-group 
Study to Assess the Efficacy, Safety, Tolerability, and Resistance Profile of 
GSK3640254 in Combination With Dolutegravir Compared to Dolutegravir Plus 
Lamivudine in HIV-1 Infected, Treatment-naïve Adults
NCT ID: NCT04900038
Date of Document: 19 May 2023


 
 
 
 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1 - A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 1  of 7 0  
 
 
St a ti sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s 
F ull S A P T e xt (t hr o u g h t o E o S) 
S p o n s or N a m e: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”) i s t h e S p o n s or of t h e Cli ni c al Tri al. Gl a x o S mit h Kli n e 
R e s e ar c h & D e v el o p m e nt Li mit e d ( G S K) o n b e h alf of Vii V H e alt h c ar e U K Li mit e d i s o ut s o ur ci n g f ull 
s er vi c e t o S y n e o s H e alt h  
 
Pr ot o c ol N u m b er: 2 1 2 4 8 3  
Pr ot o c ol Titl e: A P h a s e II b, r a n d o mi z e d, d o u bl e- bli n d, p ar all el- gr o u p st u d y t o a s s e s s t h e 
effi c a c y, s af et y, t ol er a bilit y, a n d r e si st a n c e pr ofil e of G S K 3 6 4 0 2 5 4 i n c o m bi n ati o n wit h 
d ol ut e gr a vir c o m p ar e d t o d ol ut e gr a vir pl u s l a mi v u di n e i n HI V- 1 i nf e ct e d, tr e at m e nt n aï v e 
a d ult s 
A cr o n y m : D Y N A MI C 
 
Pr ot o c ol V er si o n a n d D at e: ( D D- M m m- Y Y Y Y): A m e n d m e nt 0 3 , 1 1 - A u g-2 0 2 2  
 
S y n e o s H e alt h Pr oj e ct C o d e: 7 0 2 3 6 5 3 
 
A ut h or:  
, Sr Bi o st ati sti ci a n 
 
 
 
 
 
N oti c e  of C o nfi d e nti al a n d Pr o pri et ar y I nf or m ati o n: 
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al b el o n gi n g t o Vii V H e alt h c ar e a n d 
Gl a x o S mit h Kli n e.  A c c e pt a n c e of t hi s d o c u m e nt c o n stit ut e s a gr e e m e nt b y t h e r e ci pi e nt t h at n o i nf or m ati o n 
c o nt ai n e d h er ei n will b e p u bli s h e d or di s cl o s e d wit h o ut pri or writt e n a ut h ori z ati o n fr o m a n offi ci al of Vi i V 
H e alt h c ar e a n d Gl a x o S mit h Kli n e.  H o w e v er, t hi s d o c u m e nt m a y b e di s cl o s e d t o a p pr o pri at e I n stit uti o n al 
R e vi e w B o ar d a n d Et hi c s C o m mitt e e s or d ul y a ut h ori z e d r e pr e s e nt ati v e s of a n ati o n al r e g ul at or y a ut h orit y 
u n d er t h e c o n diti o n t h at t h e y ar e r e q u e st e d t o k e e p it c o nfi d e nti al. I n t h e e v e nt of a n a ct u al or s u s p e ct e d 
br e a c h of t hi s o bli g ati o n, S y n e o s H e alt h s h o ul d b e n otifi e d pr o m ptl y. 
 
 
 
 
 
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2  of 7 0  
I c o nfir m t h at I h a v e r e vi e w e d t hi s d o c u m e nt a n d a gr e e wit h t h e c o nt e nt. 
A p pr o v al s  
S y n e o s H e alt h A p pr o v al  
, Se ni or  Bi o st ati sti ci a n  
 
 
N a m e, Titl e  
L e a d Bi o st ati sti ci a n  
 
Si g n at ur e  
 
D at e ( D D -M m m -Y Y Y Y)  
, Bi o st ati sti c s 
 
 
N a m e, Titl e  
S e ni or R e vi e wi n g Bi o st ati sti ci a n  
 
 
Si g n at ur e  
 
D at e ( D D -M m m -Y Y Y Y)  
 
Vii V  H e alt h c ar e a n d Gl a x o S mit h Kli n e A p pr o v al  
 
 
 S e ni or St ati sti ci a n  ( G S K) 
 
 
N a m e, Titl e  
G S K  C o nt a ct  
 
Si g n at ur e  
 
D at e ( D D -M m m -Y Y Y Y)  
 
 
, St ati sti c s L e a d er  ( G S K) 
 
 
N a m e, Titl e  
G S K  C o nt a ct  
 
Si g n at ur e  
 
D at e ( D D -M m m -Y Y Y Y)  
 
 
 
El e ctr o ni c all y si g n e d b y:
R e a s o n: I a m t h e a ut h or
D at e: M a y 1 8, 2 0 2 3 1 9: 4 5 G M T + 3
El e ctr o ni c all y si g n e d b y:
R e a s o n: I a m t h e r e vi e w er
D at e: M a y 1 8, 2 0 2 3 2 0: 5 1 G M T + 1
El e ctr o ni c all y si g n e d b y
R e a s o n: I a m t h e a p pr o v er
D at e: M a y 1 9, 2 0 2 3 0 8: 2 6 G M T + 1
El e ctr o ni c all y si g n e d b y:
R e a s o n: I a m t h e a p pr o v e
D at e: M a y 1 9, 2 0 2 3 1 3: 2 3
G M T + 5. 5
P P D
P P D
P P D
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P P D
P P D
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P P D
P P D
P P D
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 3  of 7 0  
R e vi si o n Hi st or y 
V er si o n #  
D at e  
( D D-M m m -Y Y Y Y)  
D o c u m e nt O w n er  
R e vi si o n S u m m ar y  
1. 0  
0 1 -D e c -2 0 2 2  
 
I niti al R el e a s e V er si o n 
2. 0  
1 7 -M a y -2 0 2 3  
 
U p d at e s f or E n d of St u d y  a n al y si s  
 
 
 
 
 
P P D
P P D


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 70 
Table of Contents 
Approvals .................................................................................................................................. 2 
Revision History .......................................................................................................................... 3 
1. 
Glossary of Abbreviations ................................................................................................... 8 
2. 
Purpose ............................................................................................................................ 10 
3. 
Statistical Hypotheses ...................................................................................................... 11 
4. 
Study Objectives .............................................................................................................. 12 
5. 
Study Details/Design ........................................................................................................ 14 
6. 
Analysis Populations ........................................................................................................ 20 
7. 
General Aspects for Statistical Analysis ........................................................................... 22 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 5  of 7 0  
9.  
Effi c a c y ............................................................................................................................ 2 8  
1 0.  P h ar m a c o ki n eti c s ............................................................................................................. 3 5  
C CI
C CI
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 6  of 7 0  
1 1.  Vir ol o g y ............................................................................................................................ 3 6  
1 2.  S af et y ............................................................................................................................... 3 7  
1 3.  C h a n g e s fr o m A n al y si s Pl a n n e d i n Pr ot o c ol ..................................................................... 4 3  
1 4.  Q u alit y C o ntr ol ................................................................................................................. 4 4  
1 5.  A p p e n di x: ......................................................................................................................... 4 5  
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Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
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16. 
 References ...................................................................................................................... 70 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
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1.  
Gl o s s ar y of A b br e vi ati o n s 
A b br e vi ati o n  
D e s cri pti o n  
A E  
A d v er s e E v e nt  
A R T  
A nti -R etr o vir al T h er a p y  
B MI  
B o d y M a s s i n d e x  
c/ m L  
C o pi e s / m L  
D T G  
D ol ut e gr a vir  
I A 
I nt eri m A n al y si s 
I C F 
I nf or m e d C o n s e nt F or m 
I D M C 
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e  
I T T-E  
I nt e nt-t o-Tr e at E x p o s e d  
L P L V  
L a st P ati e nt L a st Vi sit  
M a x  
M a xi m u m  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
Mi n  
Mi ni m u m  
N R TI  
N u cl e o si d e R e v er s e Tr a n s cri pt a s e I n hi bit or  
P K  
P h ar m a c o ki n eti c s  
P P  
P er -Pr ot o c ol  
P P S  
P er -Pr ot o c ol S et  
P D V F  
Pr ot o c ol D efi n e d Vir ol o gi c F ail ur e  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S D  
St a n d ar d D e vi ati o n  
S E  
St a n d ar d Err or  
s F T P  
S e c ur e Fil e Tr a n sf er Pr ot o c ol  
SI  
St a n d ar d I nt er n ati o n al S y st e m of U nit s  
S O C  
S y st e m Or g a n Cl a s s  
S O P  
St a n d ar d O p er ati n g Pr o c e d ur e  
S R T  
S af et y R e vi e w T e a m  
C CI
C CI


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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Abbreviation 
Description 
SYNH 
Syneos Health 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Table, Figure and Listing 
VL 
Viral Load 
VOI 
Visit of Interest  
EoS 
End of Study 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
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2. Purpose 
The purpose of this statistical analysis plan (SAP) is to describe planned analyses and output to be 
included in the Clinical Study Reports for Protocol 212483 and to ensure that the data listings, summary 
tables and figures which will be produced, and the statistical methodologies which will be used, are 
complete and appropriate to allow valid conclusions regarding the study objectives. 
This document will cover statistical analysis plan intended to describe the efficacy, safety, virology and 
PK required through to EoS. 
An addendum to this SAP will be developed at a later stage to convey the content of the continued 
access phase. 
2.1. Responsibilities 
Syneos Health (SYNH) will perform the statistical analyses and is responsible for the production and 
quality control of all tables, figures, and listings. 
2.2. Planned Analyses 
2.2.1. Interim Analyses 
2.2.1.1. Week 12 - IDMC Analysis 
An independent data monitoring committee (IDMC) will conduct an interim analysis. Full details of 
this methods, timing, decision criteria and operating characteristics are contained in the IDMC 
charter document “208379 and 212483 IDMC Charter version 2.0 final” and the IDMC SAP, which 
also describes the tables, figures, and listings (TFL) outputs which will be presented for different 
IDMC scenarios. 
2.2.2. Final Analyses 
2.2.2.1. Week 24 - Primary Analysis 
The primary analysis will be conducted to evaluate the efficacy, safety and tolerability of 
GSK3640254 + DTG when all participants have completed their Week 24 visit or discontinued.  
Treatment code would be unblinded at Week 24, once after all criteria for unblinding the 
randomization codes have been met.  
2.2.2.2. End of Study Analysis  
The end of study analysis will be conducted after all participants have reached end of study visit 
due to early termination or discontinued. 
Each of these analyses will be performed after the completion of the following sequential steps: 
All participants have completed the end of study visits due to early termination.  
All required database cleaning activities have been completed database lock (DBL) have been 
declared by Data Management. 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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3. Statistical Hypotheses 
The primary analysis of the study is designed to investigate the efficacy, safety, tolerability and resistance 
of three doses (100 mg, 150 mg, and 200 mg) of GSK3640254 + Dolutegravir (DTG), relative to DTG/ 
lamivudine (3TC) for 24 week. Although no formal statistical analysis will be carried out in this study, 
Bayesian analyses will be conducted to evaluate the probability that the Week 24 response rate, defined 
as the proportion of participants with plasma HIV-1 RNA <50 copies/mL (c/mL) as calculated by the FDA 
snapshot algorithm, of at least one dose of GSK3640254+DTG have comparable efficacy to the reference 
treatment using a 12% margin. A positive sign of efficacy will be achieved if any GSK3640254+DTG dose 
has a high posterior probability (e.g., ≥75%) of being within the 12% margin. 
 
 
 
 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 1 2  of 7 0  
4.  St u d y O bj e cti v e s 
O bj ecti v es  
E n d p oi nts  
Pri m ar y  
 
T o e v al u at e a nti vir al effi c a c y of G S K 3 6 4 0 2 5 4 + 
D T G, r el ati v e t o D T G /3 T C at W e e k 2 4 i n HI V -
1 -i nf e ct e d, A R T-n aï v e p arti ci p a nt s   
 
Pr o p orti o n of p arti ci p a nt s wit h pl a s m a HI V -1 
R N A < 5 0 c/ m L at W e e k 2 4 u si n g t h e F D A 
s n a p s h ot al g orit h m  
S e c o n d ar y  
 
T o e v al u at e t h e a nti vir al a cti vit y of 
G S K 3 6 4 0 2 5 4 + D T G r el ati v e t o D T G /3 T C  
 
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n 
HI V -1 R N A t hr o u g h W e e k s 2 4  
 
A b s ol ut e v al u e s a n d c h a n g e s fr o m b a s eli n e i n 
C D 4 + T -c ell c o u nt s t hr o u g h W e e k s 2 4  
 
T o e v al u at e s af et y a n d t ol er a bilit y of  
G S K 3 6 4 0 2 5 4 w h e n gi v e n i n c o m bi n ati o n wit h 
D T G, r el ati v e t o D T G /3 T C  
 
Fr e q u e n c y of S A E s, D e at h s a n d A E s l e a di n g 
t o Di s c o nti n u ati o n t hr o u g h W e e k s 2 4  
 
A E s of s p e ci al i nt er e st ( A E SI s) t hr o u g h 
W e e k s 2 4  
 
T o a s s e s s t h e d e v el o p m e nt of vir al r e si st a n c e 
t o G S K 3 6 4 0 2 5 4+ D T G  a n d ot h er o n -st u d y A R T 
i n p arti ci p a nt s e x p eri e n ci n g vir ol o gi c f ail ur e  
 
C h a n g e s i n g e n ot y pi c a n d/ or p h e n ot y pi c 
pr ofil e s of vir u s c o m p ar e d t o b a s eli n e  
 
T o a s s e s s t h e st e a d y -st at e e x p o s ur e of 
G S K 3 6 4 0 2 5 4 w h e n gi v e n i n c o m bi n ati o n wit h 
D T G  
 
T h e st e a d y -st at e pl a s m a P K p ar a m et er s of 
G S K 3 6 4 0 2 5 4 + D T G  will b e a s s e s s e d b a s e d 
o n S p ar s e P K s a m pli n g  
E x pl or at or y  
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 1 3  of 7 0  
O bj ecti v es  
E n d p oi nts  
 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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SAP Text Version: SAP Text Final 2.0 17-May-2023 
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5. Study Details/Design 
5.1. Brief Description 
Study 212483 is a Phase IIb, randomized, multicenter, double-blind, active-controlled, parallel group 
study to be conducted in approximately 80 ART-naïve adults living with HIV-1. Participants will be 
stratified by screening plasma HIV-1 RNA, by <100,000 c/mL or ≥100,000 c/mL and randomized to one of 
the three doses of blinded GSK3640254 (100, 150, or 200 mg) or a reference arm of blinded 3TC – each 
in combination with open label DTG. 
 
The study will include: 
   • A Screening Phase to a maximum of 30 days 
   • A Double-blind Randomized Phase (first participant Day 1 to last participant Week 24) 
   • An Open-label Randomized Phase (at least last participant Week 24 to last participant Week 52)  
   • Continued Access Phase 
   
Another Phase 2b study, 208379 (DOMINO), has been ongoing since November 2020, a dose range 
finding trial, where this study activity may serve as a trigger for IDMC activities as well as adopting optimal 
dose selected from DOMINO into DYNAMIC study.  
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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5.1.1.  Study Completion 
 
Element 
Reporting Detail 
General 
      
Participants are considered to have completed the study if they remain on therapy 
(i.e.,have not permanently discontinued IP) and satisfy one of the following: 
 
 
Randomly assigned to either treatment group, completed the blinded treatment 
phase and open treatment phase including the Week 52 visit, and did not enter 
Continued Access Phase 
 
 
Randomly assigned to either treatment group, completed the blinded treatment 
phase and open treatment phase including the Week 52 visit, and enter 
Continued Access Phase (defined as remaining on study until commercial 
supplies of GSK3640254 become locally available or development of 
GSK3640254 is terminated). 
 
 
Randomly assigned to either treatment group, completed the blinded treatment 
phase and but did not enter open treatment phase including the Week 52 visit 
because development of GSK3640254 is terminated. 
 
 
 
5.2. Patient Selection 
5.2.1.  Inclusion Criteria 
                    The inclusion criteria are listed in section 5.1 of the protocol. 
5.2.2.  Exclusion Criteria 
                       The exclusion criteria are listed in section 5.2 of the protocol. 
5.3. Determination of Sample Size 
Approximately 160 participants will be screened to achieve approximately 80 randomly assigned to study 
intervention for an estimated total of 20 evaluable participants per GSK3640254 + DTG and DTG/3TC 
arm. However, as a result of the potential impact of the parallel Phase 2b trial, Study 208379, the 
enrolment of Study 212483 may be adaptive resulting in no more than 30 participants originally 
randomized to any treatment arm. The planned sample size of approximately 20 participants per active 
arm and approximately 20 participants assigned to the reference arm is based on the primary efficacy 
endpoint of FDA Snapshot response rate at Week 24 (proportion of participants with plasma HIV-1 RNA 
<50 c/mL). 
 
Considering the small sample size of the study, response rate 90% (N=18) is used for the reference arm, 
and a response rate of 78% on the optimal dose, the probability of declaring positive sign of efficacy is 
approximately 27.5%. Given the stage of this phase 2b study and the relatively small sample size of each 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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arm, this is considered acceptable. Conversely, assuming a response rate of 90% on the optimal dose, 
the probability of declaring a positive sign of efficacy would be 78.4%. 
 
5.4. Treatment Assignment and Blinding 
All participants will be centrally randomized using an Interactive Voice/Web Response System 
(IVRS/IWRS). 
To minimize bias, all treatment arms (GSK3640254) will be blinded to the research participants and all 
study personnel during the study through Week 24. After Week 24 in DYNAMIC and the selection of the 
optimal dose in DOMINO, the DYNAMIC study will be unblinded, and the open-label randomized phase 
will begin. 
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 and ViiV 
Healthcare policy. 
The SYNH blinded team will include a Lead Biostatistician, SDTM programmers, ADaM/TFL 
programmers as well as a Senior Reviewing Statistician. A separate unblinded team will work 
independently of the blinded team to receive, review, and manage the unblinded data. The unblinded 
team including an unblinded statistician, an unblinded senior review statistician, and unblinded 
programmers do not have any day-to-day roles in the conduct of the study.  
 Any IDMC will occur while the study is still blinded. Unblinded outputs will be presented in a masked 
fashion for treatment groups (i.e., treatment groups labelled as A, B, C, D, where the order is random). 
Further details of the roles and responsibilities of the unblinded statistician are outlined in the IDMC 
Charter. 
The blinded team will develop and validate the SAS programs necessary for analysis on the blinded data. 
Once validated, the unblinded programming team members will run the SAS programs on the unblinded 
study data in a secure, access-restricted area. The unblinded statistician will review the outputs produced 
by the unblinded team. Unblinded outputs will be distributed via SYNH Secure File Transfer Protocol 
(sFTP) in an unblinded area, where only unblinded members have access.  
Data with the potential to unblind, i.e., PK concentration data, will be available to the blinded team only in 
a blinded fashion. Any potentially unblinding information will be masked prior to hand-off to the blinded 
team.   


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 17 of 70 
5.5. Administration of Study Medication 
 
GSK3640254 
GSK3640254 
Placebo 
DTG 
3TC 
3TC Placebo 
3TCa 
Intervention 
Name 
GSK3640254  Placebo to 
match 
GSK3640254  
Tivicay  
(The clinical 
label will 
state 
Dolutegravir 
50mg to 
match the 
SPC) 
3TC  
(The clinical 
label will state 
Lamivudine 
300mg) 
3TC Placebo  
(The clinical 
label will state 
Placebo to 
match 
Lamivudine 
300mg) 
3TC  
(The clinical 
label will state 
Lamivudine 
300mg) 
Type  
Drug 
Drug 
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation 
Tablet 
Tablet 
Tablet 
Capsule 
Capsule 
Tablet 
Unit Dose 
Strength(s) 
25 mg, 100 
mg 
N/A 
50mg 
300mg 
N/A 
300mg 
Dosage Level(s) 
Variable 
depending on 
dose 
Variable 
depending on 
dose 
One tablet 
per day 
One capsule 
per day 
One capsule 
per day 
One tablet per 
day 
Route of 
Administration 
Oral 
Oral  
Oral 
Oral 
Oral  
Oral 
Use 
Experimental 
Placebo 
Background 
Comparator 
Placebo 
Comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Provided 
centrally by 
Sponsor 
Packaging and 
Labeling 
32 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
32 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
30 tablets 
per HDPE 
bottle, 
labelled per 
country 
requirement 
32 capsules 
per HDPE 
bottle, labelled 
per country 
requirement 
32 capsules 
per HDPE 
bottle, 
labelled per 
country 
requirement 
30 tablets per 
HDPE bottle, 
labelled per 
country 
requirement 
 
a 3TC (Lamivudine 300mg) tablets for the Open Label phase will not be over-encapsulated, the 
existing commercial pack presentation (with a clinical label) will be supplied. 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 1 8  of 7 0  
5. 6.  St u d y Pr o c e d ur e s a n d Fl o w c h art 
T a bl e 1: Sc h e d ul e of Ass ess m e nts 
 
 
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 1 9  of 7 0  
 
 
 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 20 of 70 
6. Analysis Populations 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
 
Comprises Screened for inclusion in the study, 
including screen-failures. 
 
This population will be based on the treatment to 
which the subject was randomized. Screen-failures 
will be categorized as “Non-randomized”. 
 
Study Population 
Randomized  
 
 
Any participant who has been randomized to study 
intervention (for this study, this means a 
randomization number was assigned), whether or not 
the participant ever took a dose of study medication. 
 
Participants will be analysed according to the 
randomized treatment regardless of what treatment 
was actually received 
 
Study Population 
 
Safety 
 
All randomized participants who were exposed to 
study intervention with the exception of any 
participants with documented evidence of not having 
consumed any amount of study intervention 
 
This population will be analysed according to the 
actual treatment the participant received. The safety 
population will be the primary population for safety 
analyses. 
 
 
Safety 
Intent-To-Treat 
Exposed (ITT-E) 
 
All randomized participants who received at least one 
dose of study treatment. 
 
Participants will be analysed according to the 
randomized treatment regardless of what treatment 
was actually received 
 
 
Study Population 
 
Efficacy 
Per-Protocol  
(PP) 
 
This population will consist of subjects in the ITT-E 
Population except for Important protocol deviations 
designated as exclusions from the analysis 
population. 
 
This population will be based on the treatment to 
which the subject was randomized. 
 
Protocol deviations before a specified analysis 
timepoint that would exclude participants from the PP 
population are defined in Section 8.3 (Protocol 
Deviations) and Appendix 1: Exclusions from Per 
Protocol Population). E.g., a subject with an important 
protocol deviation between week 24  would not be 
excluded due to this deviation from week 24 PP 
population but would be excluded from PP 
population. 
 
Efficacy 
(Sensitivity 
analysis) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 21 of 70 
Population 
Definition / Criteria 
Analyses Evaluated 
Sparse 
Pharmacokinetic 
(Sparse PK) 
 
The pharmacokinetic (PK) population will include all 
participants who receive GSK3640254+DTG, undergo 
sparse PK sampling during the study, and provide 
evaluable GSK3640254+DTG plasma concentration 
data. Participants in this population will be included in 
the PK analysis. 
Note: PK samples that may be affected by protocol 
deviations will be reviewed by the study team to 
determine whether or not the sample will be excluded. 
PK 
Viral Genotypic  
 
 
Comprise of all subjects who receive at least one 
dose of study treatment who have available On-
treatment genotypic resistance data. 
 
This population will be based on the treatment to 
which the subject was randomized 
 
Viral Genotypic 
Viral Phenotypic 
 
 
Comprise of all who receive at least one dose of study 
treatment who have available On-treatment 
phenotypic resistance data. 
 
This population will be based on the treatment to 
which the subject was randomized 
 
Viral Phenotypic 
PDVF 
 
All subjects in the ITT-E population who met the 
PDVF criteria defined in the protocol. 
 
 
PDVF is defined as any of the following (and 
confirmed by a repeat and consecutive plasma HIV-1 
RNA measurement between two and four weeks 
(approx.) after the initial suspected virologic failure 
sample):  
 
Decrease from Baseline (Day 1) in plasma HIV-1 
RNA of ˂1.0 log10 c/mL unless plasma HIV-1 RNA is 
<200 c/mL by Week 12; 
 
Confirmed plasma HIV-1 RNA levels ≥200 c/mL at or 
after Week 24 
 
Plasma HIV-1 RNA ≥50 c/mL on repeat testing of 
Week 24 results and prior to Week 28. 
 
Confirmed plasma HIV-1 RNA ≥200 c/mL after 
confirmed consecutive plasma HIV-1 RNA <50 c/mL 
 
 
 
Efficacy  
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2 2  of 7 0  
7.  
G e n er al A s p e ct s f or St ati sti c al A n al y si s 
7. 1.  G e n er al M et h o d s 
 
S A S ® v er si o n 9. 4 or hi g h er t o b e u s e d 
 
All T L F s will b e pr o d u c e d u si n g t h e C o uri er N e w f o nt, si z e 1 0  
 
C o nti n u o u s v ari a bl e s will b e s u m m ari z e d u si n g t h e n u m b er of o b s er v ati o n s ( n), m e a n, st a n d ar d 
d e vi ati o n ( S D), m e di a n, mi ni m u m, a n d m a xi m u m a n d f or s o m e o ut p ut s g e o m etri c m e a n w o ul d al s o 
b e u s e d. U nl e s s ot h er wi s e s p e cifi e d, t h e e sti m at e d m e a n a n d m e di a n f or a s et of v al u e s ar e 
pri nt e d o ut t o 1 m or e si g nifi c a nt di git t h a n t h e ori gi n al v al u e s, a n d st a n d ar d d e vi ati o n s ar e pri nt e d 
o ut t o 2 m or e si g nifi c a nt di git s t h a n t h e ori gi n al v al u e s. T h e mi ni m u m a n d m a xi m u m s h o ul d r e p ort 
t h e s a m e si g nifi c a nt di git s a s t h e ori gi n al v al u e s. C at e g ori c al v ari a bl e s will b e s u m m ari z e d u si n g 
n u m b er of o b s er v ati o n s ( n), fr e q u e n c y a n d p er c e nt a g e s of p arti ci p a nt s. 
 
All r el e v a nt p arti ci p a nt d at a will b e i n cl u d e d i n li sti n g s. All p arti ci p a nt s’ d at a e nt er e d i nt o t h e 
d at a b a s e will b e i n cl u d e d i n p arti ci p a nt d at a li sti n g s . 
 
F or o ut p ut n a m e, f or t a bl e it w o ul d st art wit h “t _”, e g t _ 0 1- 0 1 or t _ 0 1 _ 0 1 a n d f or fi g ur e it st art s wit h 
f _.  F or li sti n g, if li sti n g i s b a s e d o n I C H li sti n g, it s h o ul d st art wit h li _, e g, li _ 0 2 _ 5 1, a n d if it i s fr o m 
n o n -I C H li sti n g it s h o ul d st art wit h l o _, e g, l o _ 0 2 _ 6 1. 
7. 2.  B a s eli n e D efi niti o n s 
Fir st d o s e d at e i s d efi n e d a s t h e d at e of t h e fir st d o s e of st u d y i nt er v e nti o n r e c ei v e d aft er r a n d o mi z ati o n i n 
t h e d o u bl e- bli n d r a n d o mi z e d p h a s e ( D a y 1 t o W e e k 2 4). L a st d o s e d at e i s d efi n e d a s t h e d at e of t h e l a st 
d o s e o f st u d y i nt er v e nti o n. F or p arti ci p a nt s o n g oi n g at t h e ti m e of a n al y si s, t h e l a st d o s e d at e will b e t h e 
m o st r e c e nt st art/ e n d d at e of e x p o s ur e c oll e ct e d i n t h e d at a b a s e f or t h at p arti ci p a nt. 
F or all t h e e n d p oi nt s, u nl e s s ot h er wi s e st at e d, b a s eli n e i s d efi n e d a s t h e l at e st n o n - mi s si n g v al u e pri or t o 
fir st d o s e of tr e at m e nt a c c or di n g t o d at e a n d ti m e i n cl u di n g u n s c h e d ul e d vi sit s. B a s eli n e d at a p oi nt s ar e 
e x p e ct e d t o c o m e fr o m t h e D a y 1 vi sit. If ti m e i s n ot c oll e ct e d, D a y 1 a s s e s s m e nt s ar e a s s u m e d t o b e 
t a k e n pri or t o fir st d o s e a n d u s e d a s b a s eli n e. 
P ar a m et er  
St u d y A s s e s s m e nt s C o n si d er e d a s B a s eli n e  
B a s eli n e U s e d i n 
D at a Di s pl a y  
S cr e e ni n g  
D a y 1 ( Pr e -D o s e)  
S af et y  
Vit al Si g n s  
X  
X  
D a y 1 ( Pr e -D o s e)  
L a b or at or y 
A s s e s s m e nt s  
X  
X  
D a y 1 ( Pr e -D o s e)  
Effi c a c y  
HI V -1 R N A/  
C D 4 + T c ell  
X  
X  
D a y 1 ( Pr e -D o s e)  
Vir ol o g y  
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St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2 3  of 7 0  
P ar a m et er  
St u d y A s s e s s m e nt s C o n si d er e d a s B a s eli n e  
B a s eli n e U s e d i n 
D at a Di s pl a y  
S cr e e ni n g  
D a y 1 ( Pr e -D o s e)  
G e n ot y pi c/ 
P h e n ot y pi c  
X  
X  
D a y 1 ( Pr e -D o s e)  
 
O n D a y 1 t hr e e r e a di n g s of bl o o d pr e s s ur e a n d p ul s e will b e t a k e n. T h e fir st r e a di n g s h o ul d b e r ej e ct e d. 
T h e a v er a g e of t h e s e c o n d a n d t hir d r e a di n g s ( a s r e c or d e d i n t h e C R F) will s er v e a s b a s eli n e. 
F or G e n ot y pi c a n d P h e n ot y pi c d at a, D a y 1 vi sit d at a will s er v e a s b a s eli n e, ot h er wi s e, b a s eli n e will b e s et 
t o mi s si n g. 
U nl e s s ot h er wi s e st at e d, if b a s eli n e d at a i s mi s si n g n o d eri v ati o n will b e p erf or m e d a n d b a s eli n e will b e 
s et t o mi s si n g. 
St u d y d a y i s d efi n e d a s ( e v e nt d at e – fir st d o s e d at e + 1) if e v e nt d at e > = fir st d o s e d at e; st u d y d a y i s 
d efi n e d a s ( e v e nt d at e – fir st d o s e d at e) if e v e nt d at e < fir st d o s e d at e. T h at i s, t h e d at e of fir st d o s e 
r e pr e s e nt s st u d y d a y 1. 
D e m o gr a p hi c d efi niti o n s i n cl u d e 
A g e  
 
F or all s u bj e ct s, t h e mi s si n g d at e a n d m o nt h will h a v e t hi s i m p ut e d a s ‘ 3 0t h J u n e ’ 
 
Birt h d at e will b e pr e s e nt e d i n li sti n g s a s ‘ Y Y Y Y’.  
 
C o m pl et el y mi s si n g d at e s of birt h will r e m ai n a s mi s si n g, wit h n o i m p ut ati o n a p pli e d. 
C o n s e q u e ntl y, t h e a g e of t h e s u bj e ct will n ot b e c al c ul at e d a n d will r e m ai n mi s si n g.  
 
  
H ei g ht (i n c m) = h ei g ht (i n i n c h e s) * 2. 5 4 
  
W ei g ht (i n k g) = w ei g ht (i n l b s) * 0. 4 5 3 6 
  
B o d y M a s s I n d e x ( B MI) ( k g/ m2 ) = W ei g ht( k g)/[ H ei g ht( m)]2  
7. 3.  Mi s si n g D at a 
I n a n y effi c a c y a n al y si s a p pl yi n g t h e S n a p s h ot al g orit h m, p arti ci p a nt s wit h o ut HI V- 1 R N A d at a i n t h e 
a s s e s s m e nt wi n d o w f or t h e vi sit of i nt er e st ( d u e t o mi s si n g d at a or di s c o nti n u ati o n of st u d y i nt er v e nti o n  
pri or t o t h e vi sit wi n d o w) ar e cl a s sifi e d a s eit h er ‘ HI V- 1 R N A ≥5 0 c/ m L’ or ‘ N o Vir ol o gi c D at a’. F or f ull 
d et ail s of t h e S n a p s h ot al g orit h m s e e A p p e n di x 1 5. 4. 4.  
F or h a n dli n g of mi s si n g a n d p arti al d at e s f or ot h er a s s e s s m e nt s, pl e a s e r ef er ( A p p e n di x 1 5. 5. 2 ) 
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Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 24 of 70 
7.4. Visit Windows 
The Snapshot visit windows are used as part of the Snapshot algorithm to determine a participant’s 
category (see Appendix 15.4.4). Snapshot analysis windows apply only to VL data that is on-treatment. 
Apart from Weeks 24, the window size is one-half the duration of time between study visits per protocol. 
Analysis Set 
/ Domain 
Parameter 
(if applicable) 
Target  
Analysis Window (Days) 
Analysis 
Timepoint 
Window  
Weeks 
Beginning 
Timepoint 
(including) 
Ending 
Timepoint 
(including) 
Snapshot 
All 
Day 85 
Day 71 
Day 98 
Week 12 
10-14  
Snapshot 
All 
Day 169 
Day 127 
Day 210 
Week 24 
18-30  
 
Other analyses Sets (e.g. lab) will use analysis windows ½ the distance between the previous and 
subsequent timepoint. 
 
Please refer to Appendix 2 for visit windowing criteria for other analyses. 
7.5. Multicenter Studies 
In this multicentre global study, enrolment will be presented by country and investigative site. For 
purposes of efficacy analyses, all sites are assumed to be exchangeable and there will be no site or 
country level adjustment. Therefore, no by-center analyses are planned. Data will be summarized in an 
aggregate fashion. 
7.6. Examination of Covariates, Other Strata and Subgroups 
7.6.1.  Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and statistical analyses, 
some of which may also be used for subgroup analyses. Additional covariates and other strata of clinical 
interest may also be considered. 
Category 
Details 
Randomization 
Strata using 
Baseline Values 
The randomization is stratified by factors which are assessed using screening 
values. The baseline categories are considered to be more relevant, hence the 
randomization strata are re-derived using baseline values and will be referred to as 
the analysis strata. 
The strata is as follows: 
Screening HIV-1 RNA (<100,000 copies/mL or >=100,000 copies/mL)  
7.6.2.  Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. Additional 
subgroups of clinical interest may also be considered. 
 
If the percentage of participants is small within a particular subgroup, then the subgroup categories 
may be refined prior to unblinding the trial. 
 
If the category cannot be refined further, then descriptive rather than statistical comparisons may be 
performed for the particular subgroup. 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2 5  of 7 0  
  
D e s cri pti v e s u m m ari e s of s u b gr o u p s will o nl y i n cl u d e s u bj e ct s wit h n o n- mi s si n g d at a. T h e n u m b er of 
s u bj e ct s wit h n o n - mi s si n g d at a f or e a c h s u b gr o u p will b e di s pl a y e d i n t h e t a bl e ( n) a n d b e u s e d a s t h e 
d e n o mi n at or i n p er c e nt c al c ul ati o n s. 
S u b gr o u p  
C at e g ori e s  
7. 6. 3.   M ulti pl e C o m p ari s o n s a n d M ulti pli cit y 
T h e s t u d y i s d e si g n e d t o e v al u at e t h e effi c a c y pri m aril y o n t h e b a si s of a nti vir al a cti vit y a n d t ol er a bilit y i n 
c o nj u n cti o n wit h i m m u n ol o gi c al r e s p o n s e, s af et y, a n d p h ar m a c o ki n eti c m e a s ur e s a n d i s n ot d e si g n e d t o 
e v al u at e f or m al st ati sti c al h y p ot h e s e s. H e n c e, a dj u st m e nt s f or m ulti pli cit y ar e n ot a p pli c a bl e. 
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2 6  of 7 0  
8. 2.  S u bj e ct Eli gi bilit y 
I n cl u si o n/ e x cl u si o n crit eri a d efi niti o n s a n d I n cl u si o n/ e x cl u si o n crit eri a vi ol ati o n s will al s o b e li st e d b y 
p ati e nt f or s cr e e n e d s et. 
8. 3.  Pr ot o c ol D e vi ati o n s 
Pr ot o c ol d e vi ati o n s will b e i d e ntifi e d p eri o di c all y t hr o u g h o ut t h e tri al f oll o wi n g t h e ‘ Pr ot o c ol D e vi ati o n a n d 
N o n- c o m pli a n c e M a n a g e m e nt Pl a n’ ( S y n e o s H e alt h S O P a n d WI, 3 1 0 1 a n d 3 1 0 1. W 0 2). Fi n al d efi niti o n of 
pr ot o c ol d e vi ati o n s a n d c at e g ori z ati o n i nt o N ot I m p ort a nt / I m p ort a nt will b e p erf or m e d i n t h e Bli n d e d D at a 
R e vi e w M e eti n g ( B D R M) pri or t o d at a b a s e l o c k a n d u n bli n di n g.  
All pr ot o c ol d e vi ati o n s r el at e d t o st u d y i n cl u si o n or e x cl u si o n crit eri a, c o n d u ct of t h e tri al, p ati e nt 
m a n a g e m e nt, d o si n g, a n d s a m pli n g pr o c e d ur e s or p ati e nt a s s e s s m e nt will b e li st e d. T h e li st of pr ot o c ol 
d e vi ati o n s will b e r e vi e w e d b y t h e S p o n s or, t h e pri n ci p al i n v e sti g at or a n d t h e st u d y st ati sti ci a n, a n d 
fi n ali z e d b ef or e d at a b a s e l o c k d uri n g t h e B D R M. Al s o, t h e d et er mi n ati o n w h et h er a n i m p ort a nt pr ot o c ol 
d e vi ati o n h a s a n i m p a ct o n t h e a s s e s s m e nt of t h e pri m ar y effi c a c y w hi c h r e s ult i n e x cl u si o n of s u bj e ct s 
fr o m a n al y si s p o p ul ati o n will b e fi n ali z e d i n t h e B D R M f oll o wi n g S O P 3 9 1 1. All pr ot o c ol d e vi ati o n s ( N ot 
i m p ort a nt a n d I m p ort a nt) o b s er v e d d uri n g t h e c o n d u ct of t h e st u d y will b e li st e d. I m p ort a nt pr ot o c ol 
d e vi ati o n s ( p ati e nt s wit h at l e a st o n e i m p ort a nt P D o v er all a n d s plit b y P D c at e g or y will b e  s u m m ari z e d b y 
tr e at m e nt gr o u p f or all I T T- E p arti ci p a nt s. 
 
Pl e a s e r ef er A p p e n di x 1  f or i m p ort a nt P D s l e a di n g t o e x cl u si o n fr o m P P. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 2 7  of 7 0  
8. 5.  S m o ki n g a n d Al c o h ol Hi st or y  
S m o ki n g a n d al c o h ol hi st or y will b e s u m m ari z e d u si n g st a n d ar d d e s cri pti v e st ati sti c s a n d li st e d f or all 
p ati e nt s f or t h e I T T- E s et p ati e nt s.   
8. 6.  M e di c al Hi st or y 
C urr e nt a n d P a st m e di c al hi st or y will b e s u m m ari z e d i n s e p ar at e t a bl e s f or t h e I T T- E s et pr e s e nti n g t h e 
n u m b er a n d p er c e nt a g e s of p ati e nt s wit hi n e a c h pr ef err e d t er m ( P T) gr o u p e d b y t h e s y st e m or g a n cl a s s 
( S O C), pr e- pri nt e d i n e C R F.  
  
8. 7.  Pri or a n d C o n c o mit a nt M e di c ati o n 
T h e W H O Dr u g, M ar c h 2 0 2 1, B 3 will b e u s e d t o cl a s sif y pri or a n d c o n c o mit a nt m e di c ati o n s b y t h er a p e uti c 
cl a s s a n d dr u g n a m e.  
Pri or m e di c ati o n i s d efi n e d a s a n y m e di c ati o n t a k e n b ef or e t h e d at e of t h e fir st d o s e of st u d y tr e at m e nt. 
C o n c o mit a nt m e di c ati o n i s d efi n e d a s a n y m e di c ati o n t a k e n o n or aft er t h e d at e of t h e fir st d o s e of st u d y 
tr e at m e nt.  
T h e u s e of c o n c o mit a nt m e di c ati o n s will b e s u m m ari z e d b y t h e n u m b er a n d p er c e nt a g e of p ati e nt s f or t h e 
I T T- E s et p ati e nt s. If a p ati e nt t a k e s a s p e cifi c m e di c ati o n m ulti pl e ti m e s or t a k e s m ulti pl e m e di c ati o n s 
wit hi n a s p e cifi c t h er a p e uti c cl a s s, t h at p ati e nt w o ul d b e c o u nt e d o nl y o n c e f or t h e c o d e d dr u g n a m e or 
t h er a p e uti c cl a s s.  
Pri or a n d c o n c o mit a nt m e di c ati o n s will b e li st e d f or all p ati e nt s i n t h e I T T- E p o p ul ati o n. 
8. 8.  Tr e at m e nt C o m pli a n ce  
. Tr e at m e nt C o m pli a n c e  
 
Tr e at m e nt c o m pli a n c e will b e c al c ul at e d b a s e d o n t h e f or m ul a:   
Tr e at m e nt C o m pli a n c e = N u m b er of A ct u al D o s e s* 1 0 0 / ( Pl a n n e d Tr e at m e nt D ur ati o n i n D a y s * 
Fr e q u e n c y)  
 
Fr e q u e n c y i s 2 f or BI D a n d 1 f or Q D. Tr e at m e nt c o m pli a n c e c o ul d b e gr e at er t h a n 1 0 0 % if t h er e ar e 
e v e nt s of o v er d o s e. C u m ul ati v e c o m pli a n c e ( si n c e D a y 1) at e a c h vi sit will b e c al c ul at e d . 
 
Pl a n n e d tr e at m e nt d ur ati o n will b e d efi n e d a c c or di n g t o t h e e n d p oi nt a n al y s e d.  
E n d p oi nt  
Pl a n n e d Tr e at m e nt D ur ati o n  
W e e k 2 4 S n a p s h ot  ( Pri m ar y) 
2 4 w e e k s  
 
 
 
 
C CI


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9.   Efficacy 
9.1. Primary Efficacy Analysis 
The primary analysis of the study is designed to investigate the antiviral activity of three doses (100 mg, 
150 mg, and 200 mg) of GSK3640254 in combination with Dolutegravir (DTG), relative to DTG/lamivudine 
(3TC) at 24 weeks. To achieve this objective, Bayesian analyses will be conducted to evaluate the 
probability that the Week 24 response rate, defined as the proportion of participants with plasma HIV-1 
RNA <50 copies/mL (c/mL) as calculated by the FDA snapshot algorithm, of at least one dose of 
GSK3640254+DTG has comparable efficacy to the reference treatment using a 12% margin. A positive 
efficacy decision will be made if any GSK3640254+DTG dose has a high posterior probability (e.g., 
≥75%) of being within the 12% margin. 
9.1.1. Primary Endpoint 
The primary efficacy endpoint is the binary outcome indicating the virologic category of plasma HIV-1 
RNA <50 copies/mL at Week 24 using the FDA Snapshot algorithm (See Appendix 15.4.4). The other 
Snapshot outcomes (HIV-1 RNA ≥50  copies/mL and no virologic data at Week 24 Window) will be 
collapsed into a single category for the analysis (non-response category). 
9.1.2. Summary Measure 
For each dose of GSK3640254+DTG the following Bayesian statistics will be provided: 
- 
The number and proportion of subjects with plasma HIV 1 RNA <50 copies/mL at Week 24 using 
the snapshot algorithm. 
- 
Summary statistics of the posterior distribution of response rate for the specified dose including: 
o 
Mean, median, and mode of posterior distribution of response rate for specified dose. 
o 
95% highest posterior density credible interval of response rate for specified dose. 
For the DTG/3TC arm (control arm) the following Bayesian statistics will be provided: 
- 
The number and proportion of subjects with plasma HIV 1 RNA <50 copies/mL at Week 24 using 
the snapshot algorithm  
- 
Summary statistics of the posterior distribution of response rate for the control including: 
o 
Mean, median, and mode of posterior distribution of response rate.  
o 
95% highest posterior density credible interval of response rate. 
- 
Posterior Probability that response rate of the specific GSK3640254+DTG dose is greater than 
the DTG/3TC arm response rate -12%. That is:  
o 
Posterior Pr(Response rate GSK3640254+DTG XX mg – Response Rate DTG/3TC) > -
0.12 
This posterior probability will be compared to 75% to determine positive sign for efficacy. 
Treatment comparisons will be made by calculating differences between the posterior distributions of the 
response rate between each dose of GSK3640254+DTG arm to the control arm DTG/3TC, which will be 
summarized to obtain posterior means and CIs. The point estimates of differences in virologic response 
rate with 95% credible intervals will be calculated for the treatment comparisons. 


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Posterior probability for the differences of following comparisons will also be reported. 
1. 
Response rate GSK3640254 100 mg + DTG vs. Response Rate Control arm DTG/3TC 
2. 
Response rate GSK3640254 150 mg + DTG vs. Response Rate Control arm DTG/3TC 
3. 
Response rate GSK3640254 200 mg + DTG vs. Response Rate Control arm DTG/3TC 
Besides, frequentist treatment difference point estimate and associated 95% confidence intervals will also 
be displayed.   
9.1.3. Population of Interest  
The primary efficacy analyses will be based on the Intent-to-Treat Exposed (ITT-E) and Per Protocol 
Population for sensitivity analysis. 
9.1.4. Strategy for Intercurrent (Post-Randomization) Events 
Intercurrent events such as discontinuations, missing plasma HIV-1 RNA samples and change in 
background regimen are handled using the Snapshot algorithm (see Appendix 15.4.4), which details how 
to assign each participant’s virologic outcome.  
9.1.5. Statistical Analysis/Method 
9.1.5.1. Primary Endpoint Statistical Methodology Specification 
Endpoint / Variables 
 
Binary outcome indicating the virologic category of plasma HIV-1 RNA <50 copies/mL (c/mL) at Week 
24 using the FDA Snapshot algorithm 
Model Specification 
 
Posterior distributions of the response rates for each dose, d, of GSK3640254+DTG and the 
reference DTG/3TC treatment will be calculated according to the following Bayesian model and 
parameters: 
 
𝑝𝑑= 𝑝𝑟𝑜𝑏𝑎𝑏𝑖𝑙𝑖𝑡𝑦 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑜𝑛 𝑑𝑜𝑠𝑒 𝑑 
𝑝𝑑=
𝑒𝜃𝑑
1 + 𝑒𝜃𝑑 
 
𝜃𝑑= 𝐿𝑜𝑔 𝑜𝑑𝑑𝑠 𝑜𝑓 𝑝𝑟𝑜𝑏𝑎𝑏𝑖𝑙𝑖𝑡𝑦 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑓𝑜𝑟 𝑑𝑜𝑠𝑒 𝑑 
𝜃𝑑= ln (
𝑝𝑑
1 −𝑝𝑑
) 
 
Model details: 
A Bayesian hierarchical model will be fitted using MCMC methods (Jones HE, 2011), the noninformative 
prior Beta (1,1) will be utilized for the reference arm to estimate the posterior probability of virologic 
response rate (Week 24 response rate, defined as the proportion of participants with plasma HIV-1 RNA < 
50 c/mL as calculated by the FDA snapshot algorithm for GSK3640254+DTG dose arms and reference 
arm DTG/3TC incorporating the baseline analysis stratification factors defined below.  
 
 


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Baseline Analysis Strata  
Stratum 
B1: Baseline HIV-1 RNA (𝐼{𝐵1+}) 
<100,000 copies/mL  
B1-(<100,000 c/mL) (0) 
≥100,000 copies/mL  
B1+(≥100,000 c/mL) (1) 
 
Model for each arm: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠 𝑟𝑔~𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑔, 𝑝𝑔),
𝑔= 1, 2 
𝜃𝑔= 𝑙𝑜𝑔𝑖𝑡(𝑃𝑔) = log (
𝑃𝑔
1 −𝑃𝑔
) = 𝛾0 + 𝛾1𝐼{𝐵1+}  + 𝜓𝑔,
𝑔= 1, 2 
Where 𝛾0, 𝛾1, 𝜓𝑔 are all parameters. Thus, 
𝜃1 = 𝛾0 + 𝜓1 
𝜃2 = 𝛾0 + 𝛾1 + 𝜓2 
Priors:  
𝛾𝑘~𝑁𝑜𝑟𝑚𝑎𝑙(0, 106), 𝑘= 0, 1 
𝜓𝑔 ~ 𝑁𝑜𝑟𝑚𝑎𝑙(0, 𝜔2 ), 𝑔= 1, 2 
𝜔~𝐻𝑎𝑙𝑓−𝑛𝑜𝑟𝑚𝑎𝑙(1) 
Where we define rg as the number of Virologic responders among ng participants, pg as Virologic response 
rate 
𝑟𝑔
𝑛𝑔, θg as the log odds of treatment response log(
𝑝𝑔
1−𝑝𝑔), index g =1,2 refers to the analysis stratum 
number, 𝛾𝑘 represent fixed effects of baseline analysis stratification factors (see  below),  and 𝜓𝑔 denotes 
a random effect in analysis stratum g. 
The two analysis strata and representation of the one baseline analysis stratification factor B1 in the model 
are shown in Table above. 
For each arm, the posterior distribution of Virologic response rate P(pg|data), g=1,2 will be derived for each 
analysis stratum using the model specified above.  
𝑃(𝑝1|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃1
1 + 𝑒𝜃1 |𝑑𝑎𝑡𝑎) 
𝑃(𝑝2|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃2
1 + 𝑒𝜃2 |𝑑𝑎𝑡𝑎) 
The posterior distribution of the arm-level Virologic response rate will be derived using a mixture of the 
posterior distributions of Virologic response rate for each analysis stratum in that arm. The weights are 
proportional to the sample size of each analysis stratum in each arm. 
 


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𝑃(𝑝|𝑑𝑎𝑡𝑎) = ∑
𝑤𝑔𝑃(𝑝𝑔|𝑑𝑎𝑡𝑎)
2
𝑔=1
, where 𝑤𝑔=
𝑛𝑔
∑
𝑛𝑔
2𝑔=1
 
 
Model Checking & Diagnostics 
 
Specific model checking procedures will be implemented according to the “Bayesian Statistics Best 
Practice at GSK- Clinical Trials Using Bayesian Inference document. 
Model Results Presentation 
 
A figure will be produced which displays the posterior distribution of response rate for each of the 
doses of GSK3640254+DTG as well as the posterior distribution of response rate for the DTG/3TC 
control arm. 
 
The mean of the posterior distribution of Week 24 snapshot response rate as well as associated 95% 
highest posterior density credible interval will be calculated for each dose of GSK3640254+DTG and 
the reference DTG/3TC arm and presented in tabular form 
Sensitivity and Supportive Analyses 
 
As a sensitivity analysis, to assess the impact of significant protocol deviations, statistical analysis will 
be repeated using the Per-Protocol population and compared for consistency with the results from the 
primary ITT-E population analysis. 
 
 
As supportive analysis and to assess the robustness of the primary analysis, a strata-adjusted 
Cochran-Mantel-Haenszel (CMH) test would be conducted to estimate treatment risk difference on 
binary response indicating virologic outcome category of plasma HIV-1 RNA <50 copies/mL (c/mL) at 
24 week, using the FDA Snapshot algorithm, adjusting for Baseline HIV-1 RNA (<100,000 copies/mL 
or ≥100,000 copies/mL) between doses of (GSK3640254+DTG) and control group (DTG/3TC) and its 
corresponding 95% confidence interval will be presented. For the analysis details please see section 
9.2.6. 
 
 
Number and percent of participants with plasma HIV-1 RNA <50 copies/mL (c/mL) at Week 24 observed 
as well as using the FDA Snapshot algorithm, will be also tabulated by treatment with Clopper Pearson 
95% confidence intervals also presented graphically. 
Efficacy listings will be generated. 
9.2. Secondary Efficacy Analyses 
9.2.1. Endpoint / Variables 
Secondary analyses will be conducted on: 
  
 
Absolute values and changes from baseline in HIV-1 RNA through Weeks 24 
 
Absolute values and changes from baseline in CD4+ T-cell counts through Weeks 24 
9.2.2. Summary Measure 
Number and percent of participants with HIV-1 RNA <50 copies/mL (c/mL) for both observed and 
snapshot analysis (see Appendix 15.4.4) within each treatment group (GSK3640254+DTG) and Control 
group (DTG/3TC) at week 24 will be also tabulated by treatment and visit with Wilson 95% confidence 
intervals and presented graphically over time. 


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Study outcome category and reasons defined by snapshot algorithm will also be summarized by 
treatment at Week 12, Week 24. 
Descriptive statistics (mean, median, standard deviation, etc.) of absolute values and changes from 
baseline in HIV-1 RNA, Log10 of HIV-1 RNA, CD4+ T-cell counts through weeks 24 and presented 
graphically over time on ITT-E population.  
9.2.3.  Population of Interest  
The secondary efficacy analyses will be based on the Intent-to-Treat Exposed (ITT-E), unless otherwise 
specified. 
9.2.4. Strategy for Intercurrent (Post-Randomization) Events 
Intercurrent events such as discontinuations, missing plasma HIV-1 RNA samples and change in 
background regimen are handled using the Snapshot algorithm (see Appendix 15.4.4), which details how 
to assign each participant’s virologic outcome. 
9.2.5. Statistical Analyses / Methods 
Unless otherwise specified, endpoints / variables defined in Section 9.2.1 will be summarized using 
descriptive statistics, graphically presented (where appropriate) and listed. 
There will not be any formal statistical analysis of secondary endpoints. Only descriptive statistics will be 
reported.  
Details of the planned displays are provided TLFs Shells document. 
9.2.6. Statistical Methodology Specification 
Endpoint / Variables 
The binary response indicating the virologic outcome category of plasma HIV-1 RNA <50 copies/mL 
(c/mL) at weeks 24  using the FDA Snapshot algorithm (see Appendix 15.4.4) 
Model Specification 
The efficacy endpoint will be analysed using a stratified analysis for proportions with Cochran-Mantel-
Haenszel (CMH) weights, adjusting for Baseline HIV-1 RNA (<100,000 copies/mL or ≥100,000 
copies/mL). Details of the analysis strata can be found in the Section 7.6.1. The CMH estimate of the 
adjusted treatment difference will be calculated as a weighted average of strata-specific estimates of the 
treatment difference calculated within each of the following 2 analysis strata: 
 
<100,000 copies/mL 
 
≥100,000 copies/mL 
 
If nk is the number of Treatment treated participants, mk is the number of Comparator treated 
participants, and Nk = nk + mk is the total number of participants in the kth stratum, then the CMH 
estimate is given by 
 
 
 


 
k
k 
k
cmh 
W 
d 
W 
d 
ˆ 
ˆ 


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where, 
 
 
 
are CMH weights and dk are estimates of the differences in proportions of participants with plasma 
HIV-1 RNA <50 copies/mL (c/mL) between the two treatment arms (Doses of GSK3640254 +DTG), 
rGSK3640254 +DTG – rDTG/3TC, for the kth strata. 
The corresponding two-sided 95% CI will be calculated as 
 
 
where the variance estimator (Sato, 1989)  is consistent in both sparse data and large strata and is 
given below   









2
2
ˆ
ˆ
ˆ
raˆ
v










k
k
k
cmh
k
k
k
k
k
cmh
cmh
W
Q
P
d
N
m
n
Q
P
d
d
 
where 
2
2
2
2
/)
(
k
k
k
k
k
k
k
k
k
k
N
n
m
m
n
x
m
y
n
P




 
2
/)
(
/)
(
k
k
k
k
k
k
k
k
k
N
x
n
y
N
y
m
x
Q




 
 
with xk and yk corresponding to the number of participants with HIV-1 RNA <50 copies/mL (c/mL) at 
weeks 24 as determined by the FDA Snapshot algorithm (see Appendix 15.4.4), for treatment and 
comparator, respectively, for the kth stratum. 
Model Checking & Diagnostics 
 
Not applicable, as no formal statistical modeling is being performed 
Model Results Presentation 
Adjusted CMH estimate of the difference in the percent of participants with plasma HIV-1 RNA <50 
copies/mL (c/mL) between each treatment group (GSK3640254+DTG – DTG/3TC) and 
corresponding 95% confidence interval will be presented. 
Subgroup Analyses 
 
An analysis for subgroups listed in Section 7.6.2 will be performed. This will show the percent of 
participants with plasma HIV-1 RNA <50 copies/mL (c/mL) at the time of analysis (Weeks 24 ) based 
on the Snapshot algorithm and will be presented by treatment group. Unadjusted percent by 
subgroup and corresponding two-sided 9 (FLEISS, 1981)5% (Wilson Score) confidence intervals will 
be tabulated and may also be presented graphically in a forest plot. 
Sensitivity and Supportive Analyses 
 
Separate supportive analyses will be performed to enable the assessment of the homogeneity of the 
treatment difference across analysis strata used in the analysis. 
The weighted least squares chi-squared statistic of (FLEISS, 1981)  will be used to test for one-way 
homogeneity of the treatment difference across the levels of the strata used for the primary analysis. 
The overall test for homogeneity will use the combined strata levels constructed by cross-
classification of Baseline HIV-1 RNA . Following Lui and Kelly [Lui, 2000], ½ will be added to each 
cell in any stratum for which the stratum-specific estimates of either rGSK3640254+DTG or rDTG/3TC are zero 
or one, and tests will be one-sided.  Tests of homogeneity will be assessed at the one-sided 10% 
 
k
k
k
k
N
m
n 
W 
 
)
ˆ
r(
aˆ 
v 
96
.1
ˆ
cmh 
cmh 
d
d 
 



St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 3 4  of 7 0  
l e v el of si g nifi c a n c e. 
 
F or e a c h str at u m, t h e p er c e nt of p arti ci p a nt s wit h pl a s m a HI V -1 R N A < 5 0 c o pi e s/ m L ( c/ m L) b y 
tr e at m e nt gr o u p a n d u n a dj u st e d diff er e n c e i n p er c e nt b et w e e n tr e at m e nt gr o u p s wit h c orr e s p o n di n g 
t w o-si d e d 9 5 % CI ( u si n g  t h e Wil s o n S c or e m et h o d) will b e r e p ort e d. I n a d diti o n, t h e p-v al u e fr o m t h e 
o v er all t e st of h o m o g e n eit y will b e r e p ort e d. T h e s e r e s ult s will b e u s e d t o a s s e s s t h e st ati sti c al 
a s s u m pti o n u n d erl yi n g t h e C M H str atifi e d a n al y si s pr o c e d ur e - n a m el y t h e a s s u m p ti o n o n a c o m m o n 
tr e at m e nt diff er e n c e a cr o s s str at a. 
C CI


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 35 of 70 
10.   Pharmacokinetics 
10.1. 
Endpoint / Variables 
Only pharmacokinetic concentration will be part of this SAP. All participants will provide samples for 
Sparse PK at Weeks 2, 4, 8, 12, 24 as outlined in the SoA. Please refer Table 1. 
10.1.1. Drug Concentration Measures 
All PK concentration listing displays will be based on the Sparse Pharmacokinetic populations and will be 
sorted by subject, study visit and time (or sampling window) relative to dose. 
 The plasma concentration levels of the drug will be summarized descriptively by treatment group, visit 
and timepoint for week 2, 4, 8, 12, 24. 
10.1.2. Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters are out of scope of this analysis plan since intensive PK was not collected in 
this study. Further details on PK parameter analysis for GSK3640254+DTG will be included in a separate 
SAP. 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 36 of 70 
11.   Virology 
The virology analyses of genotype and phenotype data will be based on the Viral Genotypic, Phenotypic 
and PDVF populations with subjects having Viral load >= 200 c/ml. 
The PDVF population will be based on subjects who have experienced a PDVF at any point.  
Refer to protocol section 7.1.1 and SAP Section 15.4.5 for the details of the PDVF details. 
Summary tables will present PDVFs up to and including the time point of interest . PDVFs must be 
confirmed within the phase in which they are reported. 
Listings will present PDVFs occurring at any point. 
Full sequence reverse transcriptase (RT), integrase inhibitors (INI), protease inhibitors (PI), and the study 
drug GSK3640524+DTG maturation inhibitors (MI) available data will be analysed at baseline, Week 4, 
and at time of confirmed protocol-defined virologic failure for baseline mutations and for emergent 
mutations. Additionally, genotypic changes from baseline will be identified and listed to potentially identify 
pathways to resistance. These analyses will use the PDVF population. 
Phenotypic changes for approved drugs will be determined at baseline, Week 4, and at time of confirmed 
PDVF. Treatment Emergent phenotypic changes will be investigated in the on-treatment Genotypic and 
Phenotypic population. 
Please refer SAP shells for further details on displays related to virology. 
 
 
 
 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 3 7  of 7 0  
1 2.    S af et y 
S af et y a n al y s e s will b e c o n d u ct e d u si n g t h e S af et y P o p ul ati o n u nl e s s ot h er wi s e s p e cifi e d.. 
S af et y will b e a s s e s s e d b a s e d o n e xt e nt of e x p o s ur e, a d v er s e e v e nt ( A E) r e p ort s, r el e v a nt C O VI D- 1 9 
A s s e s s m e nt s, A E SI, vit al si g n s, 
 cli ni c al l a b or at or y d at a, C- S S R S u si n g d e s cri pti v e st ati sti c s.  
N o i nf er e nti al st ati sti c al a n al y s e s ar e pl a n n e d o n t h e s af et y p ar a m et er s of t hi s st u d y.  
1 2. 1.   
E xt e nt of E x p o s ur e 
E xt e nt of e x p o s ur e i n cl u di n g Ti m e o n St u d y Tr e at m e nt ( d a y s), S u bj e ct D ail y D o s e ( m g), a n d C u m ul ati v e 
A ct u al D o s e ( m g) will b e s u m m ari z e d b y tr e at m e nt gr o u p u si n g d e s cri pti v e st ati sti c s f or W e e k 2 4 o n 
s af et y p o p ul ati o n. T h e s u bj e ct d ail y d o s e (t h e c u m ul ati v e a ct u al d o s e di vi d e d b y t h e d ur ati o n of e x p o s ur e 
i n d a y s) i s c al c ul at e d f or e a c h s u bj e ct fir st a n d t h e s u m m ar y st ati sti c s ar e c al c ul at e d b a s e d o n t h e s u bj e ct 
a v er a g e d ail y d o s e. 
A li sti n g pr e s e nti n g all a b o v e d efi n e d v ari a bl e s of e xt e nt of e x p o s ur e a n d st u d y dr u g a d mi ni str ati o n d at a 
i n cl u di n g d at e s f or a d mi ni str ati o n, di s p e n si n g a n d d o s e i nt err u pti o n d et ail s will b e pr e s e nt e d f or t h e s af et y 
p o p ul ati o n. 
1 2. 2.   
A d v er s e E v e nt s 
U nl e s s ot h er wi s e st at e d A E m e nti o n e d i n t hi s s e cti o n r ef er s t o Tr e at m e nt- E m er g e nt A E s. 
A n y A E will b e c o n si d er e d a tr e at m e nt- e m er g e nt a d v er s e e v e nt ( T E A E) if it o c c urr e d aft er t h e fir st d o s e of 
st u d y i nt er v e nti o n a n d wit hi n fi v e d a y s aft er tr e at m e nt di s c o nti n u ati o n. W h er e ti m e of t h e A E st art i s n ot 
a v ail a bl e, t h e A E will b e c o n si d er e d a T E A E if it o c c urr e d o n t h e s a m e d a y a s fir st d o s e of st u d y 
i nt er v e nti o n. F or A E h a p p e n e d i n s u bj e ct s wit h m or e t h a n o n e tr e at m e nt, A E i s a s si g n e d t o t h e m o st 
r e c e nt tr e at m e nt t o t h e A E st art d at e. 
Fl a g  
D efi niti o n  
Tr e at m e nt 
E m er g e nt  
 
St u d y Tr e at m e nt St art D at e ≤ A E St art D at e ≤ St u d y Tr e at m e nt St o p D at e + 5 
d a y s.  
 
F or A E h a p p e n e d i n s u bj e ct s wit h m or e t h a n o n e tr e at m e nt, A E i s a s si g n e d t o t h e 
m o st r e c e nt tr e at m e nt t o t h e A E st art d at e.   
N O T E S:  
 
If t h e st u d y tr e at m e nt st o p d at e i s mi s si n g, t h e n t h e A E will b e c o n si d er e d t o b e O n-Tr e at m e nt.  
 
Ti m e of st u d y tr e at m e nt d o si n g a n d st art/ st o p ti m e of A E s s h o ul d b e c o n si d er e d, if c oll e ct e d.  
 
A d v er s e e v e nt s will b e s u m m ari z e d b y s y st e m or g a n cl a s s ( S O C) a n d pr ef err e d t er m ( P T) f or e a c h 
tr e at m e nt a n d t ot al, b a s e d o n t h e M e d D R A di cti o n ar y v er si o n 2 5. 0 or a b o v e. S e v erit y of A E s will b e 
gr a d e d a c c or di n g t o T h e Di vi si o n of AI D S T a bl e f or Gr a di n g t h e S e v erit y of A d ult a n d P e di atri c A d v er s e 
E v e nt s ( C orr e ct e d V er si o n 2. 1), J ul y 2 0 1 7 . A gr a di n g ( s e v erit y) s c al e i s pr o vi d e d f or e a c h A E t er m. 
T a bl e f or Gr a di n g t h e S e v erit y of A d ult a n d P e di atri c A d v er s e E v e nt s. 
P A R A M E T E R  
G R A D E  1  
M I L D 
G R A D E  2  
M O D E R A T E  
G R A D E  3  
S E V E R E  
G R A D E 4  
P O T E N TI A L L Y LI F E - 
T H R E A T E NI N G  
C CI


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 38 of 70 
Clinical adverse 
event  NOT 
identified 
elsewhere in 
the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference 
with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Moderate 
symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual 
social & functional 
activities 
with 
intervention or 
hospitalization 
indicated 
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death
 
Duration will be calculated for AEs that resolve as the difference between the resolution date and onset 
date plus 5 and expressed in days. 
The summary tables will include the number of patients and the number of events. Percentages will be 
based on the number of patients in the safety population. For summaries by SOC and PT, a patient will 
be counted once at the SOC level and once at each PT within the SOC level.  
For summaries by SOC, PT, and maximum severity, a patient will be counted once at the highest severity 
level for which the event occurred at the SOC level and the highest severity level for each unique PT 
within that SOC level. Therefore, patients may only contribute once to each PT and once to each SOC 
level.  
The summaries presenting frequency of AEs by SOC and PT will be ordered by total descending 
frequency of SOC and then, within a SOC by total descending frequency of PT.  
The following summaries of AEs will be provided:  
• 
AEs by system organ class and preferred term 
• 
AEs with maximum DAIDS toxicity grade by system organ class and preferred term 
• 
Drug-related AEs with maximum DAIDS toxicity grade by system organ class and preferred term;  
• 
All Grade 2-5 Adverse Events by System Organ Class, Preferred Term 
• 
Non-Serious AE by system organ class and preferred term 
• 
SAEs by system organ class and preferred term; 
• 
SAEs with maximum DAIDS toxicity grade by system organ class and preferred term 
• 
Drug-related SAEs by system organ class and preferred term 
• 
AEs leading to Withdrawal/Permanent Discontinuation of Study Intervention/ Withdrawal from 
Study by system organ class and preferred term;  
• 
AEs leading to death by system organ class and preferred term; 
• 
AEs of special interest by system organ class and preferred term; 
AE Listings will include complete list of subjects having AEs in the safety population (irrespective of 
treatment emergent). Additional listings will be provided for AESIs, serious AEs and Adverse Events 
Leading to Study Drug Discontinuation/Withdrawal from Study. 
12.3. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify each type of 
event in a separate document (AESI MedDRA). Changes to the MedDRA dictionary may occur between 
the start of the study and the time of reporting and/or emerging data from ongoing studies may highlight 
additional adverse events of special interest, therefore the list of terms to be used for each event of 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 3 9  of 7 0  
i nt er e st a n d t h e s p e cifi c e v e nt s of i nt er e st ar e d efi n e d at a c o m p o u n d l e v el a n d b a s e d o n t h e s af et y 
r e vi e w t e a m ( S R T) a gr e e m e nt s i n pl a c e at t h e ti m e of r e p orti n g.  
C urr e nt A E SI c at e g ori e s ar e a s f oll o w s: 
-  
Q T pr ol o n g ati o n 
-  
GI i nt ol er a bilit y/t o xi cit y 
-  
N er v o u s S y st e m Di s or d er s 
-  
S ki n a n d s u b c ut a n e o u s ti s s u e di s or d er s 
-  
C ar di a c Di s or d er s 
 
A d v er s e e v e nt s of s p e ci al i nt er e st c at e g ori e s will b e s u m m ari z e d s e p ar at el y u si n g d e s cri pti v e st ati sti c s 
a n d will n ot u n d er g o f or m al st ati sti c al a n al y si s.  
1 2. 4.   
C O VI D- 1 9 A s s e s s m e nt s 
R el e v a nt C O VI D- 1 9 A s s e s s m e nt s, C O VI D- 1 9 S y m pt o m s f or S u bj e ct s wit h A d v er s e E v e nt s, a n d C O VI D-
1 9 P a n d e mi c Vi sit I m p a ct s will b e s u m m ari z e d.  
1 2. 5.   
L a b or at or y D at a 
S af et y l a b or at or y s a m pl e s f or c h e mi str y, h e m at ol o g y a n d uri n al y si s will b e c oll e ct e d at v ari o u s vi sit s. R ef er 
t o S e cti o n 5. 6 f or t h e s c h e d ul e of a cti viti e s i n di c ati n g w h e n t h e r e s p e cti v e s a m pl e s ar e t a k e n. 
All p ar a m et er s ar e li st e d i n T a bl e 1 3 of S e cti o n 1 0. 2 of t h e pr ot o c ol. 
T h e f oll o wi n g d e s cri pti v e s u m m ari e s f or d at a will b e pr o vi d e d: 
N ( n u m b er of s u bj e ct s i n t h e p o p ul ati o n), n ( n u m b er of s u bj e ct s u s e d f or t h e a n al y si s), arit h m eti c m e a n, 
9 5 % CI f or t h e arit h m eti c m e a n, S D, m e di a n, mi ni m u m, m a xi m u m f or t h e u ntr a n sf or m e d d at a. 
A ct u al v al u e s a n d c h a n g e s fr o m b a s eli n e i n c h e mi str y a n d h e m at ol o g y will b e s u m m ari z e d b y vi sit u si n g 
d e s cri pti v e st ati sti c s. M a xi m u m tr e at m e nt e m er g e nt h e m at ol o g y a n d cli ni c al c h e mi str y t o xi citi e s ( D AI D S 
gr a di n g ) will al s o b e pr e s e nt e d a s  s u m m ar y t a bl e. 
Li pi d s 
St ati sti c al A n al y s e s  
E n d p oi nt s  
 
C h a n g e fr o m B a s eli n e i n F a sti n g Li pi d s ( Tri gl y c eri d e s, L D L c h ol e st er ol, H D L c h ol e st er ol, T ot al 
C h ol e st er ol a n d T C/ H D L r ati o) at W e e k s 2 4  
A n al y si s S p e cifi c ati o n  
 
T h e d at a will n ot b e l o g tr a n sf or m e d f or t h e li pi d s a n d will b e pr e s e nt e d o n t h e n or m al s c al e.  
R e s ult s Pr e s e nt ati o n  
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 4 0  of 7 0  
St ati sti c al A n al y s e s  
 
N ( n u m b er of s u bj e ct s i n t h e p o p ul ati o n), n ( n u m b er of s u bj e ct s u s e d f or t h e a n al y si s), arit h m eti c 
m e a n, 9 5 % CI f or t h e arit h m eti c m e a n, S D, m e di a n, mi ni m u m, m a xi m u m will b e pr e s e nt e d f or t h e 
u ntr a n sf or m e d d at a.  
 
 
All l a b or at or y r e s ult s will b e i n cl u d e d i n d at a li sti n g s.  
1 2. 6.   
Ot h er S af et y D at a 
T h e a n al y s e s of n o n-l a b or at or y s af et y t e st r e s ult s i n cl u di n g  
 vit al si g n s, li v er e v e nt s, 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 2. 6. 1. Li v er e v e nt s 
A s u m m ar y of s u bj e ct s m e eti n g h e p at o bili ar y l a b or at or y a b n or m alit y crit eri a at a n y p o st- B a s eli n e e m er g e nt 
vi sit will al s o b e pr o d u c e d b a s e d o n F D A G ui d a n c e f or Dr u g-I n d u c e d Li v er I nj ur y: Pr e m ar k eti n g Cli ni c al 
E v al u ati o n ( J ul y 2 0 0 9). I n a d diti o n, a s u m m ar y a n d li sti n g of s u bj e ct s wit h Li v er St o p pi n g E v e nt s will al s o 
b e pr o d u c e d. 
 
1 2. 6. 2. C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e 
A s p er pr ot o c ol e C- S S R S s h o ul d b e s u m m ari z e d b y vi sit, a s t hi s i s n ot a p pli c a bl e t o t hi s st u d y, a 
s u m m ar y t a bl e pr e s e nti n g n u m b er of p ati e nt s wit h s ui ci d al i d e ati o n, s ui ci d al b e h a vi or, a n d s elf-i nj uri o u s 
b e h a vi or wit h o ut s ui ci d al i nt e nt will b e g e n er at e d o nl y b y tr e at m e nt. P ati e nt s wit h s ui ci d al i d e ati o n, 
s ui ci d al b e h a vi or, or s elf-i nj uri o u s b e h a vi or wit h o ut s ui ci d al i nt e nt b a s e d o n t h e e C- S S R S will al s o b e 
li st e d. 
C CI
C CI


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 4 1  of 7 0  
1 2. 6. 4. Vit al Si g n s 
Vit al si g n s will i n cl u d e a v er a g e s y st oli c bl o o d pr e s s ur e ( m m H g), a v er a g e di a st oli c bl o o d pr e s s ur e ( m m H g), 
a v er a g e h e art r at e ( b e at s p er mi n ut e, b p m), r e s pir ati o n r at e ( br e at h s p er mi n ut e), a n d b o d y t e m p er at ur e 
(° C). S u m m ar y t a bl e s of t h e a ct u al v al u e s a n d c h a n g e s fr o m b a s eli n e will b e pr o vi d e d f or e a c h vit al si g n 
p ar a m et er at e a c h s c h e d ul e d vi sit b y tr e at m e nt gr o u p a n d i n t ot al.  
A d diti o n all y, b o d y w ei g ht a n d B MI will b e s u m m ari z e d wit h a ct u al v al u e s a n d c h a n g e fr o m b a s eli n e at e a c h 
s c h e d ul e d vi sit b y tr e at m e nt gr o u p, a n d i n t ot al. 
Vit al si g n s d at a will b e li st e d f or s af et y s et p ati e nt s. 
C CI


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
This document is confidential. 
SAP Text Version: SAP Text Final 2.0 17-May-2023 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 42 of 70 
Vital Sign Parameter 
(Absolute) 
Units 
Potential Clinically Important Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<85 
>140 
Diastolic Blood Pressure 
mmHg 
<45 
>90 
Heart Rate 
bpm 
<40 
>100 
 


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13. Changes from Analysis Planned in Protocol 
This section details the changes from analysis planned in protocol.  
As the study has been terminated before Week 48, any planned protocol-defined analysis related to Week 
48/52 will not be performed, instead an end of study analysis will be conducted based on the available data 
from Day 1 to EoS. 


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14.   Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health Developing Statistical Programs SOP (3907.02). 
Syneos Health Developing Statistical Programs SOP (3907.02), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908.03) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.  


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15.   Appendix:  
15.1. 
Appendix 1: Exclusions from Per Protocol Population 
A participant meeting any of the following criteria will be excluded from the Per-Protocol population: 
Number 
Exclusion Description 
01 
Subject deviates from any inclusion or exclusion criteria, as recorded in the eCRF 
02 
Subject took/received incorrect study treatment (GSK3640254+DTG or DTG/3TC), 
i.e., other than the one to which they were randomized for more than 10% of the 
total time On-treatment 
03 
Interruption/dose modification of randomized regimen (GSK3640254+DTG or 
DTG/3TC) for longer than 10% of the total time on-treatment for reasons other than 
treatment related adverse events/laboratory abnormalities. Derivation will be based 
on concomitant medication and IP eCRF forms. 
04 
Prohibited medications: receiving ART medication other than that 
prescribed/allowed by the study for more than 7 days or receiving prohibited 
Concomitant medication that would impact exposure or response to therapy with 
duration taken into consideration. 
The following, general concomitant medications or therapies are not permitted at 
any time during the study: 
 
HIV immunotherapeutic vaccines are not permitted at any time during the 
study.  
 
Other experimental agents, antiretroviral drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy may not be administered.  
 
Systemically administered immunomodulators (such as interleukin and 
interferon agents) are prohibited (a list of examples is provided in the SRM) This 
includes topical agents with substantial systemic exposure and systemic effects.  
Use of topical imiquimod is permitted.    
 
Acetaminophen (paracetamol) cannot be used in patients with acute viral 
hepatitis.  
Note: For treatment specific prohibited meds refer in Section 6.8.1.3. and 6.8.1.4. of 
the protocol 
05 
Permanent discontinuation of IP/withdrawal due to a reason of “Protocol Deviation” 
(as recorded in the eCRF). 
 
 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 4 6  of 7 0  
 
1 5. 2.   
A p p e n di x 2: A s s e s s m e nt Wi n d o w s 
1.      D efi niti o n s of A s s e s s m e nt Wi n d o w s f or S n a p s h ot A n al y s e s 
 
A n al y si s 
S et / 
D o m ai n  
P ar a m et er      
(if a p pli c a bl e) 
T ar g et ( D a y)  
A n al y si s Wi n d o w ( D a y)  
A n al y si s 
Ti m e p oi nt  
Wi n d o w 
Wee ks  
B e gi n ni n g 
Ti m e p oi nt  
E n di n g 
Ti m e p oi nt  
Effi c a c y  
S n a p s h ot 
E n d p oi nt  
-6 3  
 
< -3  
S cr e e n  
N A  
1  
-3  
1  
D a y 1  
N A  
1 5  
2  
2 1  
W e e k 2  
Da y 2 ~ 
Wee k 3  
2 9  
2 2  
4 2  
W e e k 4  
3 ~ 6  
5 7  
4 3  
7 0  
W e e k 8  
6 ~ 1 0  
8 5  
7 1  
9 8  
W e e k 1 2  
1 0 ~ 1 4  
1 1 3  
9 9  
1 2 6  
W e e k  1 6  
1 4 ~ 1 8  
1 6 9  
1 2 7  
2 1 0  
W e e k 2 4  
1 8 -3 0  
 
 
 
 
 
N O T E S:  
1.  T h e S n a p s h ot vi sit wi n d o w s ar e u s e d a s p art of t h e S n a p s h ot al g orit h m t o 
d et er mi n e a p arti ci p a nt’ s c at e g or y.  
2.  W e e k 2 4 f oll o w F D A S n a p s h ot Al g orit h m t o u s e +/ - 6 w e e k s a s t h e a n al y si s 
wi n d o w. A p pl y S n a p s h ot a n al y si s wi n d o w s o nl y t o vir al l o a d d at a t h at i s o n -
tr e at m e nt 
3.  Ot h er a n al y s e s vi sit s will u s e a n al y si s wi n d o w s ½ t h e di st a n c e b et w e e n t h e 
pr e vi o u s a n d s u b s e q u e nt ti m e p oi nt.  
4.  S n a p s h ot a n al y si s i s p erf or m e d o nl y u pt o W e e k 2 4  
 
 
 
2.  
D efi niti o n s of A s s e s s m e nt Wi n d o w s f or Ot h er A n al y s e s 
 
      Ot h er a n al y s e s S et s ( e. g. l a b) will u s e a n al y si s wi n d o w s ½ t h e di st a n c e b et w e e n t h e pr e vi o u s a n d 
s u b s e q u e nt ti m e p oi nt.  
A n al y si s 
S et / 
D o m ai n  
P ar a m et er      
(if a p pli c a bl e) 
T ar g et ( D a y)  
A n al y si s Wi n d o w ( D a y)  
A n al y si s 
Ti m e p oi nt  
Wi n d o w 
W e e k s  
B e gi n ni n g 
Ti m e p oi nt  
E n di n g 
Ti m e p oi nt  
Effi c a c y 
( O b s er v e
d)/ S af et y
( L a b, 
 
V S)/ Vir ol
o g y 1  
All  
-6 3  
 
< -3  
S cr e e n  
N A  
1  
-3  
1  
D a y 1  
N A  
1 5  
2  
2 1  
W e e k 2  
D a y 2 ~ 
W e e k 3  
2 9  
2 2  
4 2  
W e e k 4  
3 ~ 6  
X* 7 + 1  
( X-2)* 7 + 1  
( X + 2)* 7 
W e e k X, 
X = 8, 1 2, 
… , 5 2, 
o n c e e v er y 
4 w e e k s 
fr o m W e e k 
8 t o 5 2  
( X-2) 
~( X + 2)  
C CI


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Analysis 
Set / 
Domain 
Parameter      
(if applicable) 
Target (Day) 
Analysis Window (Day) 
Analysis 
Timepoint 
Window 
Weeks 
Beginning 
Timepoint 
Ending 
Timepoint 
X*7+1 
(X-2)*7+1 
(X+4)*7 
Week X, 
X= 56 
(X-2) 
~(X+4) 
X*7+1 
(X-4)*7+1 
(X+4)*7 
Week X, 
X= 64, 72, 
80,88 
(X-4) 
~(X+4) 
Study Day of 
last dose + 
28 
> =(Study 
Day of last 
dose + 28) 
 
Follow-up 
NA 
Safety 
CSSRS 
-63 
 
<-3 
Screen 
NA 
1 
-3 
1 
Day 1 
NA 
15 
2 
21 
Week 2 
Day 2 ~ 
Week 3 
X*7+1 
(X-2)*7+1 
(X+2)*7 
Week X,  
X>=4, 
In Clinic 
and Virtual 
Visit 
(X-2) 
~(X+2) 
Study Day of 
last dose + 
28 
> =(Study 
Day of last 
dose + 28) 
 
Follow-up 
NA 
NOTES: 
1. For safety endpoints and some other results collected for virtual visits, please refer 
to protocol section 1.3 SOA for details. 
 
 
 
 
 
15.3. 
Appendix 3: Study Phases and Treatment Emergent Adverse Events 
 
Study Phases  
Assessments and events will be classified according to the time of occurrence relative to Insert Study 
Specific Text Here 
 
Study Phase Overall Data 
Study Period 
Definition 
Randomized 
Phase  
If the subject does not switch to 100 mg:  
 Study Treatment Start Date < Date ≤ End of Study Date + 5 days  
 
If the subject does switch to 100 mg:  
 Study Treatment Start Date < Date ≤ Optimal Dose Switch Start Date 
Switch Phase 
Optimal Dose Switch Start Date < Date ≤ Optimal Dose Switch End Date + 5 days. 
 


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Study Phase for Laboratory, HIV Associated Conditions, Genotypic and Phenotypic Data 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 5 days 
Post-Treatment 
Date > Study Treatment Stop Date + 5 days 
Datetime will be used. If time part is not available, date would be used instead. 
Study Phase for Adverse Events and Exposure 
Study Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date <= Date ≤ Study Treatment Stop Date + 5 days 
Post-Treatment 
Date > Study Treatment Stop Date + 5 days 
Datetime will be used. If time part is not available, date would be used instead. 
Study Phases for Concomitant Medication 
 
Prior medications: Those taken (i.e., started) before the start date of investigational product.  
 
Concomitant medications: Those taken (i.e., started or continued) at any time between the start date 
and stop date of study treatment, inclusive. Prior medications that were continued during this period 
are also considered as concomitant medications.  
 
Post treatment medications: Those started after the stop date of study treatment. Concomitant 
medications that were continued during this period are also considered as post-treatment 
medications. 
It will be assumed that medication has been taken on the date in which it is reported as started or 
stopped. For any medication starting on the same date as study treatment, it will be assumed that the 
medication was taken after the subject started taking study treatment. 
NOTES:  
Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is completely 
missing. 
 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 5 
days. 
 
For AE happened in subjects with more than one treatment, AE is assigned to the 
most recent treatment to the AE start date.   
NOTES:  
 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 


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15.4. 
Appendix 4: Derived and Transformed Data 
15.4.1. General 
Multiple Measurements at One Analysis Time Point 
 
If there are multiple assessments within Screening window, the last assessment before Day 1 will be 
used 
 
If there are multiple assessments within Day 1 window, the latest pre-dose assessment will be used 
 
With the exception of the Snapshot endpoints, if after window assignment, there are multiple valid 
assessments of a parameter within the same window, then the following hierarchy will be used to 
determine the value to be used for summary statistics of observed values: 
 
the assessment closest to the window target Study Day; 
 
if there are multiple assessments equidistant from the target Study Day, then for continuous variables 
the mean of these values will be used and for categorical variables the worse assessment. For HIV-1 
RNA, the geometric mean of the number of copies will be used as opposed to the arithmetic mean 
 
Assessments not chosen for use in summary statistics by this algorithm will still appear in the 
associated listings. Also, such valid assessments will be used when determining values of potential 
clinical concern for the ‘any time On-treatment’ time point, and for any algorithm that has specific 
rules for which observation to use (e.g., SNAPSHOT). 
 
 
Study Day 
 
Calculated as the number of days from First Dose Date: 
 
Ref Date = Missing              → Study Day = Missing  
 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
15.4.2. Study Population 
Extent of Exposure 
 
Number of days of on treatment will be calculated based on the formula:   
Duration of Treatment in Days = Treatment Stop Date – (Treatment Start Date) + 1 
This information will also be categorized as: < 12 weeks, 12 to 24 weeks, >24 weeks to 48 weeks, > 
48 weeks to 108 weeks, > 108 weeks 
 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Sum of Number of Days on Dose 
This information will also be categorized as: < 12 weeks, 12 to 24 weeks, >24 weeks to 48 weeks, > 
48 weeks to 108 weeks, > 108 weeks 
 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure.  
 
"Dose interruption/delay days contribute to calculation of total dose exposure". 
Demographics 
Age 
 
GSK Statistical Display Standard algorithms will be used for calculating age where birth date will be 
imputed as follows: 
o 
For all subjects, the missing date and month will have this imputed as ‘30th June’. 
 
Birth date will be presented in listings as ‘YYYY’. 
 
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, 
the age of the subject will not be calculated and will remain missing. 


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15.4.3. Efficacy 
HIV-1 RNA 
Snapshot  
 
It is intended to be primarily a virologic assessment of the endpoint, and as such follows a 
“virology first” hierarchy. 
 
Plasma HIV1-RNA < 50 c/mL or plasma HIV1-RNA ≥ 50 c/mL within an analysis window is 
typically determined by the last available plasma HIV-1 RNA measurement in that window 
while the subject is On-treatment. 
 
When no HIV-1 RNA data is available within a window, a subject cannot be classified under 
HIV1-RNA < 50 c/mL.  Depending on the reason for lack of data, the subject will be classified 
as a HIV1-RNA ≥ 50 c/mL or reported as ‘No Virologic Data at Week X’; in the latter case, the 
algorithm further classifies the nature of the missing data. Typically, a subject withdrawn (i) 
due to AE or, (ii) for another reason yet was suppressed at the time, will be counted as ‘No 
Virologic Data at Week X’.  Should a subject withdraw for reasons other than AE and was not 
suppressed at the time, they will be a HIV1-RNA ≥ 50 c/mL. 
 
For each scheduled assessment time, the snapshot response rate for a given threshold (e.g., 
<50 c/mL) is defined as: 
Snapshot Rate= Number of responders in that analysis window   
Number of subjects in the analysis population  
 
Full details of the algorithm, including the handling of special cases, are included in Section 
15.4.4 of note, the date at which the subject ‘discontinue/withdrawn from the study’ in the 
Snapshot algorithm is the date of treatment discontinuation, rather than the date of study 
withdrawal, 
Plasma HIV-1 RNA 
 
For summaries and analyses which use HIV-1 RNA level as a continuous measure, the 
logarithm to base 10 of the value will be used. 
 
HIV-1 RNA results may be provided as censored values, such as <40 or >9,999,999 c/mL. 
For the purposes of summary statistics, such values will be replaced by the next value 
beyond the limit of detection, e.g., 39 or 10,000,000 c/mL, respectively, for the given 
examples. Data listings will show the censored values as provided.   
 
Qualitive measures (i.e. “target detected” and “target non-detected”) may also be provided by 
the laboratory vendor for values <40 c/ml. When a measurement of plasma HIV-1 RNA is 
below the limit of quantification (i.e. 40 c/mL) and is qualitatively observable that will be 
denoted as a “Target Detected” measure, while HIV-1 RNA below the limit of quantification 
that is not qualitatively observable that will be denoted as “Target Not Detected”. Any 
measurements <40 c/mL characterized as “Target Non-Detected” or “Target Detected” will be 
captured in the database. 
CDC HIV-1 Classification and HIV-associated conditions 
 
HIV associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection in Adults (see protocol Section 10.10).  
 
Any 'other’ conditions reported in the eCRFs will be identified programmatically before being 
sent for clinical review to determine whether they should be classed as stage 3 associated 
conditions. Review will be ongoing and as a minimum will take place prior to each reporting 
effort. 
 
15.4.4. Snapshot Algorithm Details 
 
Consider an analysis visit window, Week X (e.g., Week4, …Week 24, ..Week 48 etc.). The Window 
for Week X visit is defined in Appendix 15.2. e.g. Week 48 ( +/- 2 Week:  323  ≤ Study Day ≤ 350) 


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 
Consider an HIV1-RNA threshold (e.g. 40, 50, 200 copies/mL …) for a given analysis. Our study will 
use 50 copies/mL as threshold.  
 
For example: The analysis window ‘Week 48’ and HIV1-RNA threshold of ’50 copies/mL’ are used for 
the purposes of illustration. A participant’s Snapshot response and reason at Week 48 are 
categorized as below. 
 
o 
HIV1-RNA < 50 copies/mL 
o 
HIV1-RNA >= 50 copies/mL 
Data in window not below 50 
Discontinued for lack of efficacy 
Discontinued for other reason while not below 50 
Change in background therapy* 
o 
No Virologic Data at Week 48 Window 
Discontinued study due to AE or death 
Discontinued study for other reasons 
On study but missing data in window 
*All changes are considered non-permitted. 
The steps in determining response and reasons are indicated in Table below, in the order stated. 
Detailed steps 
Please note that the following scenarios will NOT be penalized Per Snapshot algorithm (i.e. please 
exclude these scenarios from Condition 1-4).  
 
Dose reduction, dropping a component, or change in formulation (e.g. ‘Tivicay + Kivexa’ to ‘Triumeq’ 
with the identical ingredients)  
 
Permitted Change in ART where date of change or date of decision to make permitted change 
(whichever is earlier) occurs prior to/on the first on-treatment viral load result 
 
 
Condition  
(Note that: “Week XX” indicates Week XX window. Week 48 is 
used as an example below) 
Response  
Reasons 
1. If non-permitted change in background therapy prior to 
Week 48  
HIV1-RNA ≥ 50  
Change in 
background 
therapy 
2.    If permitted change in background therapy prior to Week 
48 AND the latest on-treatment VL prior to/on the date of 
change is ≥ 50 c/mL [a] 
HIV1-RNA ≥ 50  
Change in 
background 
therapy 
3. If non-permitted change in background therapy during 
Week 48    
 
 


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 
     3.1  Last on-treatment VL during Week 48 prior 
to/on the date of change ≥ 50 c/mL 
HIV1-RNA ≥ 50  
Data in 
window not 
below 50 
 
     3.2  Last on-treatment VL during Week 48 prior 
to/on the date of change <50   c/mL 
HIV1-RNA < 50  
 
 
     3.3  No VL during Week 48 prior to/on the date of 
change     
HIV1-RNA ≥ 50  
Change in 
background 
therapy 
4. If permitted change in background therapy during Week 
48 AND the last on-treatment VL prior to/on the date of 
change is ≥ 50 c/mL [a] 
 
 
4.1    this last on-treatment VL occurs prior to Week 48  
HIV1-RNA ≥ 50  
Change in 
background 
therapy  
4. 2   this last on-treatment VL occurs during Week 48 but 
prior to/on the date of change 
HIV1-RNA ≥ 50  
Data in 
window not 
below 50 
5.  If none of the above conditions met 
 
 
5.1   VL available during Week 48  
 
 
      5.1.1 Last on-treatment VL during Week 48 ≥ 50 c/mL 
HIV1-RNA ≥ 50  
Data in 
window not 
below 50 
      5.1.2 Last on-treatment VL during Week 48 <50 c/mL 
HIV1-RNA < 50  
 
5.2   No VL during Week 48    
 
 
 
5.2.1     If participants still on study (i.e. The on-treatment 
period continues beyond the upper bound of Week 
48 window. For example, for oral treatment, a 
participant with IP stop date+1> Day 378 of the 
upper bound of Week 48 window, would be 
considered ‘on study’ for Week 48 snapshot 
assessment) 
No virologic data at 
Week 48 Window  
On study but 
missing data 
in window 
5.2.2     If participants withdraw before/during Week 48 due 
to : 
 
 
5.2.2.1  Safety reasons (e.g. AE/death, liver chemistry 
stopping criteria, renal toxicity withdrawal criteria, 
QTc withdrawal criteria,  as recorded in eCRF 
Conclusion form) 
No virologic data at 
Week 48 Window 
Disc. due to 
AE/death 
5.2.2.2  Non-safety related reasons (e.g. Lack of efficacy, 
protocol deviation, withdrew consent, loss to follow-
up, study closed/terminated, investigator discretion 
et al, as recorded in eCRF Conclusion Form) 
 
 
5.2.2.2.1 Last on-treatment VL <50 c/mL OR no on-
treatment VL available during study   
No virologic Data at 
Week 48 Window 
Disc. for other 
reasons 
5.2.2.2.2 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to Lack of efficacy 
HIV1-RNA ≥ 50  
Disc. for lack 
of efficacy 
5.2.2.2.3 Last on-treatment VL ≥ 50 c/mL AND 
withdrawal due to all other non-safety related reasons 
HIV1-RNA ≥ 50  
Disc. for other 
reason while 
not below 50 
[a]: Excluding permitted change in background therapy where change or decision to change is made 
prior to/on the first on-treatment viral result  


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A dataset will be created based on the Snapshot algorithm, where the dataset contains the following 
information, as a minimum: 
• 
Study identification 
• 
Participant identification  
• 
Study day and date of last blinded treatment  
• 
Virologic outcome based on the snapshot approach (i.e., HIV-1 RNA below 50 copies/mL (c/mL), 
HIV-1 RNA equal to or above 50 copies/mL, discontinued due to AE or death, discontinued for other 
reasons, on study but missing data during window)  
• 
The HIV-1 RNA measurement and the corresponding study day and date used to determine the 
above virologic outcome if the measurement was not missing 
• 
Study day and date when the participant switched to open-label treatment due to lack or loss of 
virologic suppression, if applicable 
• 
Discontinuation study day and date, reason for discontinuation, and last blinded treatment 
measurement before discontinuation for participants who discontinued study drug 
15.4.5. Virology 
PDVF 
PDVF is defined as any of the following (and confirmed by a repeat and consecutive plasma HIV-
1 RNA measurement between two and four weeks (approx.) after the initial suspected virologic 
failure sample):  
Virologic Non-response  
1. Decrease from Baseline (Day 1) in plasma HIV-1 RNA of ˂1.0 log10 c/mL unless plasma 
HIV-1 RNA is <200 c/mL by Week 12; 
o 
SVF: If there is a decrease < 1 log10 from Baseline at Week 12 and HIV-1 RNA 
>=200 c/mL, then -> Suspected Virologic Failure 
o 
PDVF: If there is a confirmatory sample after 1a, then check if there is a decrease <1 
log10 from Baseline and the HIV-1 RNA >=200 c/mL then -> Protocol Defined 
Virologic Failure 
 
2. Confirmed plasma HIV-1 RNA levels ≥200 c/mL at or after Week 24. 
o 
SVF: If a patient has a sample on/after Week 24 and the result is >=200 c/mL then -
> Suspected Virologic Failure 
o 
PDVF: If after 2c, a patient then has a 2nd consecutive sample >=200 c/mL on/after 
Week 24 then -> Protocol Defined Virologic Failure. 
3. Plasma HIV-1 RNA ≥50 c/mL on repeat testing of Week 24 results and prior to Week 28. 
o 
SVF: If a patient has a sample at Week 24 and the result is >=50 c/mL then -> 
Suspected Virologic Failure 
o 
PDVF: If after 3e, a patient then has repeat (retest) sample prior to Week 28 then -> 
Protocol Defined Virologic Failure. 
4. Virologic Non-response: If a subject met criteria 1b or 2d or 3f then -> PDVF 
(Virologic Non-response) 


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Virologic Rebound  
5. Confirmed plasma HIV-1 RNA ≥200 c/mL after confirmed consecutive plasma HIV-1 RNA 
<50 c/mL. 
o 
Patient must have 2 consecutive values <50 c/mL, followed at any time (not 
necessarily immediately) by 2 consecutive values >=200 c/mL 
o 
SVF: If a patient has two consecutive samples <50 c/mL, if any following value is 
>=200 c/mL then -> Suspected Virologic Failure 
o 
PDVF: If after 5g, a patient then has a 2nd consecutive sample >=200 c/mL then -> 
Protocol Defined Virologic Failure. 
6.  Virologic Rebound: If a subject met criteria 5h then -> PDVF (Virologic Rebound) 
 
7. Current plasma HIV-1 RNA levels ≥200 c/mL after Week 24  
a. SVF: If a patient has a sample after Week 24 and the result is >=200 c/mL  when 
previous results was <50c/mL then -> Suspected Virologic Failure 
b. PDVF: If a patient has a sample after Week 24 and the result is >=200 c/mL  when 
previous results was >=50c/mL then -> PDVF (Virologic Non-Response) 
 
Genotype 
General considerations 
 
Nominal and analysis window will be included in the listings.  
 
For summary purposes analysis window will be used.  
 
Note: Resistance testing will be performed on samples collected at the SVW timepoint (i.e. 
the timepoint of the initial HIV-1 RNA result which meets one of the Virologic Withdrawal 
criteria and will be subsequently confirmed in a repeat HIV-1 RNA test. The SVW timepoint is 
noted as the PDVF timepoint in listings and summaries. 
Amino Acid Changes 
 
A mutation is considered present whenever the encoded amino acid residue differs from the 
amino acid that would have been encoded by the wild-type (e.g., HXB2, NL43) comparator 
gene; e.g., Q148K.  
 
If the encoded amino acid is seen as a mixture of wild-type and mutant amino acid, e.g., 
Q148Q/K, the mutated amino acid is considered present at the codon of interest.  
 
If the encoded amino acid is seen as a mixture of two or more amino acids, which may or 
may not include wild type, e.g., Q184K/H or Q184K/H/Q, etc., for the purposes of calculating 
the number of mutated amino acids, only one mutation is considered to be present at the 
codon of interest. 
 
Treatment emergent mutations:  need to meet below three criteria: 
1. New mutation:  observed during treatment comparing to baseline at the same codon 
with the class/region. 
2. Mutations are based on prespecified lists usually identified in the SAP.   
a. Integrase:  may use a list generated by Virology that may include non-IAS 
guidance mutations derived using the Stanford database (e.g., mutations with 
penalty score >=15; https://hivdb.stanford.edu/dr-summary/mut-scores/INSTI/), 
or other reliable sources.  Note the list may change over time. Usually the major 
mutations are the ones with evidence of strong resistance to the ART drug.   
b. All other classes:  defined by the International Antiviral Society-USA (IAS-USA).  


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3. ART Drug class related: based on the class of the ART the subjects are taking during 
the treatment and the new major mutation within that class will be considered.  
Representation of Amino Acid Changes 
 
 
Mutations 
Amino acid change 
T69S 
Single mutation from amino acid ‘T’ (vendor reference) to ‘S’ 
(sample) at codon ‘69’  
Q148H/K/R 
Mixture of amino acid mutations ‘H’, ‘K’ and ‘R’ (sample) from amino 
acid ‘Q’ (vendor reference) at codon ‘148’ 
_69_1T 
First insertion of amino acid ‘T’ (sample) at codon ‘69’ 
_69_2S 
Second insertion of amino acid ‘S’ (sample) at codon ‘69’ 
_69_3S/A 
Third insertion of a mixture of amino acids ‘S’ and ‘A’ (sample) at 
codon ‘69’ 
L74L/- 
Mixture of amino acid ‘L’ (sample) and a deletion at codon ‘74’ 
V75- 
Single deletion of amino acid (sample) at codon ‘75’ 
Prespecified Lists – Resistance Associated Mutations 
 
Summaries and listings of resistance associated mutations in the Integrase Strand Transfer 
Inhibitor (INSTI) class will use the following pre-defined INSTI list of mutations associated 
with the development of resistance to BIC, RAL, EVG or DTG.    
 
Category 
Mutations 
Pre-defined INSTI 
mutations 
H51Y, T66A/I/K, L74M, E92Q/V/G, Q95K, T97A, G118R, F121Y, 
E138A/K, G140A/C/S, Y143C/H/R/K/S/G/A, P145S, Q146P, 
S147G, Q148N/H/K/R, V151I/L/A, S153F/Y, N155H/S/T, 
E157Q, G163R/K, S230R, R263K, L68V/I*, L74I*, E138T*, 
G193E* 
NOTES: 
 
Current list includes INSTI mutations identified via the Stanford HIV Resistance 
database, or identified during in vitro passage of DTG, or as seen in previous DTG 
studies in INSTI-experienced subjects (i.e. ING112574) and may be modified in case of 
additional substantive data availability.    
 
INSTI mutations in bold have the maximum score of 60 and are for any INSTI drug in 
the Stanford database v9.1 (https://hivdb.stanford.edu/dr-summary/mut-
scores/INSTI/,last updated on 2022-06-02); the rest have a maximum score <60. 
 
1. Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as defined by the 
International Antiviral Society-USA (IAS-USA). The most up to date IAS-USA guidelines 
available at the time of DBF will be used in the analysis.  Note that NRTIs A62V, V75I, F77L, 
and F116Y all need to be present together with Q151M to be resistant, so are not major 
mutations alone. 
Class 
Mutations 
NRTIs 
M41L, K65R/E/N, D67N, K70E/R, L74V, Y115F, M184V/I, L210W, T215Y/F, 
K219Q/E;  [A62V, V75I, F77L, F116Y, Q151M] 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138/A/G/K/Q/R, V179L, Y181C/I/V, 
Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 5 6  of 7 0  
P is  
D 3 0 N, V 3 2I , M 4 6I/ L , I 4 7 A/ V, G 4 8 V, I 50 V / L, I 5 4M /L/ V, Q 5 8 E,  T 7 4 P,  
L 7 6 V, V 8 2 A/ T/ F/ L/ S, N 8 3 D , I 8 4 V, N 8 8 S, L 9 0 M 
2.  N ot e: 2 0 1 7 Dr u g R e si st a n c e M ut ati o n s U p d at e V ol u m e 2 4, I s s u e 4, D e c e m b er 
2 0 1 6/ J a n u ar y 2 0 1 7  
P h e n ot y p e  
F ol d c h a n g e ( F C) i n I C 5 0 ( c o n c e ntr ati o n of dr u g r e q uir e d t o i n hi bit t h e s a m pl e vir u s t o 5 0 % of it s 
m a xi m u m) r el ati v e t o wil d -t y p e c o ntr ol vir u s i s r e p ort e d fr o m t h e a s s a y s. i. e., F C of s a m pl e vir u s 
= I C 5 0 of s a m pl e vir u s/I C 5 0 of c o ntr ol vir u s.  
S u m m ar y st ati sti c s f or F C will b e r e p ort e d at B a s eli n e a n d at t h e P D V F ti m e p oi nt (ti m e of 
s u s p e ct e d f ail ur e, t h at w a s s u b s e q u e ntl y c o nfir m e d) f or s u bj e ct s m e eti n g P D V F crit eri a.  
F ol d c h a n g e r ati o ( F ol d c h a n g e at t h e ti m e of P D V F/ b a s eli n e F ol d c h a n g e) will al s o b e 
s u m m ari s e d.  
 
1 5. 4. 6. 
S af et y 
A d v er s e E v e nt s   
A E S e v erit y –  D AI D S Gr a di n g  
 
T h e D AI D S gr a di n g ( V E R SI O N 2. 1, M ar c h 2 0 1 7) f or s e v erit y of cli ni c al a d v er s e e v e nt s will b e 
p erf or m e d.  
 
S e e pr ot o c ol f or D AI D S gr a di n g crit eri a.  
A d v er s e E v e nt s of S p e ci al I nt er e st ( A E SI)  
T h e pr ef err e d t er m s f or e a c h A E SI will b e r e vi e w e d b y s af et y a n d cli ni c al t e a m a n d u p d at e d b ef or e 
e a c h f or m al a n al y si s i n a s e p ar at e d o c u m e nt. T h e f oll o wi n g t a bl e b el o w s h o w s t h e A E SI 
c at e g ori e s.  
A E SI  
- 
Q T pr ol o n g ati o n  
- 
GI i nt ol er a bilit y/t o xi cit y  
- 
N er v o u s S y st e m Di s or d er s  
- 
S ki n a n d s u b c ut a n e o u s ti s s u e di s or d er s  
- 
C ar di a c di s or d er s  
L a b or at or y P ar a m et er s  
 
If a l a b or at or y v al u e w hi c h i s e x p e ct e d t o h a v e a n u m eri c v al u e f or s u m m ar y p ur p o s e s, h a s a 
n o n -d et e ct a bl e l e v el r e p ort e d i n t h e d at a b a s e, w h er e t h e n u m eri c v al u e i s mi s si n g, b ut t y pi c all y 
a c h ar a ct er v al u e st arti n g wit h ‘ < x’ or ‘ > x’ ( or i n di c at e d a s l e s s t h a n x or gr e at er t h a n x i n t h e 
c o m m e nt fi el d) i s pr e s e nt, t h e s m all e st u nit of o n e m or e si g nifi c a nt di git t h a n t h e n u m b er of 
si g nifi c a nt di git s i n t h e o b s er v e d v al u e s will b e a d d e d or s u btr a ct e d ( w hi c h e v er i s a p pli c a bl e) i n 
or d er t o i m p ut e t h e c orr e s p o n di n g n u m b er. F or e x a m pl e:  
o  
E x a m pl e 1: 2 si g nifi c a nt di git s ( a s i n “ < 2. 2”) will b e i m p ut e d a s 2. 1 9  
o  
E x a m pl e 2: 1 si g nifi c a nt di git ( a s i n “ > 5”) will b e i m p ut e d a s 5. 1  
o  
E x a m pl e 3: 0 si g nifi c a nt di git s ( a s i n “ < 0”) will b e i m p ut e d a s -1”.  
 
T h er e will b e n o i m p ut ati o n i n t h e d at a li sti n g s; all v al u e s will b e di s pl a y e d a s r e c or d e d i n t h e 
d at a b a s e.  
C CI


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Lab Toxicities – DAIDS Grading  
 
Toxicities will be based on the Division of AIDS (DAIDS) grading system, as specified in the 
protocol.  
 
Toxicity grades provided by the central laboratory do not distinguish between abnormally high 
or low criteria, when both are relevant for a particular parameter. 
 
When summarising toxicity grades for such parameters, they will be categorised as to whether 
they are above or below the midpoint of normal range. 
Parameter 
Below Midpoint 
Above Midpoint 
Calcium 
Hypocalcaemia 
Hypercalcaemia 
Fasted glucose 
Hypoglycaemia 
Hyperglycaemia 
Sodium 
Hyponatremia 
Hypernatremia 
Potassium 
Hypokalemia 
Hyperkalemia  
Glomerular Filtration Rate (GFR) 
 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [Levey et al.] will be 
used by the central laboratory to provide an estimate of GFR, in mL/min per 1.73 m2, as 
follows for the CKD-EPI creatinine equation: 
 
where age (in years) is at time of assessment, κ = 0.7 if female or 0.9 if male, α = -0.329 if female 
and -0.411 if male, min() indicates the minimum of CRT/κ or 1, max() indicates the maximum of 
CRT/κ or 1, and CRTmg/dL is serum creatinine concentration in mg/dL. The serum creatinine 
concentration in mg/dL is obtained from GSK standard units of μmol/L as CRTmg/dL =0.0113x 
CRT μmol/L.  
CKD-EPI Cystatin C Equation (2012) 
The following will be used for the CKD-EPI Cystatin C Equation: 
eGFR = 133 x min(Scys/0.8, 1)-0.499 x max (Scys/0.8, 1)-1.328 x 0.996Age x 0.932 [if female] 
Abbreviations / Units  
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
Scys (standardized serum cystatin C) = mg/l 
min = indicates the minimum of Scys/0.8 or 1 
max = indicates the maximum of Scys/0.8 or 1 
age = years 
Assays 
 
15.5. 
Appendix 5: Reporting Standards for Missing Data   
 


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15.5.1. Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o 
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Snapshot 
 
In the Snapshot dataset, subjects without HIV-1 RNA data in the assessment window for 
the visit of interest (due to missing data or discontinuation of IP prior to the visit window) 
are classified as either ‘HIV-1 RNA ≥50 c/mL’) or ‘No Virologic Data’. For full details of 
the Snapshot algorithm see Section 15.4.4 
Observed 
Case (OC) 
 
This dataset uses only the data that is available at a particular timepoint, with no 
imputation for missing values. 
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 
15.5.2. Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in participant listing displays.  
 
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 (see Section 15.3) or for specific analysis purposes as 
outlined below. 
 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events), or elapsed time 
variables (e.g., time since diagnosis). In addition, imputed dates are not used for 
deriving the last contact date in overall survival analysis dataset. 
Exposure 
 
If study treatment stop date is missing, then for the purposes of calculating 
exposure, it will be imputed using the date of last visit or the recorded date of 
withdrawal/completion whichever is earlier.  
 
Partially Missing Stop Day: Last day of the month or last month of the year will 
be used, unless this is after the stop date of study treatment or withdrawal date; 
in this case the earliest of the two dates will be used. 
Treatment 
End Date 
 
If subject is still on-going at data cut-off date, we assume the subject is still on-
treatment, treatment end date will the last visit date. 
Adverse 
Events 
 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
 
Missing start 
day 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = 1st of month. 
 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and 
year of study treatment start date then 


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Element 
Reporting Detail 
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month. 
 
Else set start date = study treatment start 
date. 
o Else set start date = 1st of month. 
Missing start 
day and month 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = January 1. 
 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment 
start date then 
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1. 
 
Else set start date = study treatment start 
date.       
o 
Else set start date = January 1. 
Missing stop day  Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
 
 
Completely missing start or end dates will remain missing, with no imputation 
applied.  
Concomita
nt 
Medication
s/Medical 
History 
 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start day 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = 1st of month. 
 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and 
year of study treatment start date then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date then 
set start date= 1st of month. 
 
Else set start date = study treatment start 
date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = January 1. 
 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment 
start date then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date then 
set start date = January 1. 


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Element 
Reporting Detail 
 
Else set start date = study treatment start 
date.       
 
Else set start date = January 1. 
Missing end day 
A ‘28/29/30/31’ will be used for the day (dependent on 
the month and year)  
Missing end day 
and month 
A ‘31’ will be used for the day and ‘Dec’ will be used for 
the month. 
Completely 
missing start/end 
date 
No imputation 
 
 
The recorded partial date will be displayed in listings. 
 
 
 


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15.6. 
Appendix 6: Time to Event Details 
15.6.1. TRDF Detailed Steps 
TRDF Detailed steps 
The steps below are for the derivation of TRDF at specific timepoints when the upper bound of the 
analysis window is used as a cut-off i.e. for the table only.  
Final step of the derivation is made in following order:  
[1] When one EVENT (1.2, 2.2, 3.2, 4.2) criterion is satisfied, select. In situations where more than one 
EVENT criteria satisfied, select the earliest event. If the earliest event date satisfies more than one criteria 
(e.g. subject had PDVF and discontinuation), select PDVF. 
[2] When one CENSOR (1.1, 2.1, 3.1, 4.1, 5.x) criterion is satisfied, select. Else in situations where more 
than one CENSOR criteria satisfied, select the latest censor day. If the latest event date satisfies more 
than one criteria, apply the ordering below. 
  
Condition 
Censor 
Status  
Event Description/AVAL 
3. Subjects met PDVF event criteria during 
the randomized period.  
(Based on derived PDVF confirmed prior to 
cut-off used for the analysis) 
 
Then set tempAVAL= Study Day of PDVF 
 
 
1.1 PDVF event date is after the upper bound 
of the analysis visit window  
i.e tempAVAL > upper bound of the analysis 
visit window for Week X 
 
CNSR=1 
EVNTDESC=Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
 
1.2 PDVF event date is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window for Week X 
 
CNSR=0 
EVNTDESC=PDVF. 
AVAL= tempAVAL. 
 


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4. Subjects with study withdrawal due to 
treatment related adverse events during 
the randomized period  
(defined as subjects that have reason for 
withdrawal =AE on disposition page and that 
the subject has at least one AE considered 
both: i) drug related (AEREL=Y) and ii) result 
in withdrawal from study (AEWD=Y))  
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
Visit domain], Study day of permanent 
treatment discontinuation [from Exposure and 
Concomitant ART domains]). 
Assumption: Study day of permanent 
treatment discontinuation is included in the 
definition to account for cases where 
discontinuation information is recorded later. 
This is a conservative approach consistent 
with treatment discontinuation preceding 
withdrawal.  
 
 
2.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
CNSR=1 
EVNTDESC=Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
2.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Treatment Related AE. 
AVAL= tempAVAL 
3:  Subjects met protocol defined stopping 
criteria during the randomized period.,  
(Based on disposition page) 
 
Then set tempAVAL=Earliest of (Day of Study 
Discontinuation [from Disposition page]), date 
of Withdrawal Visit [from Study Visit domain], 
Study day of permanent treatment 
 
 


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discontinuation [from Study Treatment or 
CONART eCRF pages]). 
 
3.1 Protocol defined stopping criteria were met 
after the upper bound of the analysis visit 
window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
3.2 Protocol defined stopping criteria were met 
on or before the upper bound of the analysis 
visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Protocol Defined Criteria. 
AVAL=tempAVAL 
4: Subjects with study withdrawal due to lack 
of efficacy during the randomized period. 
(Based on disposition page) 
 
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
Visit domain], Study day of permanent 
treatment discontinuation [from Study 
Treatment or CONART eCRF pages]) 
 
 
4.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
4.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
CNSR=0 
EVNTDESC=Study Withdrawal Due to 
Lack of Efficacy 
AVAL= tempAVAL  


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SAP Text Version: SAP Text Final 2.0 17-May-2023 
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If none of the above conditions met 
 
 
5: Subjects with study withdrawal for other 
reasons during the randomized period. 
(Based on disposition page) 
 
Then set tempAVAL= Earliest of (Day of 
Study Discontinuation [from Disposition 
page]), date of Withdrawal Visit [from Study 
Visit domain], Study day of permanent 
treatment discontinuation [from Study 
Treatment eCRF pages]) 
 
 
5.1 Study withdrawal is after the upper bound 
of the analysis visit window 
i.e tempAVAL > upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
 
5.2 Study withdrawal is on or before the upper 
bound of the analysis visit window 
i.e tempAVAL ≤ upper bound of the analysis 
visit window 
 
CNSR=1 
EVNTDESC=Censored due to Study 
Discontinuation for Other Reasons. 
AVAL=tempAVAL 
6: Subject completed the randomized 
period of the study. 
(Based on disposition page) 
 
 
CNSR=1 
EVNTDESC= Censored as completed the 
Randomized Period. 
AVAL= Date of end of Treatment Phase 


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Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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7: Subject is ongoing in the study during 
the randomized period and have not yet 
completed the randomized period  
 
Assumption: this will only be in cases where 
the reporting effort/analysis is performed 
midway through the randomized period 
CNSR=1 
EVNTDESC= Censored due to data cutoff. 
AVAL=Upper bound of analysis visit 
window. 
 
15.6.2. TRDF Detailed Steps for the Kaplan-Meier plot 
TRDF Detailed steps 
The steps below are for the derivation of TRDF overall i.e. for the Kaplan-Meier plot only.  
Final step of the derivation is made in following order:  
[1] When one EVENT (conditions 1-4) criterion is satisfied, select. In situations where more than one 
EVENT criteria satisfied, select the earliest event. If the earliest event date satisfies more than one criteria 
(e.g. subject had PDVFand discontinuation), select PDVF. 
[2] When one CENSOR (conditions 5.x) criterion is satisfied, select. Else in situations where more than 
one CENSOR criteria satisfied, select the latest censor day. If the latest event date satisfies more than one 
criteria, apply the ordering below. 
  
Condition 
Censor 
Status  
Event Description/AVAL 
5. Subjects met PDVF event 
criteria during the randomized 
period.  
(Based on derived PDVF confirmed 
prior to cut-off used for the analysis) 
CNSR=0 
EVNTDESC=PDVF. 
AVAL=Study Day of PDVF. 
 
6. Subjects with study withdrawal 
due to treatment related 
adverse events during the 
randomized period  
 (defined as subjects that have 
reason for withdrawal =AE on 
disposition page and that the 
subject has at least one AE 
considered both: i) drug related 
CNSR=0 
EVNTDESC=Study Withdrawal Due to Treatment 
Related AE. 
AVAL=Earliest of (Day of Study Discontinuation [from 
Disposition page]), date of Withdrawal Visit [from 
Study Visit domain], Study Day of permanent 
treatment discontinuation [from Study Treatment 
eCRF pages]). 


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Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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SAP Text Version: SAP Text Final 2.0 17-May-2023 
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Notes: 
Randomized Period = Randomized Phase  
(AEREL=Y) and ii) result in 
withdrawal from study (AEWD=Y))  
 
3:  Subjects met protocol defined 
stopping criteria during the 
randomized period.,  
(Based on disposition page) 
CNSR=0 
EVNTDESC=Study Withdrawal Due to Protocol 
Defined Criteria. 
AVAL=Earliest of (Day of Study Discontinuation [from 
Disposition page]), date of Withdrawal Visit [from 
Study Visit domain], Study Day of permanent 
treatment discontinuation [from Study Treatment 
eCRF pages]). 
4: Subjects with study withdrawal 
due to lack of efficacy during the 
randomized period. 
(Based on disposition page) 
CNSR=0 
EVNTDESC=Study Withdrawal Due to Lack of 
Efficacy 
AVAL= Earliest of (Day of Study Discontinuation [from 
Disposition page]), date of Withdrawal Visit [from 
Study Visit domain], Study Day of permanent 
treatment discontinuation [from Study Treatment 
eCRF pages]) 
If none of the above conditions 
met 
 
 
5: Subjects with study 
withdrawal for other reasons 
on or before the end of 
randomized period. 
(Based on disposition page) 
CNSR=1 
EVNTDESC=Censored due to Study Discontinuation 
for Other Reasons. 
AVAL=Earliest of (Day of Study Discontinuation [from 
Disposition page]), date of Withdrawal Visit [from 
Study Visit domain], Study Day of permanent 
treatment discontinuation [from Study Treatment 
eCRF pages]) 
6: Subject completed the 
randomized period of the 
study. 
(Based on disposition page) 
CNSR=1 
EVNTDESC= Censored as completed the 
Randomized Period. 
AVAL= Date of completion of randomized study 
period 
7: Subject is ongoing in the 
study during the randomized 
period and have not yet 
completed the randomized 
period 
CNSR=1 
EVNTDESC= Ongoing in the Study. 
AVAL=Last visit date 


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Efficacy visit windows should be used throughout for the upper bound of the analysis visit window 
Subjects are considered to have completed the randomized period if they completed the Randomized 
Phase. 
By definition, a subject must be on-treatment for a PDVF to be recorded therefore inclusion of study date 
of treatment discontinuation in the derivation is not required  
EVNTDESC, AVAL & CNSR variables created for the following timepoints:  
Week 24 – for the table analysis 
Overall – for the Kaplan-Meier plot  
 
15.6.3. ERDF Detailed Steps 
Similar algorithm will be applied for ERDF analyses and  Kaplan-Meier figure, where condition 2 and 3 in 
Section 15.6.1 and Section 15.6.2 will not be considered 
15.6.4. Time to Viral Suppression 
 
Time of event will be the first on-treatment viral load value <50 copies/mL   
 
Subjects who withdraw for any reason without being suppressed during on treatment will be 
censored at earliest of (day of study discontinuation, day of withdrawal visit, day of treatment 
discontinuation). 
 
Subjects who have not been withdrawn and have not had viral suppression at time of the analysis 
will be censored at last viral load date from HIV-1RNA lab data.  
 
Subjects who have completed the Double Blind and Open Label phases and have not had viral 
suppression will be censored at date of completion. 
 
 
 
 
15.7. 
Appendix 7: End of Study Analysis 
This appendix provides the details of the planned analyses and data displays for End of Study (EoS) 
reporting. 
 
The primary analysis at Week 24 has been completed based on the original SAP. This present appendix 
is written to cover only analyses included in the end of study reporting. 
 
The details of the EoS reporting and analysis plan are described below: 
 
 
The EoS analysis will include all the 4 treatment groups including data from Day 1 to EoS. 
 
Only specific outputs determined and described in the study analysis plan will be re-used for end 
of study reporting. Please refer to TLF Shells Section 2 for further details. 
 
No additional analysis is expected for EoS.  
 
 
 


St ati sti c al A n al y si s Pl a n f or I nt er v e nti o n al St u di e s  
S p o n s or: Vii V H e alt h c ar e U K Li mit e d (“ Vii V”); Pr ot o c ol N o.: 2 1 2 4 8 3 
 
T hi s d o c u m e nt i s c o nfi d e nti al. 
S A P T e xt V er si o n: S A P T e xt Fi n al 2. 0 1 7- M a y- 2 0 2 3 
C o ntr oll e d D o c u m e nt I D: 3 9 0 3 A. 0 2 , Eff e cti v e D at e 3 1- A u g-2 0 2 0  
Fili n g r e q uir e m e nt s: T M F 
P a g e 6 8  of 7 0  
1 5. 7. 1. 
St u d y P h a s e s 
Aft er t h e w e e k 2 4 a n al y si s, t h e s u bj e ct s fr o m 1 5 0 m g a n d 2 0 0 m g ar m will b e s wit c h e d t o t h e o pti m al 
d o s e of 1 0 0 m g. W h er e a s, s u bj e ct s o n D T G/ 3 T C a n d 1 0 0 m g ar m will r e m ai n o n t h e s a m e r e gi m e n 
u ntil E o S.   
 
F or E o S r e p orti n g, d at a c oll e ct e d d uri n g r a n d o mi z e d p h a s e a n d s wit c h p h a s e i n 1 5 0 a n d 2 0 0 m g ar m a n d 
c o m pl et e d at a till E o S i n 1 0 0 m g a n d D T G/ 3 T C ar m will b e c o n si d er e d. 
 
1 5. 7. 2.  A n al y si s P o p ul ati o n f or E o S 
T h e st u d y p o p ul ati o n s will r e m ai n t h e s a m e a s d efi n e d i n S e cti o n 6  of  t h e S A P . 
1 5. 7. 3. 
Effi c a c y A n al y si s  
F or HI V- 1 R N A vir al l o a d, all t h e s u m m ari e s a n d li sti n g s d efi n e d i n S e cti o n 9  of S A P will b e u s e d f or E oS 
a n al y si s e x c e pt f or t h e o ut p ut s u si n g S n a p s h ot al g orit h m. N o f or m al i nf er e nti al st ati sti c al a n al y si s i s 
pl a n n e d. 
O v er vi e w of t h e k e y pl a n n e d effi c a c y e n d p oi nt s: 
  
Pr o p orti o n of P arti ci p a nt s wit h Pl a s m a HI V- 1 R N A < 5 0 c/ m L/ > = 5 0 c/ m L- o b s er v e d d at a 
  
Pr o p orti o n of P arti ci p a nt s wit h Pr ot o c ol- D efi ne d Vir ol o gi c F ail ur e ( P D V F) – o b s er v e d d at a  
  
I n ci d e n c e of di s e a s e pr o gr e s si o n a n d HI V- a s s o ci at e d c o n diti o n s 
  
I n di vi d u al Pl a s m a HI V- 1 R N A a n d C D 4 + Pr ofil e s 
 
F ull d et ail s of t h e d at a di s pl a y s ar e gi v e n i n S e cti o n 2 of t h e T L F s h ell s d o c u m e nt. 
1 5. 7. 4. S af et y A n al y si s  
O nl y s p e cifi c s af et y o ut p ut s at E o S will b e i n cl u d e d i n E o S a n al y si s.  All s af et y di s pl a y s will b e b a s e d o n 
t h e S af et y p o p ul ati o n.  
O v er vi e w of t h e k e y pl a n n e d s af et y e n d p oi nt s: 
  
E xt e nt of E x p o s ur e 
  
A d v er s e E v e nt s/ S p e ci al I nt er e st 
  
L a b or at or y ( H e m at ol o g y, C h e mi str y) 
 
 
 
F ull d et ail s of t h e d at a di s pl a y s ar e gi v e n i n S e cti o n 2 of t h e T L F s h ell s d o c u m e nt. 
 
1 5. 7. 5. C O VI D – 1 9 A n al y si s 
T h e i nf or m ati o n r e g ar di n g t h e n u m b er of p arti ci p a nt s aff e ct e d b y C O VI D- 1 9 a n d it s s y m pt o m s will b e 
a n al y z e d at E o S . 
F ull d et ail s of t h e d at a di s pl a y s ar e gi v e n i n S e cti o n 2 of t h e T L F s h ell s d o c u m e nt. 
 
C CI


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Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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15.7.6. Virology Analysis 
All the planned virology summaries and Listings with subjects who met Confirmed Virologic Withdrawal 
criteria will be part of EoS analysis. 
All genotypic and phenotypic analysis at or prior to EoS  will be included in the EoS analysis. 
Full details of the data displays are given in Section 2 of the TLF shells document. 
15.7.7. Pharmacokinetic analysis 
Pharmacokinetic analysis would include all the data collected till the end of study with summaries and 
listing at EoS. 
Full details of the data displays are given in Section 2 of the TLF shells document. 
 
15.7.8. Other Analyses 
Overview of the key other analyses: 
 
Liver Monitoring/Stopping Event Reporting 
 
Hepatobiliary Laboratory Abnormalities 
Summaries and listings will be same at EoS. 
Full details of the data displays are given in Section 2 of the TLF shells document. 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: ViiV Healthcare UK Limited (“ViiV”); Protocol No.: 212483 
 
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SAP Text Version: SAP Text Final 2.0 17-May-2023 
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16. References 
FLEISS, J. (1981). Statistical methods for rates and proportions. second edition. New York: John Wiley & 
Sons. 
Jones HE, O. D. (2011). Bayesian models for subgroup analysis in clinical trials. Clin Trials. 8:129–143. 
Sato, T. G. (1989). On the Variance Estimator for the Mantel-Haenszel Risk Difference. Biometrics, 45(4), 
1323–1324.  
 
 


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