A Phase IIIb, Open-label, Hybrid Type III Trial Evaluating Implementation Strategies for Long-acting Cabotegravir Plus Long-acting Rilpivirine Every Two Months in HIV-1 Infected, Virologically Suppressed Adults in Select European Healthcare Settings
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

T M F -1 3 7 9 4 0 9 2  
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 3 1 9 9  
 
1  
 
TI T L E P A G E  
Pr ot oc ol Title:  A P has e III b, o pe n -la bel, h y bri d t y p e III tri al e val uati n g i m ple me ntati o n 
strate gies f or l o n g-acti n g ca b ote gra vir pl us l o n g -acti n g ril pi viri ne e v er y t w o m o nt hs i n 
HI V -1 i nf ecte d, vir ol o gic all y s u p presse d a d ults i n select E ur o pea n  healt hcare setti n gs.  
Pr ot oc ol N u m ber : 2 1 3 1 9 9  / A me n d me nt 0 2  
C o m p o u n d 
N u m ber : 
G S K 1 2 6 5 7 4 4  
St u d y P h ase :  
P hase 3  
A p pr o v al D ate : 
0 1 -J U L-2 0 2 1  
S h ort Title : A st u d y e val uati n g i m ple me ntati o n strate gies f or ca b ot e gra vir + ril pi viri ne 
l o n g-acti n g i njecta bles f or HI V-1 tr eat me nt  i n E ur o pea n c o u ntries . 
C A RI S E L : C A B A n d R P V I m ple me ntati o n St u d y  i n E ur o pea n L ocati o ns  
A ut h or (s):  
, 
S p o ns or Le g al Re gistere d A d dress (e xcl u di n g U S):  
Vii V Healt hcare  
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  
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 vel 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 is i m ple me nti n g a n d 
ma na gi n g all as pects of t his st u d y o n b e half of Vii V Healt hcare.  
Me dic al M o nit or  a n d S p o ns or Seri o us A d verse E ve nts ( S A E) 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 dy Refere nce M a n u al  
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  
I N D: 1 0 9, 6 7 8 
E u dra C T #:  2 0 2 0 -0 0 0 4 2 4 -1 9  
C o p yri g ht 2 0 2 1  Vii V Healt hcare gr o u p of c o m p a 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
P P D

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SPONSOR SIGNATORY: 
Protocol Title: A Phase IIIb, open-label, hybrid type III trial evaluating implementation 
strategies for long-acting cabotegravir plus long-acting rilpivirine every two months in 
HIV-1 infected, virologically suppressed adults in select European healthcare settings. 
Protocol Number: 213199 / Amendment 02 
Compound 
Number: 
GSK1265744 
 
 
 
 
 
 
Sherene Shakib Min, MD, MPH 
Vice President, Head of Clinical Development 
ViiV Healthcare 
 
Date 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 02 
01-JUL-2021 
TMF-13794092 
Amendment 01 
02-DEC-2020 
2019N420690_02 
Original Protocol (Republishing) 
06-MAY-2020 
2019N420690_01 
Original Protocol 
05-FEB-2020 
2019N420690_00 
 
 Amendment 02 01-JUL-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union due to the change in the allowance of participants becoming pregnant to 
continue on study. 
Overall Rationale for the Amendment:  
The primary purposes of this amendment are: 
• To allow participants who become pregnant while in the study to remain in the 
study and not be withdrawn due to pregnancy. Allowing pregnant participants 
to continue in the study will negate any additional and subsequent fetal 
exposures to new antiretroviral agents that would occur if the pregnant 
participant was withdrawn from the study and placed on an oral SOC regimen. 
An appendix, “Information and Guidance for Managing Pregnant Participants” 
was inserted as Appendix 15 and all subsequent appendices were renumbered 
accordingly. 
• Detail added around the end of the study and transition to commercial supply or 
other HAART regimen. 
• Removal of the optional collection of cord blood and/or breast milk after 
delivery. 
• Clarification of which participants enter the LTFU phase when CAB+RPV LA 
marketed product is locally available. 
• Medical Device reporting requirement added. 
• Clinical and safety references updated. 
 
Other additional edits were made, for clarity and/or correction. 
 
 

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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added clarifying text;  
Participants will 
continue CAB LA + 
RPV LA until:  
They have completed 
the study (reached dose 
7,  Month 12) and the 
intervention is locally 
approved and available 
for the Investigator to 
prescribe.   
Added text confirming 
the Home Visit 
Handbook for home 
visits  also provides 
supplementary 
information as well as 
the SRM. 
For clarification 
purposes. 
Section 1.1 Long Term Follow-Up 
(LTFU) Phase 
Section 4.1. Overall Design 
Section 4.3.4. LTFU Phase- 
Following the IM Regimen Only 
Section 7. Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal 
Section 7.1 Discontinuation of 
Study Intervention 
 
New text added: 
- 
Any participant 
who receives at 
least one dose of 
CAB LA and/or 
RPV LA and 
discontinues the 
CAB LA + RPV 
LA regimen for 
any reason 
before CAB LA 
+ RPV LA 
marketed 
product is 
locally available 
must enter the 
LTFU Phase. 
 
- 
Where CAB LA 
+ RPV LA 
marketed 
product is 
locally available, 
Transition to marketed 
product. 

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only participants 
that discontinue 
the CAB LA + 
RPV LA 
regimen for 
safety-related 
reasons should 
enter the LTFU 
Phase. 
 
Section 1.3. Schedule of Activities 
Table 
Added new column and 
footnote w for Safety 
Follow-Up visit to 
clarify visit 
requirements. 
Prothrombin time (PT)/ 
partial thromboplastin 
time 
(PTT)/international 
normalized ratio (INR) 
removed from 
withdrawal visit. 
Task added for safety 
follow-up visit to 
review transition to 
commercial product. 
Footnote b updated to 
clarify definition of 
extension phase. 
Footnote f updated to 
clarify the assessment 
of height and body 
mass index (BMI) are 
collected at screening 
only. 
Footnote g updated to 
detail pregnancy testing 
not required for 
pregnant participants 
remaining on study. 
Transition to marketed 
product. 

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Footnote h updated to 
clarify the viral load 
assessments 
requirement for 
pregnant patients. 
Footnote m updated to 
add safety follow-up 
requirement if no 
withdrawal visit. 
Benefit/Risk Assessment 
Section 2.3.1. Oral CAB and CAB 
LA (GSK1265744/GSK1265744 
LA) 
Updated section 
Potential Risk of 
Clinical Significance: 
Drug Induced Liver 
Injury (DILI) for CAB, 
Summary of 
Data/Rationale for Risk 
text removed: 
- 
(total exposure 
>3100 
participants) 
Summary of 
Data/Rationale for Risk 
text updated to include 
proportion of 
participants effected; 
Less than 1%. 
Removed; All 
participants with 
suspected DILI 
identified to date were 
receiving oral CAB.   
For clarification 
purposes. 
Benefit/Risk Assessment 
Section 2.3.1. Oral CAB and CAB 
LA (GSK1265744/GSK1265744 
LA) 
Updated section 
Potential Risk of 
Clinical Significance: 
Effects in pregnancy 
seen in non-clinical 
studies. 
Summary of 
Data/Rationale for Risk 
To allow participants 
who become pregnant 
to remain in the study. 

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Animal reproduction 
studies data updated. 
Mitigation Strategy 
updated to allow 
participants who 
become pregnant to 
remain in the study. 
Benefit/Risk Assessment 
Section 2.3.1. Oral CAB and CAB 
LA (GSK1265744/GSK1265744 
LA) 
Updated section: 
Potential effects in 
females exposed to 
dolutegravir during 
conception and early 
pregnancy.  
Summary of 
Data/Rationale for Risk 
with data from 
preliminary analysis of 
an ongoing birth 
outcome surveillance 
study in Botswana 
involving women 
exposed to dolutegravir 
(DTG). 
Mitigation Strategy 
updated to allow 
participants who 
become pregnant to 
remain in the study. 
To allow participants 
who become pregnant 
to remain in the study. 
Benefit/Risk Assessment 
Section 2.3.1. Oral CAB and CAB 
LA (GSK1265744/GSK1265744 
LA) 
Section 2.3.2 Oral RPV and RPV 
LA (GSK1265744/GSK1265744 
LA) 
Section 4.3.4. LTFU Phase- 
Following the IM Regimen Only 
 
Updated section: 
Development of 
Resistance following 
discontinuation of 
CAB LA. 
Updated text (HAART) 
regimens will be 
prescribed within 1 
month (-7 days) after 
the last Q1M dose or 
within  2 months (+/-7 
days) after the last 
Q2M dose. 
For clarification 
purposes. 

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Updated to 
differentiate the long 
term follow-up 
requirements pre and  
post commercial 
availability.  
Benefit/Risk Assessment 
Section 2.3.2 Oral RPV and RPV 
LA (GSK1265744/GSK1265744 
LA) ORAL RPV 
Updated text: For 
safety and risk 
mitigation for oral RPV 
refer to the RPV local 
prescribing information 
[Current Edurant 
Prescribing 
Information] 
For clarification 
purposes. 
Benefit/Risk Assessment 
Section 2.3.2 Oral RPV and RPV 
LA (GSK1265744/GSK1265744 
LA) RPV LA 
Updated text: Systemic 
reactions following 
RPV LA injections 
have been observed in 
clinical trials. These 
occur infrequently (in 
less than 0.5% of 
participants) and 
typically begin to 
resolve within minutes 
of the injection, some 
participants have 
required supportive 
care. Where timely PK 
data has been available. 
For clarification 
purposes. 
Benefit/Risk Assessment 
Section 2.3.2 Oral RPV and RPV 
LA (GSK1265744/GSK1265744 
LA) RPV LA  
Updated section: Risk 
of Treatment Failure 
Updated with text: 
recently approved EU 
and under review in 
other countries. Both 
IM CAB and RPV 
have demonstrated 
antiviral activity in 
large clinical studies 
and the two-drug 
combination dosed 
Q4W has demonstrated 
sustained antiviral 
activity in studies 
For clarification 
purposes. 

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200056, 201584 and 
201585 and in studies 
(200056 and 207966) 
when dosed Q8W. 
Benefit/Risk Assessment 
Section 2.3.3. Benefit Assessment 
Updated list of ongoing 
studies and duration.  
For clarification 
purposes. 
 
 
 
Section 4.2.4 Enhanced 
Implementation Arm (arm-e) 
Description 
Added text; Face-to-
Face injection training: 
Where new staff join 
the study the injection 
training should also be 
provided face-to-face 
where possible. 
For clarification 
purposes. 
Section 4.3.3 Patient study 
participant 
Section: Patient study participants 
enrollment and  Table 7 Dosing 
Regimen 
Section 6.1 Study Intervention(s) 
Administered; Dosing and 
Administration 
End of study 
clarification; Until after 
dose 7 (Month 12) 
when locally approved 
and commercially 
available. 
 
Section 4.3.4. LTFU Phase- 
Following the IM Regimen Only 
 
New text added: 
Clarified HAART 
initiation in months 
rather than weeks. 
Transition to marketed 
product. 
 
Section 4.5.1.2. Participant Study 
Participants 
Section 6.8. Intervention after the 
End of the Study or Extension 
Phase 
 
Clarity added around 
study completion, the 
extension phase and 
transition to 
commercial supplies of 
CAB LA + RPV LA, 
or alternate 
antiretroviral therapy. 
Added Safety Follow-
Up visit details. 
Transition to marketed 
product. 

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Section 6. Study Intervention  
New section added: 
6.9. Medical Devices. 
Medical Device 
reporting requirement. 
Section 6.7. Treatment of Study 
Treatment Overdose 
 
Updated the text 
around IM 
maladministration 
should this occur at a 
home visit. 
Removed text: (at least 
5 days for oral CAB 
and oral RPV, and 52 
weeks for CAB LA and 
RPV LA. 
Added text: (number of 
days will vary by 
compound – Medical 
Monitor/ study team 
can advise) 
For clarification 
Purposes. 
Section 7. Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal 
Removed text: 
Pregnancy 
(intrauterine), 
regardless of 
termination status of 
pregnancy. 
Updated text: If a 
participant is 
prematurely or 
permanently withdrawn 
from the study, and not 
continuing into the 
LTFU, the procedures 
described in the 
Schedule of Activities 
Table for the in-clinic 
Withdrawal visit are to 
be performed. Where a 
participant does not 
complete a withdrawal 
visit or enter the LTFU, 
an in-clinic or remote 
Safety Follow-Up visit 
will be conducted 4 
weeks after the last 
dose of study 
To allow participants 
who become pregnant 
to remain in the study. 
Clarification on 
withdrawal and safety 
follow-up visit. 

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medication when there 
are ongoing AEs 
serious adverse events 
(SAEs) related & not 
related to study drug 
and also any laboratory 
abnormalities that are 
considered to be AEs 
or potentially harmful 
to the participant, at the 
last on-study visit. 
Section 7.1 Discontinuation of 
Study Intervention 
 
Added text: The start of 
the 52-week follow-up 
period begins the day 
of the last CAB LA 
and/or RPV LA dose 
with the first visit at 
Month 3.  
Clarification on start 
of 52 weeks LTFU 
phase.  
Section 8.4.1. Clinical Evaluation 
Added text: 
Participants who are 
enrolled in the study 
and have a positive 
pregnancy test during 
the course of the study, 
will be allowed to 
remain in the study, 
provided a pregnancy 
specific ICF addendum 
is signed by the 
participant. No IP can 
be continued (oral or 
LA) in any pregnant 
participant until the 
benefit/risk assessment 
is discussed with the 
participant and the 
pregnancy specific ICF 
addendum has been 
signed. See details in 
Appendix 15: 
Information and 
Guidance for 
Managing Pregnant 
Participants.  
To allow participants 
who become pregnant 
to remain in the study. 

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Pregnant participants 
who remain in the 
study do not need 
pregnancy testing 
during the study, for 
the duration of their 
pregnancy.  
Section 8.4.4. Clinical Safety 
Laboratory Assessments 
Text updated:  
• Prothrombin Time 
(PT)/International 
Normalized Ratio 
(INR)/ Partial 
Thromboplastin 
Time (PTT) 
(screening) 
• Pregnancy test for 
women of 
childbearing 
potential.  
• Text added to 
clarify additional 
pre-dose PK 
samples collection 
for pregnant 
participants who 
elect to remain in 
the study. 
 
Text added: Where lab 
samples are missed in 
error, including not 
analysed by the central 
lab, see the Study 
Reference Manual 
(SRM) for guidance on 
which samples should 
have subjects brought 
back in for a central lab 
retest (local lab only 
sites require a local 
retest only). Retesting 
to be entered as an 
unscheduled visit in the 
eCRF. 
For clarification 
purposes. 

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Section 8.5. Adverse Events  and 
Serious Adverse Events 
Added text throughout 
sections 8.5. and 8.5.1. 
referring to the new 
requirement to report 
Medical Device 
incidents. 
New sections added to 
cover the new 
requirement to report 
Medical Device 
incidents. 
 
8.5.8. Medical Device 
Deficiencies 
 
8.5.8.1. Time Period 
for Detecting Medical 
Device Deficiencies 
 
8.5.8.2. Follow-up of 
Medical Device 
Deficiencies  
8.5.8.2.1. Prompt 
Reporting of Medical 
Device Deficiencies to 
Sponsor 
 
8.5.8.2.2. Regulatory 
Reporting 
Requirements for 
Medical Device 
Deficiencies 
Added Medical 
Device incident 
reporting 
requirements. 
Section 8.5.5. Pregnancy 
Added text throughout 
all sections below to 
allow subjects who 
become pregnant to 
remain in the study: 
Added text in Section 
8.5.5.1. Pregnancy 
Testing 
To allow subjects who 
become pregnant to 
remain in the study. 

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Added new Section 
8.5.5.2. Rationale for 
Continued Use in 
Pregnancy 
Amended Section 
8.5.5.3. Time Period 
for Collecting 
Pregnancy Information 
Amended Section 
8.5.5.4. Action to be 
Taken if Pregnancy 
Occurs 
Section 8.5.5.4. Actions to be taken 
if Pregnancy occurs 
Removed text: 
Additionally, there will 
be an optional 
umbilical cord blood 
collection at time of 
delivery, requiring 
additional parental 
consent. Cord blood 
and breast milk 
samples would be used 
to better understand the 
level of PK exposure to 
the neonate, if any. 
Removal of optional 
umbilical cord blood 
and/or breast milk PK 
testing. 
Section 8.6. Pharmacokinetics 
Added text: Pregnant 
participants will have 
additional PK samples 
collected during the 
duration of the 
pregnancy. See 
Appendix 15: 
Information and 
Guidance for Managing 
Pregnant Participants. 
Added PK collection 
during pregnancy. 
Section 9.4.1. Primary Endpoints 
(S) 
Text corrected in the 
Primary SSP endpoints 
AIM, IAM, FIM to 
correctly refer to 
‘Implementation,’ 
rather that Intervention. 
For clarification 
purposes. 

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Section 10.1.3. Informed Consent 
Process 
Added text: 
• 
Participants 
who become 
pregnant 
while in the 
study and who 
elect to 
continue to 
receive CAB 
+ RPV LA 
injections 
must sign the 
pregnancy 
specific ICF 
addendum. 
• 
If follow-up 
information 
from a 
treating 
physician or 
other licensed 
medical 
practitioner is 
required for a 
medical 
device 
incident with 
an AE/SAE 
involving an 
associated 
person(s), the 
Associated 
Person Safety 
Reporting 
Information 
and 
Authorization 
Letter must be 
signed by the 
associated 
person to 
obtain 
consent.  
 
To allow patients who 
become pregnant to 
remain in the study 
and medical device 
deficiency reporting 
requirements. 

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Section 10.6.4. Grade 3 
Toxicity/Adverse Event 
Clarification that a 
follow-up visit should 
occur 2-4 weeks after 
the last dose of IP. 
For clarification 
purposes. 
Section 10.6.5.10. Rash Without 
HSR Symptoms 
Updated CAB IB 
document number 
For clarification 
purposes. 
Section 10.7. Appendix 7 
Contraceptive Guidance and 
Collection of Pregnancy 
Information 
Added text throughout 
section for cases of 
pregnancy during the 
study. 
To allow patients who 
become pregnant to 
remain in the study. 
Section 10.9. Appendix 9 
New abbreviation 
added 
 
Section 10.15. Appendix 15 
New appendix added: 
Appendix 15: 
Information and 
Guidance for Managing 
Pregnant Participants. 
To allow participants 
who become pregnant 
to remain in the study. 
Section 10.16. Appendix 16 
New appendix added: 
Appendix 16: Device 
Deficiencies: 
Definition and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting in Medical 
Device Studies. 
Medical Device 
Reporting 
Requirements. 
Section 10.17. Appendix 17 
Appendix 17: Protocol 
Amendment History 
updated. 
 
 
 
 
 

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C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
1 7  
 
 
T A B L E O F C O N T E N T S  
P A G E  
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  ..................................... 3  
1.  
P R O T O C O L S U M M A R Y  ........................................................................................ 2 3  
1. 1.  
S y n o p si s  ..................................................................................................... 2 3  
1. 2.  
S c h e m a  ...................................................................................................... 3 1  
1. 3.  
S c h e d ul e of A cti v iti e s ( S o A) ........................................................................ 3 2  
2.  
I N T R O D U C TI O N .................................................................................................... 4 0  
2. 1.  
St u d y R ati o n al e  .......................................................................................... 4 0  
2. 2.  
B a c k gr o u n d  ................................................................................................ 4 1  
2. 2. 1.  
Tr e at m e nt B a c k gr o u n d  ................................................................ 4 1  
2. 2. 2.  
N e w Tr e at m e nt P ar a di g m  ............................................................ 4 1  
2. 3.  
B e n efit/ Ri s k A s s e s s m e nt  ............................................................................ 4 3  
2. 3. 1.  
Or al C A B a n d C A B L A ( G S K 1 2 6 5 7 4 4/ G S K 1 2 6 5 7 4 4 L A)  ............. 4 3  
2. 3. 2.  
Or al R P V a n d R P V L A ( G S K 1 2 6 5 7 4 4/ G S K 1 2 6 5 7 4 4 L A)  ............. 5 0  
2. 3. 2. 1.  
Ot h er Cli ni c all y R el e v a nt I nf or m ati o n  .......................... 5 6  
2. 3. 3.  
B e n efit A s s e s s m e nt  ..................................................................... 5 6  
2. 3. 4.  
O v er all B e n efit: Ri s k C o n cl u si o n  .................................................. 5 6  
3.  
O B J E C TI V E S A N D E N D P O I N T S ........................................................................... 5 7  
4.  
S T U D Y D E SI G N  .................................................................................................... 5 9  
4. 1.  
O v er all D e si g n  ............................................................................................ 5 9  
4. 2.  
D e si g n of I m pl e m e nt ati o n R e s e ar c h  ........................................................... 6 0  
4. 2. 1.  
I m pl e m e nt ati o n Fr a m e w or k s: ....................................................... 6 1  
4. 2. 2.  
E x pl or ati o n, Pr e p ar ati o n, I m pl e m e nt ati o n, S u st ai n m e nt 
( E PI S) .......................................................................................... 6 2  
4. 2. 3.  
I m p a ct of I m pl e m e nt ati o n Str at e gi e s o n C A B L A + R P V 
L A  ................................................................................................ 6 4  
4. 2. 4.  
St u d y Ar m s  .................................................................................. 6 5  
4. 2. 4. 1.  
E n h a n c e d I m pl e m e nt ati o n Ar m ( ar m -e) 
D e s cri pti o n  ................................................................. 6 5  
4. 2. 4. 2.  
St a n d ar d I m pl e m e nt ati o n Ar m ( ar m -s) 
D e s cri pti o n  ................................................................. 6 6  
4. 2. 5.  
K e y E v al u ati o n of I m pl e m e nt ati o n Str at e gi e s & I n si g ht s  .............. 6 7  
4. 2. 6.  
C o u ntr y S p e cifi c C h all e n g e s a n d I m pl e m e nt ati o n 
Str at e gi e s  .................................................................................... 7 1  
4. 2. 6. 1.  
Fr a n c e  ........................................................................ 7 1  
4. 2. 6. 2.  
S p ai n  .......................................................................... 7 2  
4. 2. 6. 3.  
B el gi u m  ...................................................................... 7 2  
4. 2. 6. 4.  
G er m a n y  .................................................................... 7 2  
4. 2. 6. 5.  
N et h erl a n d s  ................................................................ 7 3  
4. 3.  
Tr e at m e nt Gr o u p s a n d D ur ati o n  ................................................................. 7 3  
4. 3. 1.  
St u d y sit e s  ................................................................................... 7 3  
C CI

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4.3.2. 
Study staff participants ................................................................. 74 
4.3.3. 
Patient study participant ............................................................... 75 
4.3.4. 
LTFU Phase – Following the IM Regimen Only ........................... 77 
4.4. 
Justification for Dose .................................................................................. 78 
4.4.1. 
Oral Lead-In Phase ...................................................................... 78 
4.4.2. 
Long-Acting Injectable Phase ...................................................... 79 
4.4.2.1. 
CAB LA Pharmacokinetics .......................................... 81 
4.4.2.2. 
RPV LA Pharmacokinetics .......................................... 82 
4.5. 
End of Study Definition ............................................................................... 85 
4.5.1. 
Study Completion ........................................................................ 85 
4.5.1.1. 
Study Staff Participants .............................................. 85 
4.5.1.2. 
Patient Study Participants........................................... 85 
5. 
STUDY POPULATION ........................................................................................... 86 
5.1. 
Inclusion Criteria ......................................................................................... 86 
5.2. 
Exclusion Criteria ........................................................................................ 89 
5.2.1. 
Additional Eligibility Criteria .......................................................... 92 
5.3. 
Lifestyle Considerations .............................................................................. 92 
5.4. 
Screen Failures........................................................................................... 92 
6. 
STUDY INTERVENTION ........................................................................................ 93 
6.1. 
Study Intervention(s) Administered ............................................................. 93 
6.1.1. 
Formulations of CAB + RPV ........................................................ 94 
6.1.1.1. 
Cabotegravir Tablets (CAB) ........................................ 94 
6.1.1.2. 
Rilpivirine Tablets (RPV)............................................. 94 
6.1.1.3. 
Cabotegravir Injectable Suspension (CAB LA) ........... 94 
6.1.1.4. 
Rilpivirine Injectable Suspension (RPV LA) ................ 95 
6.1.1.5. 
CAB LA Packs ............................................................ 95 
6.1.1.6. 
RPV LA Packs ............................................................ 95 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 95 
6.2.1. 
Dosing Considerations for CAB LA + RPV LA .............................. 96 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 97 
6.4. 
Study Intervention Compliance ................................................................... 97 
6.5. 
Dose Modification ....................................................................................... 98 
6.5.1. 
Protocol Permitted Substitutions .................................................. 98 
6.5.1.1. 
Oral Bridging- Oral CAB LA + RPV LA ....................... 98 
6.5.1.2. 
Oral Bridging- Standard of Care Antiretroviral 
Therapy (SOC ART) ................................................... 98 
6.5.2. 
COVID-19 .................................................................................... 99 
6.5.3. 
IM Dosing .................................................................................... 99 
6.5.4. 
Oral Dosing ................................................................................ 100 
6.6. 
Concomitant Therapy................................................................................ 101 
6.6.1. 
Permitted Medications and Non-Drug Therapies ........................ 101 
6.6.2. 
Prohibited Medications and Non-Drug Therapies ....................... 102 
6.6.2.1. 
Concurrent with CAB and/or RPV ............................. 103 
6.6.2.2. 
Concurrent with oral RPV ......................................... 103 
6.6.3. 
Concurrent with either CAB LA or RPV LA ................................. 103 
6.6.4. 
Prohibited Medications for Participants Receiving HAART 
during the Long-Term Follow-Up Phase .................................... 104 
6.7. 
Treatment of Study Treatment Overdose .................................................. 104 
6.8. 
Intervention after the End of the Study or Extension Phase ...................... 105 
6.9. 
Medical Devices ........................................................................................ 105 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 105 
7.1. 
Discontinuation of Study Intervention ........................................................ 108 
7.1.1. 
Liver monitoring event – Increased monitoring ........................... 108 
7.1.2. 
Asymptomatic Liver Enzyme Elevations .................................... 108 
7.1.3. 
Liver Chemistry Stopping Criteria .............................................. 109 
7.1.4. 
Temporary Discontinuation ........................................................ 109 
7.1.5. 
Restart ....................................................................................... 109 
7.1.6. 
Virologic Failure ......................................................................... 110 
7.1.7. 
Definition of Protocol-Defined Confirmed Virologic Failure ......... 110 
7.1.8. 
Managing Virologic Failure ........................................................ 110 
7.1.8.1. 
HIV-1 RNA Blips ....................................................... 111 
7.1.8.2. 
Suspected Virologic Failure ...................................... 111 
7.1.8.3. 
Confirmed Virologic Failure ...................................... 112 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................. 112 
7.3. 
Lost to Follow Up ...................................................................................... 113 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 113 
8.1. 
Screening Assessments ........................................................................... 114 
8.2. 
Baseline Assessments .............................................................................. 115 
8.2.1. 
Patient Study Participants .......................................................... 115 
8.2.2. 
Staff Study Participants .............................................................. 116 
8.3. 
Efficacy Assessments- Patient Study Participants .................................... 116 
8.3.1. 
Plasma HIV-1 RNA .................................................................... 116 
8.3.2. 
Lymphocyte Subsets, CD4+ and CD8+ ..................................... 116 
8.3.3. 
HIV-Associated Conditions ........................................................ 116 
8.4. 
Safety Assessments- Patient Study Participants ....................................... 116 
8.4.1. 
Clinical Evaluations .................................................................... 116 
8.4.2. 
Physical Examinations ............................................................... 117 
8.4.3. 
Vital Signs .................................................................................. 118 
8.4.4. 
Clinical Safety Laboratory Assessments .................................... 118 
8.4.5. 
Suicidal Ideation and Behavior Risk Monitoring ......................... 119 
8.5. 
Adverse Events and Serious Adverse Events ........................................... 120 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE ............. 120 
8.5.2. 
Method of Detecting AEs and SAEs ........................................... 120 
8.5.3. 
Follow-up of AEs and SAEs ....................................................... 121 
8.5.4. 
Regulatory Reporting Requirements for SAEs ........................... 121 
8.5.5. 
Pregnancy ................................................................................. 121 
8.5.5.1. 
Pregnancy Testing.................................................... 121 
8.5.5.2. 
Rationale for Continued Use in Pregnancy ............... 122 
8.5.5.3. 
Time Period for Collecting Pregnancy 
Information ............................................................... 122 
8.5.5.4. 
Action to be Taken if Pregnancy Occurs ................... 123 
8.5.6. 
Cardiovascular and Death Events .............................................. 124 
8.5.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................. 124 
8.5.8. 
Medical Device Deficiencies ...................................................... 125 
8.5.8.1. 
Time period for Detecting Medical Device 
Deficiencies .............................................................. 125 
8.5.8.2. 
Follow-up of Medical Device Deficiencies ................. 125 
8.6. 
Pharmacokinetics ..................................................................................... 126 
8.7. 
Pharmacodynamics .................................................................................. 126 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
2 0  
 
8. 8.  
G e n eti c s  ................................................................................................... 1 2 6  
8. 9.  
Bi o m ar k er s  ............................................................................................... 1 2 6  
8. 1 0.  Vir al G e n ot y pi n g a n d P h e n ot y pi n g  ............................................................ 1 2 6  
8. 1 0. 1.  
HI V -1 P ol y m er a s e Vir al G e n ot y pi n g a n d P h e n ot y pi n g  ............... 1 2 7  
8. 1 1.  H e alt h E c o n o mi c s  ..................................................................................... 1 2 7  
9.  
S T A TI S T I C A L C O N SI D E R A TI O N S ...................................................................... 1 2 7  
9. 1.  
St ati sti c al H y p ot h e s e s ............................................................................... 1 2 7  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ...................................................................... 1 2 7  
9. 3.  
P o p ul ati o n A n al y s e s  ................................................................................. 1 3 2  
9. 4.  
St ati sti c al A n al y s e s  ................................................................................... 1 3 2  
9. 4. 1.  
Pri m ar y E n d p oi nt( s)  ................................................................... 1 3 4  
9. 4. 2.  
S e c o n d ar y E n d p oi nt( s)  .............................................................. 1 3 5  
9. 4. 4.  
Ot h er A n al y s e s  .......................................................................... 1 3 8  
9. 5.  
I nt eri m A n al y s e s ....................................................................................... 1 3 9  
9. 6.  
D at a M o nit ori n g C o m mitt e e  ...................................................................... 1 3 9  
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 4 0  
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  .............................. 1 4 0  
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 4 0  
1 0. 1. 2.  
Fi n a n ci al Di s cl o s ur e  ................................................................... 1 4 0  
1 0. 1. 3.  
I nf or m e d C o n s e nt Pr o c e s s ........................................................ 1 4 1  
1 0. 1. 4.  
D at a Pr ot e cti o n  .......................................................................... 1 4 1  
1 0. 1. 5.  
Q u alit y C o ntr ol ( St u d y M o nit ori n g)  ............................................. 1 4 2  
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 4 2  
1 0. 1. 7.  
D at a Q u alit y A s s ur a n c e  ............................................................. 1 4 3  
1 0. 1. 8.  
S o ur c e D o c u m e nt s  .................................................................... 1 4 4  
1 0. 1. 9.  
St u d y a n d Sit e Cl o s ur e  .............................................................. 1 4 4  
1 0 . 2. A p p e n di x 2: 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 a e di atri c A d v er s e E v e nt s V er si o n 2. 1, M ar c h 2 0 1 7  .......................... 1 4 6  
1 0 . 3. A p p e n di x 3: Li v er S af et y: R e q uir e d A cti o n s, F oll o w -u p A s s e s s m e nt s 
a n d St u d y I nt er v e nti o n R e st art G ui d eli n e s  ................................................ 1 7 0  
1 0. 3. 1.  
Li v er c h e mi str y st o p pi n g crit eri a a n d 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 7 0  
1 0. 3. 2.  
St u d y I nt er v e nti o n R e st art aft er St o p pi n g f or Li v er Crit eri a  ........ 1 7 3  
1 0. 3. 2. 1.  Dr u g R e st art  ............................................................. 1 7 4  
1 0. 4.  A p p e n di x 4: C D C Cl a s sifi c ati o n f or HI V -1 I nf e cti o n ( C D C, 2 0 1 4)  .............. 1 7 8  
1 0. 5.  A p p e n di x 5 : D efi niti o n of 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 of A d v er s e E v e nt s  ............................................. 1 8 0  
1 0. 5. 1.  
D efi niti o n of A d v er s e E v e nt s  ...................................................... 1 8 0  
1 0. 5. 2.  
D efi niti o n of S eri o u s A d v er s e E v e nt s  ......................................... 1 8 1  
1 0. 5. 3.  
D efi niti o n of C ar di o v a s c ul ar E v e nt s  ........................................... 1 8 3  
1 0. 5. 4.  
R e c or di n g of A E s a n d S A E s  ...................................................... 1 8 4  
1 0. 5. 5.  
E v al u ati n g A E s a n d S A E s  .......................................................... 1 8 4  
1 0. 5. 6.  
R e p orti n g of S A E s t o G S K  ......................................................... 1 8 6  
1 0. 6.  A p p e n di x 6: T o xi cit y M a n a g e m e nt  ............................................................ 1 8 7  
C CI
C CI
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
2 1  
 
1 0. 6. 1.  
Tr e at m e nt I nt err u pti o n D u e t o a n A d v er s e E v e nt  ....................... 1 8 7  
1 0. 6 . 2. 
Gr a d e 1 or Gr a d e 2 T o xi cit y/ A d v er s e E v e nt  ............................... 1 8 7  
1 0. 6. 3.  
Gr a d e 3 T o xi cit y/ A d v er s e E v e nt  ................................................. 1 8 8  
1 0. 6. 4.  
Gr a d e 4 T o xi cit y/ A d v er s e E v e nt  ................................................. 1 8 8  
1 0. 6. 5.  
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  ........................ 1 8 9  
1 0. 6. 5. 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 8 9  
1 0. 6. 5. 2.  Di arr h e a  ................................................................... 1 9 0  
1 0. 6. 5. 3.  S ei z ur e s  ................................................................... 1 9 0  
1 0. 6. 5. 4.  Cr e a ti n e P h o s p h o ki n a s e ( C P K) El e v ati o n ................ 1 9 1  
1 0. 6. 5. 5.  Li p a s e El e v ati o n s a n d P a n cr e atiti s  ........................... 1 9 1  
1 0. 6. 5. 6.  D e cli n e i n R e n al F u n cti o n  ......................................... 1 9 2  
1 0. 6. 5. 7.  Pr o xi m al R e n al T u b ul e D y sf u n cti o n s ( P R T D)  ........... 1 9 2  
1 0. 6. 5. 8.  I nj e cti o n Sit e R e a cti o n s (I S R s) ................................. 1 9 2  
1 0. 6. 5. 9.  All er gi c r e a cti o n  ........................................................ 1 9 3  
1 0. 6. 5. 1 0.  R a s h Wit h o ut H S R S y m pt o m s  .................................. 1 9 3  
1 0. 7.  A p p e n di x 7: C o ntr a c e pti v e G ui d a n c e a n d C oll e cti o n of Pr e g n a n c y 
I nf or m ati o n ................................................................................................ 1 9 4  
1 0. 7. 1.  
C oll e cti o n of Pr e g n a n c y I nf or m ati o n  .......................................... 1 9 7  
1 0. 8.  A p p e n di x 8: C o u ntr y -s p e cifi c r e q uir e m e nt s  ............................................... 1 9 8  
1 0. 9.  A p p e n di x 9: A b br e vi ati o n s a n d Tr a d e m ar k s  .............................................. 1 9 9  
1 0. 1 0.  A p p e n di x 1 0: P ati e nt St u d y P arti ci p a nt Q u e sti o n n air e s  ............................ 2 0 3  
1 0. 1 4.  A p p e n di x 1 4: C O VI D -1 9 P a n d e mi c a n d Cli ni c al Tri al C o nti n uit y  ............... 2 1 1  
1 0. 1 4. 1.  C h a n g e s  t o St u d y Vi sit s a n d St u d y Pr o c e d ur e s ......................... 2 1 1  
1 0. 1 4. 2.  C h a n g e s t o I nf or m e d C o n s e nt  ................................................... 2 1 2  
1 0. 1 4. 3.  P er mi s si bl e U s e of A ntir etr o vir al T h er a p y  .................................. 2 1 2  
1 0. 1 4. 4.  Dir e ct -T o -P ati e nt ( D T P) S hi p m e nt of Or al St u d y I P  ................... 2 1 4  
1 0. 1 4. 5.  C O VI D -1 9 E x p eri m e nt al A g e nt s  ................................................ 2 1 5  
1 0. 1 4. 6.  C O VI D -1 9 S p e cifi c D at a C a pt ur e  ............................................... 2 1 5  
1 0. 1 4. 6. 1.  C a pt uri n g C O VI D -1 9 S p e cifi c Pr ot o c ol 
D e vi ati o n s  ................................................................ 2 1 5  
1 0. 1 4. 6. 2.  C a pt uri n g C O VI D -1 9 S p e cifi c A E s a n d S A E s  ........... 2 1 5  
1 0. 1 4. 7.  W H O C a s e D efi niti o n s  ............................................................... 2 1 6  
1 0. 1 5.  A p p e n di x 1 5: I nf or m ati o n a n d G ui d a n c e f or M a n a gi n g Pr e g n a nt 
P arti ci p a nt s  ............................................................................................... 2 1 8  
1 0. 1 5. 1.  C oll e cti o n of Pr e g n a n c y I nf or m ati o n  .......................................... 2 1 8  
1 0. 1 5. 2.  I ntr o d u cti o n ................................................................................ 2 1 8  
1 0. 1 5. 3.  B a c k gr o u n d  ............................................................................... 2 1 9  
1 0. 1 5. 4.  B e n efit/ Ri s k A s s e s s m e nt  ........................................................... 2 1 9  
1 0. 1 5. 4. 1.  C a b ot e gr a vir  ............................................................. 2 2 0  
1 0. 1 5. 4. 2.  Ril pi viri n e  .................................................................. 2 2 2  
1 0. 1 5. 5.  Cli ni c al C o n si d er ati o n s  .............................................................. 2 2 2  
1 0. 1 5. 5. 1.  E x p o s ur e  .................................................................. 2 2 2  
1 0. 1 5. 5. 2.  U s e of S u p pl e m e nt s wit h C A B + R P V L A  ................. 2 2 4  
1 0. 1 5. 5. 3.  O v er all B e n efit: Ri s k C o n cl u si o n  ............................... 2 2 4  
1 0. 1 5. 6.  St u d y A s s e s s m e nt s a n d Pr o c e d ur e s: s p e cifi c 
a s s e s s m e nt s f or pr e g n a nt p arti ci p a nt s  ....................................... 2 2 5  
C CI

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10.15.6.1. Safety Assessments ................................................. 225 
10.15.6.2. Pharmacokinetics ..................................................... 226 
10.15.7. References ................................................................................ 226 
10.16. Appendix 16: Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting in Medical Device 
Studies ..................................................................................................... 227 
10.16.1. Definition of Device Deficiency ................................................... 227 
10.16.2. Recording and Follow-Up of Device Deficiencies ....................... 227 
10.16.3. Reporting of Medical Device Deficiencies for participants .......... 228 
10.16.4. Reporting of Medical Device Deficiencies for Associated 
Person ....................................................................................... 229 
10.17. Appendix 17: Protocol Amendment History ............................................... 230 
11. REFERENCES ..................................................................................................... 234 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase IIIb, open-label, hybrid type III trial evaluating implementation 
strategies for long-acting cabotegravir plus long-acting rilpivirine every two months in 
HIV-1 infected, virologically suppressed adults in select European healthcare settings. 
Short Title: A study evaluating implementation strategies for cabotegravir + rilpivirine 
long-acting injectables for HIV-1 treatment in European countries. 
Rationale: 
Cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) is an 
investigational HIV-1 treatment regimen administered as two individual intramuscular 
injections every two months (following an oral lead-in [OLI] period).  
The overall objective of the CAB LA + RPV LA clinical development program is to 
develop a highly effective, well-tolerated, two-drug, long-acting injectable regimen 
which has the potential to offer improved treatment convenience, compliance and 
improved quality of life for people living with HIV (PLHIV) compared to current 
standard of care. 
This new HIV treatment will require changes to the current standard of prescribing oral 
antiretroviral therapies to prescribing and delivering a complete antiretroviral long-acting 
injectable regimen. As this is a new treatment modality, it is important to understand how 
to optimize the delivery of CAB LA + RPV LA from a patient, healthcare provider and 
healthcare system perspective in order to implement into routine care with fewer 
obstacles.  Each country’s healthcare system has its own challenges and nuanced 
differences in the delivery of HIV care. Strategies to support the unique and dynamic 
contexts for CAB LA + RPV LA implementation is key.  As a result, this research study 
will examine different implementation strategies in different clinic settings across 
European countries to identify which strategies best meet the needs in each local context. 
The research in this study will involve both patients receiving the study treatment CAB 
LA + RPV LA (patient study participants, PSP) as well as the healthcare providers at the 
investigator site level (staff study participants, SSP). 
    
For PSPs, the study is single-arm, unblinded and interventional, where all patients who 
fulfil eligibility requirements will be assigned to receive CAB LA + RPV LA and 
complete assessments as per the study protocol. 
For SSPs, the study is two-arm, unblinded, non-interventional and cluster-randomized at 
the country level. Sites within a given country will be randomized to either the Standard 
(Arm-s) or the Enhanced (Arm-e) implementation arm. The two arms will involve the 
provision of overlapping but distinct types of implementation components that are 
designed to assist in the local implementation of the study drug at each site. Arm-s 
represents the traditional provider support by a medical science lead and product 

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materials.  Arm-e models a higher level of provider support with added face to face 
meeting, trainings, and additional touchpoints for administration of CAB LA + RPV LA. 
The study will evaluate both qualitative and quantitative measures across arm, clinic type, 
provider type, and country to determine the most effective implementation strategies and 
to identify barriers and facilitators (including solutions). Clinical data will be collected to 
monitor safety and efficacy.   
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
Staff Study Participants (SSP): 
To evaluate 
 
• acceptability  
• appropriateness 
• feasibility  
 
Quantitative 
Change of Acceptability of Implementation 
Measure (AIM) Score, Implementation 
Appropriateness Measure (IAM) Score, Feasibility 
of Implementation Measure (FIM) Score over time 
assessed quantitatively via questionnaires through 
Month 12.a 
 
Qualitative  
Semi-structured interviews (SSI) assessed 
qualitatively through Month 12. 
 
Secondary 
 
Staff Study Participants: To 
evaluate 
 
• Facilitators to 
implementation 
• Barriers to 
implementation 
• Adaptations/Modifications 
to address barriers and 
facilitators 
 
 
Quantitative: 
Change of Implementation Leadership Scale 
(ILS), Change of Implementation Climate Scale 
(ICS) over time assessed quantitatively via 
questionnaires through Month 12.a 
 
Summarize components from Enhanced 
Implementation & Standard Implementation: 
• FRAME-IS outcome Months 2 – 12 
(monthly) 
 
Summarize components from Enhanced 
Implementation: 
• CQI 1-hour calls/PDSAs minimum of 
Months 2-7 (monthly) 
 
Qualitative  
SSIs assessed qualitatively through Month 12. 
Patient Study Participants 
(PSP) To evaluate 
 
• Facilitators to 
implementation 
Quantitative: 
Questionnaires assessed quantitatively through 
Dose 7.b 
 

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Objectives 
Endpoints 
• Barriers to 
Implementation 
 
Length of patient study participant visit from 
arrival until departure from clinic assessed at Dose 
1, Dose 2, Dose 4, and Dose 5. 
 
Qualitative  
SSIs assessed qualitatively through Dose 7. 
 
To evaluate Patient Study 
Participants experience of 
delivering CAB LA + RPV LA, 
including 
• Acceptability 
• Appropriateness 
• Feasibility     
Quantitative 
Change in Acceptability of Intervention Measure 
(AIM) Score, Intervention Appropriateness 
Measure (IAM) Score, and Feasibility of 
Intervention Measure (FIM) Score over time. 
Assessed via questionnaires at Dose 7. b 
 
Qualitative  
SSIs assessed qualitatively through Dose 7. 
 
To evaluate sustainability of CAB 
LA + RPV LA with Study Staff 
Participants each clinic 
 
Total score of the Clinical Sustainability 
Assessment Tool (CSAT) at Month 12. 
To assess fidelity to CAB LA 
+RPV LA injection dosing 
windows 
Percentage of injections occurring within target 
window from the target date. 
Evaluate efficacy and safety 
measures of CAB LA + RPV LA 
Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time  
Proportion of participants with confirmed 
virologic failure (CVF) over time  
Incidence of treatment-emergent genotypic and 
phenotypic resistance to CAB and RPV in patient 
study participants with CVF 
Incidence and severity of AEs, SAEs and 
proportion of participants who discontinue 
treatment due to AEs over time  
To assess preference between 
CAB LA + RPV LA and oral 
ART medication received prior to 
entering the study 
Preference between CAB + RPV LA and daily 
oral ART medication (received prior to entering 
the study) quantitatively assessed via preference 
questionnaire at Dose 7 
a) Month 1 is established by site activation, Month 5 is ~ the 1st patient receiving Dose 3 at the site, Month 12 is 
~the 1st patient receiving Dose 7 (last dose) at the site. 

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b) Dose 1 is the first injection and Dose 7 is the last injection 
 
Overall Design:  
This is a single-arm, open-label interventional study in respect to the drug regimen 
whereby all patients enrolled will receive the same intervention of the CAB LA + RPV 
LA regimen with a month oral lead in at Day 1 followed by CAB LA + RPV LA 
injections at Month 1, Month 2 and every 2 months (Q2M) thereafter. For the 
implementation science aspect, this is a two-arm study where clinics will be randomized 
to either Enhanced or Standard Implementation Arms at the country level. 
For Clinics:  
Arm 1: The Enhanced Implementation Arm (arm-e) contains the Skilled Wrap-Around 
Team (SWAT) which is an interactive problem-solving meeting and an introduction to 
the principles of Continuous Quality Improvement (CQI) with follow-up CQI calls.  
Arm 2: The Standard Implementation Arm (arm-s) will provide sites with the 
traditional standard practices for each country at the time of product availability provided 
by a medical science liaison or medical lead.   
Both arms will have access to the toolkits aimed to support education and proper 
administration of CAB LA + RPV LA.  We propose a cluster randomized, hybrid type III 
implementation trial with a mixed methods evaluation.  Results from the study will 
provide best practice recommendations for implementation of CAB LA + RPV LA.   
Sample Implementation Assessments: 
The proposed study design will identify key barriers (e.g., clinical capacity, injection 
training, cold chain storage) and facilitators (e.g., existing infrastructure for appointment 
reminders) to translating CAB LA + RPV LA into routine care by understanding:  
1) How do clinical team members and administrators perceive the acceptability, 
feasibility, and appropriateness of arm-e and arm-s strategies? 
2) How do clinical providers (and administrators) perceive the usefulness and ease 
of use of the toolkit components? 
3) How feasible are the two strategies to support rapid implementation of CAB LA + 
RPV LA in routine care in various countries and archetypes?  
4) How prepared are healthcare settings across Europe to incorporate a high volume 
of patient study participants receiving the CAB LA + RPV LA regimen into their 
clinical flow in various countries and clinic archetypes?  
5) What are the multi-level barriers to, and facilitators of, successful implementation 
in different countries, by a variety of providers, and by archetype? 

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Archetypes are descriptors that, in the context of this study, are used to broadly classify 
the anticipated types of care setting for the study treatment when locally available.  
Archetype 1 represents those where study treatment is administered in a hospital-based 
setting. Archetype 2 represents those where study treatment will be delivered primarily 
via (semi-) specialized physician office in primary care.  Archetype 3 represents those 
where the study treatment will be administered in a broad care setting which is 
anticipated to trigger new alternative injection facilities. 
Sample Effectiveness Assessments: 
The study design proposed here allows for simultaneous examination of both 
implementation and effectiveness outcomes.  Throughout the course of the study, viral 
load suppression and safety markers will be examined to further contribute to our 
understanding of CAB LA + RPV LA.  
Study Aims: 
✓ Aim 1: Evaluate the feasibility, acceptability, and appropriateness of staff 
study participants to support the integration of CAB LA + RPV LA in a 
variety of clinical settings. 
✓ Aim 2: Assess patient study participant acceptability, appropriateness, and 
feasibility of CAB LA + RPV LA treatment.   
✓ Aim 3: Identify multi-level barriers to, and facilitators of, CAB LA + RPV 
LA implementation and sustainment across Europe experienced by staff study 
participants and patient staff participants in both arms.    
✓ Aim 4: Assess the safety and effectiveness of CAB LA + RPV LA.  
Disclosure Statement: This is a single-arm, open-label interventional study in respect to 
the drug regimen whereby all patients enrolled will receive the same intervention of the 
CAB LA + RPV LA regimen. For the implementation science aspect, this is a two-arm 
study, which will assume a cluster randomization design, where clinics will be 
randomized to either arm-e or arm-s implementation strategy. 
Intervention Groups and Duration: 
Study sites  
Investigational sites or investigators that have not previously delivered the CAB LA + 
RPV LA regimen will be preferred for this study. Selection will be based on ability to 
recruit the desired number of study participants, clinic size, demographic, geographic 
diversity, and patient population. Sites will be selected in order to cover a wide variety of 
real-world HIV care settings and classified by the sponsor based on the care delivery 
system. Sites will be asked to operate through their regular clinic pathways rather than a 
research pathway wherever possible.   
 

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Each clinic selected will be categorized by country, archetype (defined above), number of 
providers/ staffs, number of patients, and other clinical characteristics that may be 
considered confounders or influence implementation.    
Sites across the following countries: France, Spain, Netherlands, Germany and Belgium 
will be selected. Exact site number will be based on feasibility assessments with an 
approximation of 18 sites to be selected. 
 
Site staff participants 
Study staff participants will be included that are central to best practices delivery of CAB 
LA + RPV LA within each local context. This will be decided site by site based on the 
local clinical infrastructure and practices at each site. At least three staff participants, 
identified prior to study commencement, will be included at each site.  
 
Data will be collected from study staff participants per Table 2. Informed consent will be 
obtained prior to any study assessments for study staff participants (where applicable, as 
determined by local regulatory and compliance requirements).  
 
The total number of staff study participants will be a minimum of approximately 3 per 
site (~n= 54).   
Patient study participant  
Patient study participants are HIV-1-infected adults that fulfil the eligibility criteria. 
Each patient study participant will receive CAB LA + RPV LA and clinical assessments 
throughout the study per the Schedule of Activities (SoA). Data will be collected from 
patient study participants per Table 1.  
 
A goal of this study is to enroll 20% female participants, as this population is often 
underrepresented in clinical studies. 
 
Each site will be asked to recruit enough patient study participants to serve as a 
reasonable number reflective of a real-world situation. This will be based on feasibility 
assessment and site capacity to inform subject recruitment allocation, ensuring a balance 
without compromising study subject safety. This approach will allow sites adequate 
opportunity to describe the challenges and practical limitations experienced during initial 
implementation of CAB LA + RPV LA, as well as opportunity to evaluate the resources 
needed and alternative strategies for successful implementation. 
The enrolment period and rate will be monitored continuously and adjustments to the 
enrolment period and patient distribution may occur based on site feasibility and 
recruitment.    
The maximum number of patient participants included in this study is anticipated to be 
approximately 450. 

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Patient study participants Enrollment:   
All patient study participants will complete the screening phase of up to 35 days prior to 
enrollment.  Participants may be re-screened once. Participants who are enrolled into the 
trial and subsequently withdrawn from the study, for any reason, may not be re-screened. 
Participants may be enrolled as soon as all eligibility requirements have been confirmed 
at the site. Informed consent must be obtained prior to any study procedures for patient 
study participants, including any screening assessment. 
HIV-1 infected participants who meet all eligibility criteria will be switched from their 
pre-baseline regimen to an oral regimen (CAB 30 mg + RPV 25 mg once daily) during 
the oral lead-in phase. Participants will return to the clinic, and if laboratory and clinical 
evaluations continue to support progression into the LA portion of the study, will take the 
last dose of their oral regimen (CAB 30 mg + RPV 25 mg) and receive the first dose of 
CAB LA (600 mg) + RPV LA (900 mg) injections on the same day (Month 1). The 
participant will receive the second injections CAB LA (600 mg) + RPV LA (900 mg) one 
month later (Month 2).   All subsequent injections will occur every two months thereafter 
(Month 4, Month 6, etc).  The total length of the treatment phase is approximately one 
year. 
Note: Patient study participants with  Grade 1 LFTs at screening and or day 1 must be 
discussed with the Medical Monitor prior to initiation of LA dosing; continuation in the 
study or progression onto LA dosing may require additional evaluations, including labs 
drawn after a period of oral dosing with CAB + RPV. 
The dosing window for the second injections will be +0 / -7 days from the projected 
target date (target date is established at Month 1). All subsequent injection windows 
(starting with Dose 3) will be +7/-7 days from the projected target date. Doses outside of 
the window may be allowed with prior Medical Monitor approval. 
Participants will continue CAB LA + RPV LA until:  
• They have completed the study (reached dose 7,  Month 12) and the intervention 
is locally approved and available for the Investigator to prescribe  
• the participant no longer derives clinical benefit 
• the participant meets a protocol-defined reason for discontinuation   
• the development of CAB LA and/or RPV LA is terminated 
• participant withdraws consent 
• participant is withdrawn due to investigator discretion 
• participant is withdrawn due to participant or investigator non-compliance 
• termination of the study by the Sponsor. 
Safety and efficacy assessments will be conducted as per the Schedule of Activities 
(Section 1.3).  
If the intramuscular (IM) dosing regimen is discontinued as a result of an independent 
data monitoring committee (IDMC) review from the ongoing Phase 3 studies, any 
subsequent analysis, or any other programmatic analysis, those participants who have not 

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met any clinical management criteria for discontinuation will be discontinued 
permanently from the study and will enter into the long-term follow-up (LTFU) phase of 
the study. 
Long-Term Follow-up (LTFU) Phase – Following the IM Regimen Only 
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason before CAB LA + RPV LA 
marketed product is locally available must enter the LTFU Phase. Participants must 
remain on suppressive highly active antiretroviral therapy (HAART) for at least 52 weeks 
after the last dose of CAB LA and/or RPV LA in order to prevent selective pressure on 
HIV during the period of declining drug exposures and the potential for selection of 
resistant mutants.  
Where CAB LA + RPV LA marketed product is locally available,  only the participants 
that discontinue the CAB LA + RPV LA regimen for safety-related reasons included in 
Section 7, must enter the LTFU Phase. Participants transitioning to CAB+RPV LA 
marketed product or alternative HAART (except due to safety-related reasons) do not 
need to enter the LTFU Phase.  
Dose Modifications 
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study beyond what is allowed within the 
protocol any necessary modifications approved by the study Medical Monitor. Protocol 
waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements is essential and required for study conduct. 
In exceptional circumstances, and in consultation with the Medical Monitor, investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA.  Should a participant need “oral bridging”, sites 
must contact the Medical Monitor for guidance on treatment strategies prior to a planned 
missed CAB LA + RPV LA dose. Should a participant not notify the site in advance, the 
Medical Monitor must be contacted for further treatment guidance. 
Supplementary study information not mandated in this protocol is provided in the 
accompanying Study Reference Manual (SRM)and Home Visit Handbook for home 
visits if applicable in country.  
Data Monitoring or Other Committee:  No data monitoring committee will be assigned 
to this study as all subjects are receiving the same regimen (open-label) and appropriate 
safety medical and laboratory monitoring is included in the study. 
 

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1.2. 
Schema  
 

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1.3. 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities for Patient Study Participants 
Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm         
 
 
Safety Follow-up 
Visitw 
Long Term 
Follow-upn 
Day 1 
Month 
1 
Month 
2 
Month 
4 
Month 
6 
Month 
8 
Month 10 
b 
Month 12 
b 
Oral 
Lead-
in 
Dose 1   
(D1) 
 
Dose 2 
(D2) 
Dose 3 
(D3) 
Dose 4 
(D4) 
Dose 5 
(D5) 
Dose 6 
(D6) 
Dose 7 
(D7) 
Written Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Verification 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
 
 
 
 
 
 
 
 
 
Xw 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
Current medical conditions   
X 
 
 
 
 
 
 
 
 
 
 
 
Center for Disease Control 
and Prevention (CDC) HIV-
1 Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
Syphilis serology + reflex 
Rapid Plasma Reagin (RPR) 
X 
 
 
 
 
 
 
 
 
 
 
 
Injection site reaction (ISR) 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm         
 
 
Safety Follow-up 
Visitw 
Long Term 
Follow-upn 
Day 1 
Month 
1 
Month 
2 
Month 
4 
Month 
6 
Month 
8 
Month 10 
b 
Month 12 
b 
Oral 
Lead-
in 
Dose 1   
(D1) 
 
Dose 2 
(D2) 
Dose 3 
(D3) 
Dose 4 
(D4) 
Dose 5 
(D5) 
Dose 6 
(D6) 
Dose 7 
(D7) 
Symptom Directed Physical 
Exam and Medical 
Assessmentc  
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
HIV-associated Conditions, 
AE and serious adverse 
event (SAE) Assessmentsd, 
Con Meds 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Vital Signs 
(blood pressure [BP], heart 
rate [HR])e 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Weight, Height & body 
mass index (BMI)f  
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Clinical Chemistry, 
Hematology and other 
Testso 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Xw 
X 
HIV-1 RNA and plasma 
sample for storageh  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
CD4+ count  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 

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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm         
 
 
Safety Follow-up 
Visitw 
Long Term 
Follow-upn 
Day 1 
Month 
1 
Month 
2 
Month 
4 
Month 
6 
Month 
8 
Month 10 
b 
Month 12 
b 
Oral 
Lead-
in 
Dose 1   
(D1) 
 
Dose 2 
(D2) 
Dose 3 
(D3) 
Dose 4 
(D4) 
Dose 5 
(D5) 
Dose 6 
(D6) 
Dose 7 
(D7) 
CD8+ cell count (will be 
reported at Baseline and 
Month 12) 
 
X 
 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis Serologyq 
X 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood PBMCp 
 
X 
 
 
 
 
 
 
 
X 
 
 
Prothrombin time (PT)/ 
partial thromboplastin time 
(PTT)/international 
normalized ratio (INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing  
Urine (U) or Serumg  
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
 
U 
Notification of Interviewt 
 
X 
 
 
 
 
 
 
 
 
 
 
Oral CAB + RPV 
Medication Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
CAB LA + RPV LA IM 
Treatment Administrationi 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
3 5  
 
Pr o ce d ure  
Scree ni n g a  
u p t o 3 5 d  
 
I nter ve nti o n Peri o d ( M o nt h) 
 Wit h dr a w al
m                                      
 
 
 
S afet y F oll o w -u p 
Visit w  
L o n g Ter m  
F oll o w -u p n  
D a y 1  
M o nt h 
1  
M o nt h 
2  
M o nt h 
4  
M o nt h 
6  
M o nt h 
8  
M o nt h 1 0  
b  
M o nt h 1 2
 
b  
Or al 
Le a d -
i n 
D ose 1            
( D 1) 
 
D ose 2 
( D 2) 
D ose 3 
( D 3) 
D ose 4  
( D 4) 
D ose 5  
( D 5) 
D ose 6  
( D 6) 
D ose 7  
( D 7) 
P artici p a nt Visit Re mi n der 
C o nt a ct  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
P artici p a nt C o nt a ct Det ail 
C o nfir m ati o n  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
P atie nt T o ol kit s 
 
X  
X  
X  
X  
X  
 
 
 
Rec or d Visit Le n gt h j 
 
 
X  
X  
 
X  
X  
 
 
 
 
 
C o ntr ace pti o n C o u nseli n g u  
 
 
 
 
 
 
 
 
 
X  
 
X  
H A A R T dis pe ns ati o n v 
 
 
 
 
 
 
 
 
 
X  
 
X  
P atie nt Q uesti o n n aires k  
 
 
X  
 
X  
 
 
 
X  
 
 
 
Selecte d P atie nt I nter vie ws l 
 
X  
 
 
 
 
 
 
X  
 
 
 
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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm         
 
 
Safety Follow-up 
Visitw 
Long Term 
Follow-upn 
Day 1 
Month 
1 
Month 
2 
Month 
4 
Month 
6 
Month 
8 
Month 10 
b 
Month 12 
b 
Oral 
Lead-
in 
Dose 1   
(D1) 
 
Dose 2 
(D2) 
Dose 3 
(D3) 
Dose 4 
(D4) 
Dose 5 
(D5) 
Dose 6 
(D6) 
Dose 7 
(D7) 
Preference Question 
 
 
 
 
 
 
 
 
X 
 
 
 
Review plan to transition to 
commercial product or 
alternative ARTv 
 
 
 
 
 
 
 
 
 
 
X 
 
a) A screening visit will be conducted within 35 days of Day 1.  However, it is preferred for Day 1 to be conducted as soon as practical after all screening results 
are available. 
b) Continue this pattern for visits for the remainder of the study if needed, until CAB LA + RPV LA is locally approved and available. For example, Dose 8 will 
be conducted as per Dose 6, Dose 9 will be conducted as per Dose 7, Dose 10 will be conducted as per Dose 6 and so on. The exception to this pattern is that 
no questionnaires, study visit length collection, or patient interviews will be conducted after Dose 7 visit. Visit after Month 12 will be considered, ‘extension 
phase.’ See Section 6.8. 
c) Physical exams should be conducted as part of normal routine clinical care but data will not be collected in the electronic case report form (eCRF) unless 
abnormalities are observed. Medical assessments include any decisions the study staff must make for participant management. 
d) AE and SAEs will not be proactively assessed at M 2, M 6 and M 10. However, all AEs and SAEs reported by study participants must be recorded in eCRF at 
all visits and reported within required timelines as per Section 8.5.1 . 
e) Measure vital signs after about 5 minutes of rest in a semi-supine position. 
f) 
Height and body mass index (BMI) are collected at screening only. 
g) A (-) urine pregnancy test is required prior to oral lead-in at day 1 and prior to any injection and as required by Medical Monitor after a treatment interruption. 
A (+) urine test should be confirmed with a stat serum test.  If (+), participant will need to be withdrawn. A Serum pregnancy test should be performed at any 
time pregnancy is suspected by the Investigator. Pregnant participants who remain in the study do not need pregnancy testing for the duration of the pregnancy 
see Appendix 15: Information and Guidance for Managing Pregnant Participants. 
h) Plasma for storage samples are collected for possible future analyses. Can be used for back-up in cases of loss/damage in transit, geno/pheno analyses for 
virologic failures. Only for women becoming pregnant and continuing on CAB LA+RPV LA as if pregnant a plasma HIV-1 RNA test and plasma for storage 
samples at Month 6 and Month 10 visits are required. 
i) 
All injections are 1 x CAB LA 600 mg IM + 1 x RPV LA 900 mg IM.  Doses 1 and 2 are one month apart.  Subsequent injections beginning at Dose 3 are 
every two months.  The injections should be spaced approximately 2 cm from one another and from the site of any previous injection and/or any injection site 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
3 7  
 
reacti o n. Bri n g R P V L A t o a p pr o xi matel y r o o m te m perat ure pri or t o i nj ecti n g. Ti me a n d l ocati o n of i nj ecti o n (ri g ht or left) a s well as nee dle le n gt h use d will 
be c ollecte d i n t he e C R F. I M d osi n g is e x pecte d t o occ ur o n t he s a me d ate of  t he m o nt h as deter mi ne d b y I M D ose 1 visit d ate , t his is t he T ar get D ate; 
w here p ossi ble, t his first i njecti o n s h o ul d be perf or me d wit hi n 2 h o urs of t a ki n g t he l a st or al re gi me n d ose.  F or D ose 2, a d osi n g wi n d o w of + 0 / -7 
d a ys f r o m  t he t ar get visit d ate is sti p ul ate d. A ( + or -) 7-d a y wi n d o w f r o m t he t ar get d ate visit is sti p ul ate d f or I M d osi n g be gi n ni n g at D ose  3. All 
decisi o ns re g ar di n g d ose i nterr u pti o n/ res u m pti o n m ust be disc usse d wit h t he M e dic al M o nit or i n a d v a nce.  
j) 
Le n gt h of st u d y visit fr o m arri val u ntil de part ure fr o m cli nic will be e val uate d. P artici pa nt’s t i me of arri val, act ual start ti me of t he a p p oint me nt, a n d 
act ual e n d ti me of  t he a p p oi nt me nt  will be c ollecte d i n t he e C R F. 
k)  Q uesti o n naires s h o ul d be c o m plete d  bef ore  recei vi n g t he i nj ecti o ns.  
l) 
I nter vie ws s h o ul d be c o n d ucte d bef ore t he P S P recei ves D os e 1 a n d wit hi n 4 wee ks of recei vi n g D ose 7.  I nter vie ws ma y be d o ne i n pers o n, virt uall y , or 
b y p h o ne . A mi ni m u m of 6 patie nts per site will be selecte d f or i nter vie ws.    
m)  Wit h dra wal Visit - C o n d uct ~ 4 wee ks after t he last d ose of i n vesti gati o nal pr o d uct (I P) if n ot e nteri n g L o n g -T er m F oll o w U p a n d o nl y if t he partici pa nt 
has o n g oi n g A Es or la b a b n or malities at t he last o n -st u d y visit. If visit is n ot p ossi ble e ns ure a safet y f oll o w-u p visit is c o m plete d.   
n)  P artici pa nts recei vi n g o ne or m ore i nj ecti o ns wit h C A B L A a n d/ or R P V L A will be assess e d wit h cli nic visits at m o nt hs 3, 6, 9  a n d 1 2 d uri n g t he L o n g -
T er m F oll o w -U p p hase. T he start of t he 5 2 -wee k f oll o w -u p peri o d be gi ns t he da y of t he last C A B L A a n d/ or R P V L A d ose.  
o)  See Secti o n 8. 4. 4  f or list of tests  
p)  W h ole bl o o d/ P B M C c ollecti o n sa m ples ma y be use d f or vir ol o gic a nal yses. P B M Cs will be c ollecte d at ba seli ne Da y 1 a n d at Wit h dra wal.  
q)  He p atitis B ( H Bs A g), A nti -H B c, A nti -H Bs A g , He p atitis C (a nti -H C V A b) . A ( +) a nti-H C V A b will b e f oll o we d b y a c o nfir mat or y n ucleic aci d test f or 
H C V R N A. H B V D N A will o nl y be perf or me d f or partici pa nts wit h a ( +) a nti -H B c a n d (-) H Bs A g a n d (-) a nti-H Bs ( past a n d/ or c urre nt e vi de nce).  
r) 
.  
s) At a mi ni m u m t he st u d y t o ol kit will be offere d at t he ti me p oi nte d n ote d i n t he T a ble 6 .  H o we ver, t he t o ol kit ite ms are i nte n de d t o be use d t hr o u g h o ut 
t he stu d y.     
t) 
N otificati o n of i nter vie ws ma y occ ur bet wee n Da y 1 or d uri n g t he 7 da ys after Da y 1.  
u)  W o me n of c hil d beari n g p ote ntial s h o ul d c o nti n ue t o recei ve c o u nselli n g o n t he nee d t o use a de q uate c o ntrace pti o n f or t he e nti ret y of t he L o n g-T er m 
F oll o w -U p p eri o d. 
v)  I n vesti gat ors m ust disc uss c h oice of H A A R T re gi me n a n d ti mi n g of i nitiati o n wit h t he M e dical M o nit or bef ore i nitiati n g.  
w)  Re q uire d w he n a patie nt  st u d y partici pa nt lea ves t he st u d y f oll o wi n g c o m mercial a vaila bilit y of I P, or , if a n o n-site wit h dra wal  visit is n ot p ossi ble  a n d 
t here are o n g oi n g A Es, S A Es relate d a n d n ot relate d t o st u d y dr u g , or  a n y la b orat or y a b n or malities t hat are c o nsi dere d t o be A Es or are p ote ntiall y 
har mf ul t o t he partici pa nt, at t he last o n -st u d y visit. S h o ul d be c o n d ucte d a p pr o xi matel y 2 -4 wee ks after t he last d ose of I P. Ca n be c o m plete d b y 
re m otel y, if a p plica ble a n d tests nee de d t o be d o ne at cli nic ma y n ot be perf or me d. 
 
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Table 2 
Schedule of Assessments Table for Staff Study Participants 
Assessments 
 
 
Time (Months) 
Both 
Arms 
arm- e 
Only 
1a 
2 
3 
4  
5 
6 
7 
8 
9 
10 
11 
12 
Until 
end of 
study 
Informed 
Consentg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire  
X 
 
Xb 
 
 
 
Xc 
 
 
 
 
 
 
Xd 
 
Interviews 
(SSI)   
X 
 
Xb 
 
 
 
Xc 
 
 
 
 
 
 
Xd 
 
CQI Callse  
 
X 
Initial 
SWAT 
Meeting 
and 
Intro to 
CQI 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
SWATf  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FRAME-IS  
   X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CSAT  
X 
 
 
 
 
 
 
 
 
 
        
 
 
X 
 
Provider 
Toolkith 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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a) Month 1 starts at site activation 
b) Questionnaire and interview should be conducted prior to the site’s first patient receiving their first CAB LA + RPV LA injection at that site. 
c) Questionnaire and interview should be conducted within approximately 4 weeks of the site’s first patient receiving their third injection.   
d) Questionnaire and interviews should be conducted within approximately 4 weeks of the site’s first patient receiving their last injection. 
e) Intro to CQI calls will occur within four weeks of site activation. Additional CQI calls will be scheduled if deemed necessary.  
f) Initial SWAT meeting will occur within four weeks of site activation. Additional SWAT meetings with each site will occur as needed throughout the study. 
g)  Informed consent will be obtained prior to any study assessments (where applicable, as determined by local regulatory and compliance requirements). 
h) At a minimum the study toolkit will be offered at the time pointed noted in the Table 6.  However, the toolkit items are intended to be used throughout the 
study.     
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
Cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) is an 
investigational HIV-1 treatment regimen administered as two individual intramuscular 
injections every two months (following an oral lead-in [OLI] period).  
The overall objective of the CAB LA + RPV LA clinical development program is to 
develop a highly effective, well-tolerated, two-drug, long-acting injectable regimen 
which has the potential to offer improved treatment convenience, compliance and 
improved quality of life for people living with HIV (PLHIV) compared to current 
standard of care. 
This new HIV treatment will require changes to the current standard of prescribing oral 
antiretroviral therapies to prescribing and delivering a complete antiretroviral long-acting 
injectable regimen. As this is a new treatment modality, it is important to understand how 
to optimize the delivery of CAB LA + RPV LA from a patient, healthcare provider and 
healthcare system perspective in order to implement into routine care with fewer 
obstacles.  Each country’s healthcare system has its own challenges and nuanced 
differences in the delivery of HIV care. Strategies to support the unique and dynamic 
contexts for CAB LA + RPV LA implementation is key.  As a result, this research study 
will examine different implementation strategies in different clinics settings across 
European countries to identify which strategies best meet the needs in each local context. 
The research in this study will involve both patients receiving the study treatment CAB 
LA + RPV LA (patient study participants, PSP) as well as the healthcare providers at the 
investigator site level (staff study participants, SSP). 
 
For PSPs, the study is single-arm, unblinded and interventional, where all patients who 
fulfil eligibility requirements will be assigned to receive CAB LA + RPV LA and 
complete assessments as per the study protocol. 
For SSPs, the study is two-arm, unblinded, non-interventional and cluster-randomized at 
the country level. Sites within a given country will be randomized to either the Standard 
(Arm-s) or the Enhanced (Arm-e) implementation arm. The two arms will involve the 
provision of overlapping but distinct types of implementation components that are 
designed to assist in the local implementation of the study drug at each site. Arm-s 
represents the traditional provider support by a medical science lead and product 
materials.  Arm-e models a higher level of provider support with added face to face 
meeting, trainings, and additional touchpoints for administration of CAB LA + RPV LA. 
The study will evaluate both qualitative and quantitative measures across arm, clinic type, 
provider type, and country to determine the most effective implementation strategies and 
to identify barriers and facilitators (including solutions). Clinical data will be collected to 
monitor safety and efficacy.   

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2.2. 
Background 
2.2.1. 
Treatment Background 
The treatment of HIV-1 infection has advanced since the first oral antiretroviral agent 
(zidovudine, AZT) was approved for the treatment of HIV-1 infected individuals in 1987. 
Newer antiretrovirals are more potent, better tolerated and have enabled the formulation 
of multiple regimens that can provide viral suppression with a single tablet once daily. 
Moreover, clinic visits for laboratory monitoring have become less frequent; current 
standard of care for virally suppressed patients is a clinic visit with laboratory every 3-6 
months. While there have been major advances in the field of HIV therapeutics, 
tolerability, long term safety concerns and adherence remain significant limitations to 
treatment success. Consistent lifetime daily adherence is difficult for many patients, 
reducing effectiveness of these treatments (DHHS, 2019). Moreover, intermittent 
compliance can result in HIV drug resistance, with subsequent regimens being more 
complicated to construct. 
 
Long-acting injectable versions of drugs are being developed to enable therapy with 
infrequent dosing injection and represent an emerging paradigm for the treatment of HIV 
infection. CAB is a potent integrase inhibitor that possesses attributes that allow 
formulation and delivery as a long-acting product. RPV, also formulated as a LA product, 
is a diarylpyrimidine derivative and a potent non-nucleoside reverse transcriptase 
inhibitor (NNRTI) with in vitro activity against wild type HIV-1 and select NNRTI-
resistant mutants. A two-drug regimen with CAB LA plus RPV LA (CAB LA + RPV 
LA) may offer many potential advantages over daily oral regimens including infrequent 
dosing that decreases the daily reminder to patients of their HIV status, decreased 
development of viral resistance due to intermittent compliance with oral agents and 
overall treatment satisfaction in virologically suppressed patients. Results to date have 
demonstrated the efficacy of a two-drug regimen of CAB LA + RPV LA as maintenance 
therapy with several on-going Phase 2 and 3 studies including LATTE-2, ATLAS, 
FLAIR, and ATLAS 2M [Margolis, 2017].   
 
2.2.2. 
New Treatment Paradigm 
This new HIV treatment will require changes to the current standard of prescribing oral 
antiretroviral therapies to prescribing and delivering a complete antiretroviral long-acting 
injectable regimen. This new treatment paradigm will require more frequent visits by 
patients to see a provider and receive injections, as well as potentially require greater 
resources in the clinical setting to administer the injection. As this is a new treatment 
modality for people living with HIV (PLHIV), it is important to understand how to 
optimize the delivery of CAB LA + RPV LA from the perspective of PLHIV, health care 
providers (HCP) and the healthcare system. Without a plan that meets the needs of all 
three of these groups, the implementation of CAB LA + RPV LA may be hindered. 
Concerns raised about chronic dosing injections include overburdening the health-care 
system.  Additionally, there are concerns that patients will miss scheduled injections also 
resulting in a fear of inadequate antiretroviral therapy coverage. 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
4 2  
 
T he nee d f or pra g matic d at a is esse ntial t o f ull y u n dersta n d t he barriers a n d facilitat ors 
f or deli ver y of t his treat me nt. T he effecti ve n ess of C A B L A  + R P V L A has bee n 
d oc u me nte d i n se veral P hase 2 b st u dies wit h se veral lar ger P hase 3 st u dies ( A T L A S, 
A T L A S -2 M a n d F L AI R) a n d res ulte d i n p ositi ve patie nt -le vel o utc o mes.  It is critical t o 
u n dersta n d h o w  t o effecti vel y i m ple me nt t his treat me nt t o e ns ure o pti mal i m pact o n 
healt hcare ser vi ce s yste m - a n d patie nt -le vel o utc o mes. U nf ort u natel y,  5 0 % of effecti ve 
i nter ve nti o ns d o n ot ma ke it i nt o r o uti ne care , n ot  as a res ult of lac k of effecti ve ness, b ut 
rat her a lac k of u n d ersta n di n g of t he c o nte xt ual fact ors t hat ma ke u pta ke c halle n gi n g 
(Ba u er , 2 0 1 9).   
 
(Ba u er , 2 0 1 9).   
I m ple me nt ati o n scie nce has bee n de pl o ye d acr oss n u mer o us c o nte xts, i ncl u di n g t he area 
of l o n g -acti n g i njecta ble a nti ps yc h otics f or t he treat me nt of sc hiz o p hre nia ( Kis hi m ot o , 
2 0 1 3).  T he use of a l o n g -acti n g a nti ps yc h otic i njecta ble me dicati o n was a si g nifica nt 
para di g m s hift wit hi n t he ps yc hiatric c o m m u nit y a n d re q uire d w or k t o a d dress b ot h 
or ga niz ati o nal a n d at tit u di nal barriers b y p h ysici a ns i n cli nical practice. I m ple me ntati o n 
researc h be ga n i n t his area t o u n dersta n d t he b arriers nee de d t o o v erc o me a n d s u p p ort t he 
use of t he l o n g -acti n g i nj ecta ble, b ut o nl y aft er i de ntif yi n g si g nifi ca nt diffic ulties i n 
u pta ke . T he la g b et wee n t he a vaila bilit y of t his i njecta ble a n d t he use of i m ple me ntati o n 
researc h hi n dere d t he rat e of a d o pti o n a n d reac h of t his i n n o vati ve treat me nt.  E x a m ples 
w here i m ple me ntati o n scie nce has b ee n use d t o i m pr o ve a vaila bilit y of e vi de nce -b ase d 
treat me nt i n r o uti ne care i ncl u des a ra n ge of fi el ds i ncl u di n g H P V vacci nati o n, ca ncer 
care, pri mar y care wei g ht ma na ge me nt, a n d ps yc h ot hera p y ( S oi , 2 0 1 9; Lee ma n , 2 0 1 9; 
S mit h , 2 0 1 8; Tri plett , 2 0 2 0). 
Wit hi n HI V, i m ple me ntati o n scie nce has la g ge d b e hi n d ot her fiel ds.  T he l o w u pta ke of 
pre -e x p os ure pr o p h yl a xis ( Pr E P) is a pri me e x a m ple w here i m ple me nt ati o n scie nce c o ul d 
ha ve s u p p orte d a greater u pta ke i n t he real w orl d gi ve n t he si g nifica nt ga p bet wee n t he 
n u m ber of pe o ple rec o m me n de d f or Pr E P a n d t he act ual n u m ber rece i vi n g it ( hi v. g o v; 
Part ners Scale -u p Ref).  T he la g ti me bet wee n a v aila bilit y of a n i n n o vati o n, i de ntificati o n 
of barriers t o tra nslati o n i nt o t he real w orl d t hr o u g h i m ple me ntati o n researc h, a n d t he use 
of i m ple me ntati o n strate gies ca n i m pact t he rate at w hic h t he HI V e pi de mic ca n b e 
e n de d.  I m ple me ntati o n s cie nce ca n h el p ma xi mize t he i m pact of a n i n n o v ati o n w he n 
use d pr oacti vel y i n e arl y sta ges of i nter ve nti o n de vel o p me nt a n d a vaila bilit y.   
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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This study is the first of its kind to examine the use of CAB LA + RPV LA by both 
healthcare professionals and patients in different clinical care settings in Europe.  
Incorporating implementation research into CAB LA + RPV LA across Europe will 
increase the impact of the treatment at a population level.  Data in implementation 
science and CAB LA + RPV LA is in its infancy.  While CUSTOMIZE (209493) is an 
ongoing initial implementation study of CAB LA + RPV LA, results remain forthcoming 
and only focused on sites in the United States.  
 
Clinical care is a dynamic environment with multiple factors impacting an interventions’ 
success or failure.  The proposed approach in this study allows for each site to operate as 
close to routine care as possible while helping address barriers, supporting facilitators of, 
and implementation of CAB LA + RPV LA. Barriers are any perceived factors that 
obstruct a site from successfully implementing CAB LA + RPV LA.  For example, this 
might include availability of clinical staff to accommodate additional appointments, lack 
of injection training or patient education and support.  Facilitators are any perceived 
factors that enable successful implementation of CAB LA + RPV LA.  Examples of 
facilitators include existing systems for cold chain storage, previous injector experience 
with intramuscular injections, and existing patient support applications or communication 
channels to assist in adherence and education.  Despite different overarching components 
that define the arm-e and arm-s, both strategies leverage existing facilitators and aim to 
overcome barriers to successful implementation of CAB LA + RPV LA.   
 
Additional examples of implementation strategies at a country level to address identified 
barriers in the arm-e may be found in a supplemental implementation science handbook.  
 
2.3. 
Benefit/Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with oral 
and CAB LA or RPV LA can be found in the current Investigator’s Brochures. 
Oral RPV is an approved medicinal product and detailed information on its benefit/risk 
profile together with any risk mitigation measures are described in product labelling. 
(Current Edurant Prescribing Information) 
 
2.3.1. 
Oral CAB and CAB LA (GSK1265744/GSK1265744 LA) 
Since CAB Exposure in humans with and without HIV infection is limited, the clinical 
safety profile in humans has yet to be fully elucidated.  The following risks have 
primarily been identified during routine preclinical testing and/or from the clinical trial 
experience to date and are considered of potential relevance to clinical usage in the 
context of this protocol. Additional information about the clinical experience to date and 
possible risks associated with treatment using CAB can be found in the Summary of Data 
and Guidance for the Investigator section of the investigator’s brochure (IB). 

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Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
Drug Induced Liver 
Injury (DILI) 
Less than 1% of participants in the CAB program to date have 
developed transaminitis (elevated liver transaminases 
characterized by predominant alanine aminotransferase (ALT) 
elevation).  In most participants, transient transaminitis was 
explained by acute hepatitis C infection (majority) and other 
systemic infections.  In a small number of participants, there was 
not an alternative explanation, suggesting a mild form of drug 
induced liver injury (DILI) without hepatic dysfunction, which 
resolved upon withdrawal of treatment with CAB.  
 
Exclusion criteria as described in Section 5.2 will prohibit 
participation of PLHIV who have significant liver impairment 
based on screening liver chemistry including transaminases 
(ALT and aspartate aminotransferase [AST]) as well on prior 
medical history. Participants with a history of chronic liver 
disease with ongoing inflammation and/or fibrosis will have 
additional confirmatory assessments to confirm suitability for 
entry into the study.  
 
Liver transaminases (ALT and AST) will be monitored 
throughout this study and the liver chemistry stopping criteria 
will be adopted as described in Section 7.1, Section 10.6.2, 
and Section 10.6.5 of this protocol. Participants will be 
withdrawn from CAB treatment where no compelling 
alternative cause is identified and DILI is suspected. 
Injection Site 
Reactions (ISRs) 
Clinical experience to date has demonstrated ISRs occur in the 
majority of exposed participants treated with CAB LA but are 
generally mild (Grade 1) or moderate (Grade 2) and include 
events of pain, tenderness, erythema, or nodule formation of 
several days duration (median duration for individual events <1 
week). 
ISRs may occur more than once in an individual participant 
receiving multiple injections. Although some Grade 3 ISRs have 
Administration advice will be given to minimize risk of poor 
administration technique giving rise to injection site reactions. 
Advice on care, monitoring, natural course, and treatment of 
ISRs is given in study documentation.  
 
Advice will be given to participants on care of injection site 
on day/days immediately post administration, use of 
analgesia, compresses where appropriate. 
 

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been reported, overall ISRs appear tolerable and have not to date 
been associated with an excess of participants’ withdrawal. 
Participants will be closely monitored for ISRs particularly for 
signs of pain, tenderness, infections, erythema, swelling, 
induration, or nodules (granulomas or cysts) throughout the 
study.  
 
 
Complications of ISRs such as infections (abscess, cellulitis) 
and collections of fluid requiring drainage will be monitored  
Significant ISRs may be photographed and referred to a 
dermatologist for specialist advice. 
 
Hypersensitivity 
Reactions (HSR) 
Hypersensitivity reactions have been reported as uncommon 
occurrences with integrase inhibitors (INI), including the closely 
related compound dolutegravir, and were characterized by rash, 
constitutional findings, and sometimes, organ dysfunction, 
including liver injury.  
While there have been no clinical cases of hypersensitivity to 
CAB to date, there is a theoretical risk of systemic or severe 
hypersensitivity reactions with or without hepatic symptoms 
associated with use of IM CAB. The long exposures anticipated 
after IM CAB injection may complicate the management of a 
drug hypersensitivity reaction, were it to occur. 
The risk of developing a hypersensitivity reaction post 
administration of IM CAB will be minimized by the use of a 
4-week oral lead-in of oral CAB to determine individual 
safety and tolerability prior to the introduction of IM CAB.  
 
Clinical assessments, laboratory tests (including liver 
transaminases) and vital signs will be performed throughout 
this study. Results from these assessments may aid early 
detection of HSR.  
 
Oral CAB will be withdrawn immediately for cases with 
suspected HSR during the oral CAB lead-in phase and would 
not proceed to the injection phase. Participants receiving the 
injection who develop suspected HSR would not receive 
further injections. During oral (oral bridge) and IM CAB 
treatment, any HSR reactions that occur would be managed 
supportively. 

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Effects in pregnancy 
seen in nonclinical 
studies 
In animal reproduction studies, CAB when administered to rats at 
> 30 times the systemic exposure at the maximum recommended 
oral human dose (MRHD) of 30 mg during organogenesis through 
delivery, had adverse effects on labor and delivery that may be 
related to a delay in the onset of parturition, resulting in increased 
fetal mortality (stillbirths) and neonatal deaths immediately after 
birth. 
A delay in the onset of parturition, increased stillbirths and 
neonatal deaths were observed in a rat pre- and postnatal 
development study at greater than 28 times the exposure at the 
recommended human dose (RHD). No evidence of adverse 
developmental outcomes was observed with oral cabotegravir in 
rats or rabbits (greater than 28 times or similar to the exposure at 
the RHD, respectively) given during organogenesis. 
The clinical significance of these finding in humans is unknown.  
For pregnant participants remaining in the study, refer to 
Appendix 15 for additional data regarding CAB and pregnancy.  
Female participants on LA dosing who become pregnant will 
have exposures throughout pregnancy due to the long half-life 
and PK tail of CAB/RPV. Pregnant participants who are 
withdrawn from study and are initiated on an alternative oral 
ART regimen consisting of either 2 or 3 antiretrovirals to protect 
the life of the mother and for the prevention of MTCT, 
potentially expose the fetus to additional ARVs during gestation 
(in some cases upwards of 5 antiretrovirals). 
• 
Pregnant females are excluded from enrollment in this 
study and women of childbearing potential (WOCBP) 
are required to adopt highly reliable means of 
contraception during participation, and throughout the 
long term follow up phase of this study following 
exposure to CAB LA. 
 
• 
WOCBP are also required to undergo regular pregnancy 
testing throughout study conduct. Pregnant participants 
who remain in the study do not need pregnancy testing 
for the duration of the pregnancy 
 
• 
Participants who become pregnant during the study may 
remain in the study provided all protocol defined 
pregnancy related assessments, procedures and 
documentation are completed, and a pregnancy specific 
ICF addendum is signed by the participant. Details 
regarding management of pregnant participants are 
found in Appendix 15  
 
 
Potential effects in 
women exposed to 
dolutegravir during 
A preliminary analysis of an ongoing birth outcome surveillance 
study in Botswana involving women exposed to dolutegravir 
(DTG), a different molecule in the same integrase class of 
• 
Pregnant females are excluded from enrollment in 
clinical trials of CAB at this time and women of 
childbearing potential (WOCBP) are required to adopt 

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conception and early 
pregnancy 
medications as CAB, identified four cases (as of May 2018) of 
neural tube defects in 426 infants born to mothers who were 
exposed to DTG-containing regimens from the time of conception. 
In the same study, no infant born to a woman who started DTG 
during pregnancy had a neural tube defect, out of 2,824 women. A 
causal relationship of these events to the use of DTG 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 fetal development (at 
which time the neural tubes are sealed) this potential risk would 
concern women exposed to DTG at the time of conception and in 
early pregnancy. Recently updated data (April 2020) for this birth 
outcome study showed that among women who were on DTG 
when they became pregnant, 7/3591 neural tube defects (NTD) 
occurred (0.19%). In comparison, NTDs were identified in 
21/19,361 (0.11%) women delivering on any non-DTG 
antiretrovirals. There was not a significant difference in the 
number of neural tube defects between births to women taking 
DTG and those taking other non-DTG antiretroviral treatments 
(0.09% difference). 
The clinical relevance of either of these findings in relation to 
CAB use is unknown  
 
highly reliable means of contraception during 
participation and throughout long term follow up phases 
of studies after exposure to CAB LA. 
• 
WOCBP also undergo regular pregnancy testing 
throughout study conduct. Pregnant participants who 
remain in the study do not need pregnancy testing for 
the duration of the pregnancy. It should be noted that 
CAB concentration could remain for prolonged periods 
despite discontinuation of CAB LA 
• 
Participants who become pregnant during the study may 
remain in the study, provided all protocol defined 
pregnancy related assessments, procedures and 
documentation are completed and a pregnancy specific 
ICF addendum is signed by the participant. Details 
regarding management of pregnant participants is found 
in Appendix 15. 
 

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Development of 
Resistance following 
discontinuation of 
CAB LA 
Residual concentrations of CAB would remain in the systemic 
circulation of participants who stop CAB LA treatment for 
prolonged periods (more than 1 year, in some participants after 
last injection (e.g., for tolerability issues or treatment failure). 
Participants discontinuing CAB LA regimen may be at risk for 
developing HIV-1 resistance to CAB many weeks after 
discontinuing injectable therapy. 
After participants stop CAB LA, oral highly active antiretroviral 
therapy (HAART) regimens will be prescribed within 1 month 
(-7 days) after the last Q1M dose or within  2 months (7 days) 
after the last Q2M dose, and following consultation with the 
Medical Monitor. This would be anticipated to result in 
continued suppression or rapid re-suppression of HIV-1 RNA 
thus minimizing the risk of emergent resistance.  
 
The Sponsor will continue to monitor participants in this study 
who discontinue the LA regimen prior to local availability of 
CAB LA+ RPV LA for a minimum of 52 weeks from the time 
of the last LA administration. Post- commercial local 
availability, the Sponsor will continue to monitor participants in 
this study who prematurely discontinue a LA regimen for safety 
reasons for a minimum of 52 weeks from the time of the last LA 
administration. 
 
 
 
Drug-Drug Interactions 
(DDIs) 
For a complete listing of permitted and prohibited concurrent 
medications for CAB and CAB LA, refer to Section 6.6 
CAB and CAB LA should not be co-administered with the 
following medicinal products, as significant decreases in CAB 
plasma concentrations may occur (due to UDP-
glucuronosyltransferase (UGT) enzyme induction), which may 
result in loss of therapeutic effect of CAB. 
- the anticonvulsants carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin 
All participants will be informed of prohibited medications 
throughout the study and updates provided as needed via the 
informed consent. 

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- the antimycobacterials rifampicin, rifapentine, rifabutin 
- St John’s wort (Hypericum perforatum) 
Oral CAB administration only:  Antacid products containing 
divalent cations (e.g., aluminum, calcium, and magnesium) must 
be taken at least 2 hours before or at least 4 hours after CAB.  
Participants discontinuing a LA regimen may be at risk for 
developing drug-drug interactions (DDIs) many weeks after 
discontinuing injectable therapy.   
Inadvertent 
intravenous injection 
(accidental 
maladministration) 
As with any intramuscular injection, it is possible that CAB LA 
can be inadvertently administered intravenously instead of 
intramuscularly possibly resulting in higher than expected 
concentrations of CAB shortly after injection and lower 
concentrations thereafter.  This could be due to administrator 
error, improper injection technique and / or improper needle 
length used based on body type.     
The clinical consequences of overdose with CAB LA are currently 
unknown.  HIV-1 viral suppression may not be effective following 
accidental maladministration. 
 
Training will be provided to all sites on proper injection 
technique.   
 
Should IM maladministration be suspected at any time (e.g. 
suspected under or overdose or inadvertent IV dosing), a post 
dose electrocardiogram (ECG), vital signs, or any other 
supportive testing may be obtained at the discretion of the 
investigator, and the Medical Monitor will be notified.   
Laboratory samples for safety parameters and HIV-1 RNA will 
be closely monitored in all participants.  Additionally, an 
unscheduled PK sample may be drawn approximately 2 hours 
post dosing for future evaluation of CAB concentrations. 

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2.3.2. 
Oral RPV and RPV LA (GSK1265744/GSK1265744 LA) 
ORAL RPV 
For safety and risk mitigation for oral RPV refer to the RPV local prescribing information 
[Current Edurant Prescribing Information] 
RPV LA 
Information about the clinical experience to date and possible risks associated with 
treatment using RPV LA can be found in the Summary of Data and Guidance for the 
Investigator section of the IB. Systemic reactions following RPV LA injections have 
been observed in clinical trials. These occur infrequently (in less than 0.5% of 
participants) and typically begin to resolve within minutes of the injection, some 
participants have required supportive care. Where timely PK data has been available, 
high RPV PK plasma concentrations have been observed which may have resulted from 
an accidental partial IV injection of RPV. Refer to study protocols for instructions on 
injection administration.  The following risks are considered to be of specific clinical 
relevance in the context of IM use. 

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Injection Site Reactions 
Clinical, experience to date has demonstrated ISRs occur in the 
majority of exposed participants treated with RPV LA but are 
generally mild (Grade 1) or moderate (Grade 2) and include events 
of pain, tenderness, erythema, or nodule formation of several days 
duration (median duration for individual events <1 week). ISRs may 
occur more than once in an individual participant receiving multiple 
injections. Although some Grade 3 ISRs were reported, overall ISRs 
have been well tolerated and have not to date been associated with 
an excess of participants’ withdrawal due to ISRs. 
None of the ISRs was serious and no clinical significant 
complications were reported 
Administration advice to minimize risk of poor administration 
technique giving rise to injection site reactions. Advice on care, 
monitoring, natural course, and treatment of ISRs given in study 
documentation.  
Advice to participants on care of injection site on day/days immediate
post administration, use of analgesia, compresses where appropriate. 
Participants will be closely monitored for ISRs particularly for 
signs of pain, tenderness, infections, erythema, swelling, 
induration, or nodules (granulomas or cysts) throughout the study.  
Complications of ISRs such as infections (abscess, cellulitis) and 
collections of fluid requiring drainage will be monitored  
Significant ISRs may be photographed and referred to a 
dermatologist for specialist advice. 

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Rash 
Some observations of rash with oral RPV have been reported in 
clinical studies executed to date (the majority are mild).  
 
Participants with a Grade 1 or 2 rash will be allowed to continue 
treatment, depending on the clinical judgment of the investigator. 
All participants experiencing a Grade 3 or 4 rash should discontinue 
their antiretroviral (ARV) medication (study medication and 
background regimen) and be withdrawn from the study. 
All rash events should be assessed with special attention to 
systemic symptoms, laboratory abnormalities, or mucosal 
involvement. Close clinical follow-up, including follow-up of 
laboratory abnormalities, and appropriate medical intervention, 
including referral to dermatologist as appropriate, should be 
instituted for these events; daily follow-up is recommended for 5 
days from the onset of the event to monitor for progression of the 
event. See Section 10.6.5.10 for additional guidance on 
management of rash. 
Development of 
Resistance 
Residual concentrations of RPV LA can remain in the systemic 
circulation of participants who stopped treatment (e.g., for 
tolerability issues or treatment failure) for prolonged periods 
(months to more than a year, in some participants) 
Participants discontinuing a LA regimen may be at risk for 
developing resistance to RPV many weeks after discontinuing 
injectable therapy. 
After participants stop RPV LA, Oral HAART regimens will be 
prescribed within one month (- 7 days)  after the last dose if 
interruption is prior to Dose 2 and within 2 months ( 7days)  after 
the last injection if interruption is following Dose 2, and following 
consultation with the medical monitor. This would be anticipated to 
result in continued suppression or rapid re-suppression of HIV-1 
RNA thus minimizing the risk of emergent resistance.  
The Sponsor will continue to monitor participants in this study who 
discontinue the LA regimen prior to local availability of CAB LA+ 
RPV LA for a minimum of 52 weeks from the time of the last LA 
administration. Post- commercial local availability, the Sponsor 
will continue to monitor participants in this study who prematurely 
discontinue a LA regimen for safety reasons for a minimum of 52 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Drug-Drug Interactions 
(DDIs) 
For a complete listing of permitted and prohibited concurrent 
medications for RPV and RPV LA, refer to Section 6.6. 
RPV LA should not be co-administered with the following 
medicinal products, as significant decreases in RPV plasma 
concentrations may occur (due to CYP3A enzyme induction), which 
may result in loss of therapeutic effect of RPV LA. 
- 
the anticonvulsants carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin 
- 
the antimycobacterials rifampicin, rifapentine, rifabutin 
- 
the glucocorticoid systemic dexamethasone, except as a 
single dose treatment 
- 
St John’s wort (Hypericum perforatum). 
Of note, evidence to date indicates that clinically relevant DDIs with 
RPV LA and other antiretrovirals are unlikely to occur.  
Oral RPV administration only:   
-Antacid products containing divalent cations (e.g., aluminum, 
calcium, and magnesium) must be taken at least 2 hours before or at 
least 4 hours after RPV. 
-H2-antagonists must be taken at least 12 hours before or at least 4 
hours after taking RPV. 
-RPV should not be co-administered with proton pump inhibitors, 
such as esomeprazole, lansoprazole, omeprazole, pantoprazole, 
rabeprazole; 
All participants will be informed of prohibited medications 
throughout the study and updates provided as needed via informed 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Participants discontinuing a LA regimen may be at risk for 
developing DDIs many weeks after discontinuing injectable therapy. 
Inadvertent Intravenous  
Injection (Accidental  
Maladministration) 
As with any intramuscular injection, it is possible that RPV LA can 
be inadvertently administered intravenously instead of 
intramuscularly possibly resulting in higher than expected 
concentrations of RPV shortly after injection and lower 
concentrations thereafter. This could be due to administrator error, 
improper injection technique and / or improper needle length used 
based on body type.   
In addition, HIV-1 viral suppression may not be effective following 
accidental intravenous maladministration. 
Training will be provided to all sites on proper injection technique. 
 
Should IM maladministration be suspected at any time (e.g., 
suspected under or overdose or inadvertent intravenous [IV] 
dosing), post dose ECG monitoring and vital signs or any other 
supportive testing may be obtained at the discretion of the 
Investigator, and the medical monitor notified. 
 
Laboratory samples for safety parameters and HIV-1 RNA will be 
closely monitored in all participants.  Additionally, an unscheduled 
PK sample may be drawn approximately 2 hours post dosing for 
future evaluation of RPV concentrations.   
Overall Study Related Risks 
Venipuncture 
Participants will be required to have blood samples taken. Risk of 
bruising, and rarely, infection 
Trained personnel will perform venipuncture 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Risk of Treatment 
Failure 
This study employs a novel 2 drug LA ART treatment regimen 
dosed Q8W for the treatment of HIV-1 infection recently approved 
EU and under review in other countries. Both IM CAB and RPV 
have demonstrated antiviral activity in large clinical studies and the 
two-drug combination dosed Q4W has demonstrated sustained 
antiviral activity in studies 200056, 201584 and 201585 and in 
studies (200056 and 207966) when dosed Q8W. 
 
Doses of the CAB LA and RPV LA have been selected to achieve 
exposures that are expected to maintain virologic efficacy on the 
basis of available data with the oral and LA formulations. 
Due to administration error, it is possible that a participant could 
receive an inadequate dose of CAB LA or RPV LA. Sub-therapeutic 
concentrations of either CAB LA or RPV LA could lead to virologic 
failure and possibly the development of viral resistance. 
Viral loads and CD4+ cell counts will be closely monitored 
throughout the study (treatment and extension phases), allowing 
for early detection of failing treatment. Where confirmed 
virological failure occurs, participants would be discontinued from 
study drugs and transferred to an oral HAART regimen. 
 
 

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2.3.2.1. 
Other Clinically Relevant Information 
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochures. Refer to ‘Summary of data and guidance 
for the Investigator’. 
Seizure 
Several cases of seizure have occurred during the cabotegravir program. These cases 
have had alternative explanations for their occurrence. Overall, there is not convincing 
evidence that cabotegravir exposure may be causally associated with seizure or with 
reduction of seizure threshold, due to the low frequency of reports, the confounders 
present in the cases received to date and lack of any pre-clinical signal or identified 
plausible mechanism. However, seizure and seizure-like events are considered as AEs of 
special interest for CAB. Subjects with an unstable or poorly controlled seizure disorder 
will be excluded from study participation. Site should report any cases of seizure or 
seizure like events immediately. 
2.3.3. 
Benefit Assessment 
The antiviral activity against HIV-1 of CAB has been well established through in vitro 
and clinical studies. RPV is an established antiviral agent against HIV-1 in treatment 
naive participants, with long term durability (>96 weeks in Phase 3 and >240 weeks in 
Phase IIb). 
Participants receiving CAB LA + RPV LA are anticipated to benefit from maintenance of 
virological suppression using LA agents and will not take concomitant daily oral 
antiretroviral therapy. Adherence in these participants is expected to be improved and 
will be directly observed during IM injections. Efficacy of this two-drug regimen, as IM 
agents administered Q2M (every two months), has been demonstrated through  
Week 256 of the ongoing LATTE-2 (200056) study (ID Week, 2020)) and through Week 
96 of the ATLAS 2M (207966) study (CROI, 2021). 
2.3.4. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with the CAB LA and RPV LA 
regimen and the study are justified by the anticipated benefits that may be afforded to 
virologically suppressed, treatment-experienced participants with HIV-1 infection. 
The questionnaires, interviews, and additional implementation activities to be 
administered to clinical staff and study participants are not associated with additional 
risk. 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary  
Staff Study Participants (SSP): 
To evaluate 
 
• acceptability  
• appropriateness 
• feasibility  
 
Quantitative 
Change of Acceptability of Implementation 
Measure (AIM) Score, Implementation 
Appropriateness Measure (IAM) Score, Feasibility 
of Implementation Measure (FIM) Score over time 
assessed quantitatively via questionnaires through 
Month 12.a 
 
Qualitative  
Semi-structured interviews (SSI) assessed 
qualitatively through Month 12. 
 
Secondary 
 
Staff Study Participants: To 
evaluate 
 
• Facilitators to 
implementation 
• Barriers to 
implementation 
• Adaptations/Modifications 
to address barriers and 
facilitators 
 
 
Quantitative: 
Change of Implementation Leadership Scale 
(ILS), Change of Implementation Climate Scale 
(ICS) over time assessed quantitatively via 
questionnaires through Month 12.a 
 
Summarize components from Enhanced 
Implementation & Standard Implementation: 
• FRAME-IS outcome Months 2 – 12 
(monthly) 
 
Summarize components from Enhanced 
Implementation: 
• CQI 1-hour calls/PDSAs minimum of 
Months 2-7 (monthly) 
 
Qualitative  
SSIs assessed qualitatively through Month 12. 
Patient Study Participants 
(PSP) To evaluate 
 
• Facilitators to 
implementation 
• Barriers to 
Implementation 
 
Quantitative: 
Questionnaires assessed quantitatively through 
Dose 7.b 
 
Length of patient study participant visit from 
arrival until departure from clinic assessed at Dose 
1, Dose 2, Dose 4, and Dose 5. 
 
Qualitative  
SSIs assessed qualitatively through Dose 7. 
 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
5 8  
 
O bjecti ves  
E n d p oi nts  
T o e val uate P atie nt St u d y 
P artici p a nts  e x perie nce of 
deli veri n g C A B L A + R P V L A, 
i ncl u di n g 
•  Acce pt a bilit y  
•  A p pr o priate n ess  
•  Feasi bilit y     
Q ua ntitati ve  
C ha n ge i n Acce pta bilit y of I nter ve nti o n Meas ure 
( AI M) Sc ore, I nter ve nti o n A p pr o priate ness 
Meas ure (I A M) Sc ore, a n d Feasi bilit y of 
I nter ve nti o n Meas ure ( FI M) Sc ore o ver ti me. 
Assesse d via q uesti o n naires at D ose 7.  b 
 
Q ualitati ve  
S SIs assesse d q u alitati vel y t hr o u g h D os e 7.  
 
T o e v al uate s ustai na bilit y of C A B 
L A + R P V L A wit h St u d y St aff 
P artici p a nts  eac h cli nic  
 
T otal sc ore of t h e Cli nical S ustai na bilit y 
Assess me nt T o ol ( C S A T) at M o nt h 1 2.  
T o assess fi delit y t o C A B L A +  
R P V L A i njecti o n d osi n g 
wi n d o ws  
Perce nta ge of i njecti o ns occ u rri n g wit hi n tar get 
wi n d o w fr o m t he tar get date.  
E val uate efficac y a n d safet y 
meas ures of C A B L A + R P V L A  
Pr o p orti o n of partici pa nts wit h plas ma HI V -1 
R N A < 5 0 c/ m L o ver ti m e .  
Pr o p orti o n of partici pa nts wit h c o nfir me d 
vir ol o gic fail ure ( C V F) o ver ti me  
I n ci de nce of treat me nt-e mer ge nt ge n ot y pic a n d 
p he n ot y pic resista nce t o C A B a n d R P V i n patie nt 
st u d y partici p a nts wit h C V F 
I n ci de nce a n d se v erit y of A Es, S A Es a n d 
pr o p orti o n of partici pa nts w h o disc o nti n ue 
treat me nt d ue t o A Es o ver ti me 
T o assess prefere nc e b et wee n 
C A B L A + R P V L A a n d oral 
A R T me dicati o n recei ve d pri or t o 
e nteri n g t he st u d y 
Prefere nce b et wee n C A B + R P V L A a n d dail y 
oral A R T me dicati o n (recei ve d pri or t o e nteri n g 
t he st u d y) q ua ntitati vel y assesse d via prefere nce 
q uesti o n naire at D ose 7  
Tert i ar y 
 
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
5 9  
 
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 3 1 9 9 ( C a b ot e gra vir A n d R il pi viri ne Im ple me ntati o n St u d y  i n E ur o pea n 
L ocati o ns  -C A RI S E L) is a cl uster ra n d o mize d, t w o-ar m, o pe n-l a bel, h y bri d 
effecti ve ness -i m ple me nt ati o n st u d y desi g ne d t o e val uate t w o i m ple me ntati o n strate g y 
c o n diti o ns ( E n ha nce d  [ Ar m-e]  vs Sta n dar d  [ Ar m-s]) i n vari o us cli nical setti n gs acr oss 
fi ve E ur o pea n c o u ntries.   
T his st u d y is a n e val u ati o n of  i m ple me ntati o n strate gi es o n t he de gree of acce pta bilit y, 
a p pr o priate n ess, feasi bilit y, fi delit y, a n d s ustai na bilit y of cli nic practices t o deli ver t he 
C A B  L A +  R P V L A re gi me n. T he st u d y will use a n i m ple me ntati o n scie nce a p pr oac h t o 
u n dersta n d t he barrie rs a n d facilitat ors f or b ot h patie nts a n d pr o vi ders, i ncl u di n g best 
practices f or deli veri n g C A B L A + R P V L A wit hi n a n i nter ve nti o nal cli nical trial w here 
t he C A B L A  + R P V L A re gi me n is deli vere d t o HI V -1 -i nf ecte d, vir ol o gicall y-s u p presse d 
a d ult patie nts.  
All patie nts w h o f ulfill eli gi bilit y re q uire me nts will recei ve t h e st u d y tr eat m e nt of C A B 
L A + R P V L A a n d will b e gi n or al t hera p y wit h C A B 3 0 m g + R P V 2 5 m g o nce dail y f or 
a p pr o xi matel y o ne m o nt h t o deter mi ne i n di vi d ual safet y a n d t olera bilit y pri or t o 
recei vi n g C A B L A + R P V L A  f or a n a d diti o nal 1 1 m o nt hs.  T otal patie nt st u d y 
partici pa nt d urati o n i n t he st u d y is a p pr o xi matel y 1 3 m o nt hs i ncl u di n g scree ni n g.   
 
Patie nt p artici pa nts i n C A RI S E L w h o s u ccessf ull y c o m plet e t he st u d y ( D ose 7), wit h o ut 
meeti n g st u d y -d efi ne d wit h dra wal criteria, will be gi ve n t he o pti o n t o c o nti n ue t o recei ve 
C A B L A + R P V L A, a d mi nistere d Q 2 M i n t he E xte nsi o n P hase u ntil t he st u d y treat me nt 
is eit her l ocall y a p pr o ve d a n d c o m merci all y a vaila ble (i ncl u di n g t hr o u g h l o cal 
p u blic/ g o ver n m e nt healt h sect ors), t he partici pa nt n o l o n ger deri ves cli nical be nefit, t he 
partici pa nt meets a pr ot oc ol -defi ne d reas o n f or disc o nti n uati o n or u ntil de vel o p me nt of 
eit her C A B L A + R P V L A Q 2 M is ter mi nate d. Alter nati vel y, partici pa nts ca n c h o ose t o  
c o m plete st u d y p artici pati o n a n d e nter t he 5 2-wee k L T F U p has e of t he st u d y.  
 
A n y p artici pa nt w h o recei ves at least o ne d ose of C A B L A a n d/ or R P V L A a n d  
disc o nti n ues t he C A B L A + R P V L A re gi me n f or a n y reas o n  bef ore C A B  L A + R P V L A  
mar kete d pr o d u ct  is l ocall y a v aila ble m ust  e nter t h e 5 2 -wee k L T F U  
P hase. W here t he C A B L A + R P V L A m ar ket e d pr o d uct is l ocall y a v aila ble, o nl y t he 
partici pa nts t hat disc o nti n ue t he C A B L A + R P V L A re gi me n f or safet y -relate d reas o ns 
C CI

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must enter the 52-week LTFU Phase. Those participants must remain on suppressive 
highly active antiretroviral therapy 
(HAART) for at least 52 weeks after the last dose of CAB LA and/or RPV LA. 
 
There are two arms for the providers (arm-e and arm-s) which contain different levels and 
type of support for the implementation of the HIV Regimen.  Different implementation 
components are found in Table 3. Cluster randomization will be used to randomize sites 
in each country to either arm-e or arm-s.  
 
Table 3 
Implementation Components 
 
Implementation Component 
Arm-e 
Arm-s 
1 
Study Treatment Injection Training 
Face-to-face 
Virtual 
2 
Toolkits 
X 
X 
3 
SWAT Meeting 
X 
 
4 
CQI Meetings (once monthly) 
X 
 
 
Schema:  
 
 
 
4.2. 
Design of Implementation Research 
The proposed study is a cluster-randomized, implementation-effectiveness hybrid type III 
study.  This design allows for a simultaneous focus on both implementation and 
effectiveness, which allows for maximizing our understanding of how-to best support 
translation of CAB LA + RPV LA into routine care while continuing to collect 
effectiveness and safety data.  The hybrid type III focuses primarily on the impact of the 
implementation to get the intervention (CAB LA + RPV LA) into routine care.  As a 

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result, the primary focus of this study is implementation.  The secondary focus is on the 
clinical effectiveness. 
 
To adequately measure the impact of this study, implementation outcomes will be 
measured in addition to service and patient level outcomes.  Implementation outcomes 
are different from clinical outcomes in clinical trial research. These research outcomes 
are typically provider and/or system focused and often rely on triangulation of both 
qualitative and quantitative data. Outcomes can include levels and rates of acceptability, 
adoption, and fidelity to the clinical intervention and the impact of the implementation 
strategies on these rates (Proctor, 2011).  
 
In addition, implementation research focuses on addressing the question of ‘what works 
where, and why.’ By identifying factors and processes that negatively and positively 
affect implementation outcomes, these issues can be effectively addressed in subsequent 
real-world implementation efforts. The study will allow the tailoring of implementation 
strategies and clinical support materials to match the specific needs of different clinical 
settings across Europe. Importantly, the design will also allow for tailoring of strategies 
within countries to ensure each unique context is understood and considered throughout 
the study.  As a result, this proposal is guided by frameworks that are appropriate to the 
proposed stage of implementation research, including both a process and determinants 
framework and an outcomes taxonomy.  The chosen frameworks are highly sensitive to 
the contexts in which the implementation efforts will occur when CAB LA + RPV LA 
goes to scale in the real world.  
 
4.2.1. 
Implementation Frameworks: 
Implementation research often utilizes multiple frameworks or models to guide the aims, 
methods (including implementation strategies), and evaluation.  In this study, the 
Exploration, Preparation, Implementation and Sustainment Framework (EPIS, Aarons 
2011) is a process and determinants framework that will guide all aspects of the study 
including study aims, consideration of implementation strategies, and implementation 
evaluation.  This framework will be used in conjunction with the Proctor and colleagues 
(Proctor, 2011) outcomes guidelines to provide guidance on study design and outcomes 
(Figure 1).   
 
This study requires rigorous application of a determinants implementation framework to 
identify and assess the factors—across multiple system levels and at the clinic and 
individual provider levels—that explain why the implementation of CAB LA + RPV LA 
is or is not successful across contexts, clinical settings, and implementation strategies. 
Over 150 implementation frameworks exist, making the choice idiographic to each study.  
Having a framework that is highly specified operationally and widely used in 
implementation science is advantageous.   
 

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Figure 1 
Synergy between frameworks. The EPIS Framework and Proctor 
guidelines will guide all aspects of the study design and outcomes. 
 
 
4.2.2. 
Exploration, Preparation, Implementation, Sustainment (EPIS) 
 
The EPIS Framework emphasizes the central role of context, identification of multi-level 
barriers, and provides important guidance on both implementation process and 
determinants. EPIS emphasize the role of services delivery organizations and service 
systems in which they operate, while being designed to articulate variables that are 
hypothesized to play key roles in implementation of evidence-based interventions.  As a 
result, EPIS will enable us to not only characterize and explain the ways in which 
implementation strategies and service system processes have and have not been 
successful across contexts and settings, but it will also allow us to examine important 
variables that will be important for implementation sustainment in Europe.  Findings 
from the study will have enough detail to inform the tailoring of implementation 
strategies, if needed, to enhance the implementation effectiveness of CAB LA + RPV LA 
once locally available.   
 
EPIS (Aarons, 2011) both guides and describes the implementation process while 
enumerating common and unique factors that may impact success or failure of 
implementation efforts.  These factors span outer context (system) and inner 
(organizational) context across phases, as well as factors that bridge the outer and inner 
context (Aarons, 2011).  The inclusion of leadership, considering bridging factors, as well 
as the nature of the actual innovation provides important guidance for the current study.  
Leadership is particularly important as it plays a key role in organizational change needed 
to support successful implementation.  Leaders play a number of key roles including and 

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ability to foster an organizational climate receptive to necessary change.  Their 
implementation support occurs through a variety of outlets including securing funding 
and resources, and enforcing policies, all of which impact the success of implementation 
efforts in a local setting.   
 
A recent review (Moullin, 2019) summarizes EPIS use to guide and test theory and 
process across different countries, health systems, and health problems. EPIS has four 
phases that align with, and guide, implementation processes.  The phases are outlined in 
Table 4. The current study capitalizes on initial data from the CUSTOMIZE study 
(209493), as well as the market research done across Europe to provide important 
information that would otherwise need to be gathered in the Exploration phase.  This 
study will focus on Preparation (e.g., arm-e and arm-s) to identify barriers and facilitators 
unique to each context) and Implementation (e.g., initiate use of CAB LA +RPV LA in 
each setting).  Given the duration of the study, we are unable to fully examine the 
Sustainment phase. However, embedded assessment on sustainment will provide sites 
support to continue to endure the proper procedures for CAB LA + RPV LA in routine 
care after the study.  Including evaluation of sustainment in this study will ultimately 
support both tailoring of implementation strategies during study, as well as supporting 
sustained gains using CAB LA + RPV LA at the time of local availability in countries 
across Europe. 
 
Table 4 
EPIS Framework Phases and Definitions (Aarons, 2011) 
EPIS Phase 
Definition 
Exploration 
A service system, organization, research group, or other 
stakeholder(s) consider the emergent or existing health 
needs of the patients, clients, or communities and work 
to identify the best evidence-based intervention to 
address those needs, and subsequently decides whether 
to adopt the identified evidence-based intervention 
Preparation 
The primary objectives of this phase are to identify 
potential barriers and facilitators of implementation at 
the outer and inner contexts, further assess needs for 
adaptation, and to develop a detailed plan to capitalize 
on implementation facilitators and address potential 
barriers. 
Implementation  
Evidence-based intervention use is initiated and 
instantiated in the system and/or organization(s). 
Sustainment 
The outer and inner context structures, processes, and 
supports are ongoing so that the evidence-based 
intervention continues to be delivered, with or without 
some adaptation, to realize the resulting public health 
impact of the implemented evidence-based intervention 
 
Proctor Implementation Outcomes (Proctor, 2011):  
The evaluation of preparation and implementation from the EPIS framework is on five 
key implementation outcomes: (1) acceptability, (2) appropriateness, (3) feasibility, (4) 

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fidelity, and (5) sustainability (see Table 5). According to Proctor, 2011, these outcomes 
represent key intermediate factors in relation to service system outcomes or clinical 
outcomes in treatment effectiveness and quality of care research.  
 
The implementation outcomes will be assessed through validated quantitative 
questionnaires and qualitative interviews (See Section 10.10 and Section 10.11 for a 
summary of elements to be evaluated in the questionnaires). By measuring acceptability, 
appropriateness and feasibility, these can act as surrogate markers for adoption (and can 
be extrapolated to real-world adoption outside of a clinical trial environment). All five of 
these outcomes will also be incorporated into the qualitative interviews, which is the  
standard measurement for implementation outcomes.  
 
Table 5 
Primary Implementation Outcomes 
Acceptability 
Perception amongst implementation stakeholders (providers, 
administrators, and patients) that the new intervention is agreeable, 
palatable and satisfactory 
Appropriateness The perceived fit, relevance, or compatibility of the innovation or 
evidence-based practice for a given practice setting, provider, or 
consumer; and/or perceived fit of the innovation to address a 
particular issue or problem. 
Feasibility 
Extent to which an intervention can be successfully used or carried 
out in a given setting 
Fidelity 
Extent to which an intervention gets applied as originally 
designed/intended.  
Sustainability 
Extent to which the intervention becomes routinely 
available/maintained post introduction.  The current study will 
measure each sites capacity to sustain gains made to CAB LA + 
RPV LA implementation.  
 
4.2.3. 
Impact of Implementation Strategies on CAB LA + RPV LA 
This study offers opportunity to identify the best implementation strategies to support real 
world uptake.  Implementation strategies are methods or techniques used to enhance the 
adoption, implementation, and sustainability of a clinical program, practice or 
intervention.  Implementation strategies are broadly applicable to a range of context and 
offer evidence-based approaches to fit dynamic, real world barriers that require problem 
solving on the implementation journey.  The protocol evaluates arm-s, which includes 
access to patient and HCP facing toolkits, and arm-e which includes Skilled Wrap-around 
Team (SWAT), Implementation Slide kit, patient and HCP facing toolkits plus a dynamic 
implementation strategy, CQI.  The addition of CQI allows for a more nuanced 
understanding of the level of support sites may need as they transition to the use of CAB 
LA + RPV LA in their clinics.  CQI can also be incorporated into their routine clinical 
and organizational culture which is key to success.   The two-arm design will help 
elucidate the level of support, best practices, and required tools needed to implement this 
novel evidenced-based intervention into a variety of clinical settings across Europe.   

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4.2.4. 
Study Arms 
Although all sites enrolled in the study will have access to the study toolkits intended to 
be available at the point when CAB LA + RPV LA is locally available in each country, 
each site will be cluster randomized to one of two implementation arms.  Each is intended 
to provide sites enough care to support changes needed for CAB LA +RPV LA 
implementation in the real world. The two conditions are: 
1) 
Enhanced Implementation Arm (arm-e) 
2) 
Standard Implementation Arm (arm-s) 
 
4.2.4.1. 
Enhanced Implementation Arm (arm-e) Description  
In the initial CQI meeting, discussions will occur about how CQI offers a preemptive 
method to address problems that may ultimately contribute to low rates of CAB LA 
+RPV LA uptake an intervention and the delivery context is ultimately crucial for 
sustainability.   CQI inherently assumes there will be some deviation from procedures 
around scheduling, staffing, and other logistics, to ensure fit of the innovation and the 
context. For CAB LA + RPV LA, this is crucial as each context will likely need to 
engage in refinement of procedures to improve local fit in the real world outside of 
efficacy trials.  Once study sites are determined and language preferences are identified, 
it will be determined if these calls are done by country, clinic, or groups of 2-3 clinics 
that speak the same language.  
 
The other component that is unique to sites in arm-e is access to top challenges 
anticipated by each country with recommendations for how to overcome these challenges 
through different implementation strategies.  These resources have been developed 
through information collected during advisory boards as well as discussions with country 
medical leads.  These tailored implementation strategies are not meant to limit what can 
be done to overcome challenges in each country, but rather to help start discussions with 
the key stakeholders at each site to begin to overcome challenges from the start of the 
study.  They can be used both in the initial SWAT meeting as well as in the CQI calls.   
 
To understand important modifications and adaptions to the implementation of CAB LA 
+ RPV LA, the FRAME-IS will be completed each month by key staff study participants 
identified as being aware of daily operations and modifications.    This will allow for a 
nuanced understanding of local changes made to implementation strategies, which will 
also allow for capturing cultural adaptations that are otherwise difficult to measure, as 
well as the relationship between different forms of modification and subsequent health 
and implementation outcomes.  Lastly, sites in this condition will also have access to the 
all the patient- and HCP-facing toolkit items.  These tools may vary slightly by country 
but will be made available to help support capacity planning, storage, and many other 
variables that may impact CAB LA + RPV LA administration and access.   
 
The Arm-e will contain the following components:  
1. Investigator Meeting: All site principal investigators and key staff will attend the 
investigator meeting that will provide information on effectiveness of CAB LA + 
RPV LA, study procedures, and an overview of safety information.  

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2. SWAT Meeting with sponsor team and principle clinic stakeholders: This meeting 
will occur following the investigator meeting, ideally within the first month of the 
study.  At this meeting, site-specific key personnel (e.g., staff study participants, 
local leadership, administrators, clinical staff) will work with the SWAT to review 
the Implementation Slide kit and spend time discussing the rationale for CQI and 
how it will be used to support implementation in the study.  Participants in the CQI 
calls (2 personnel per site) will be identified and confirmed at this time. 
Participants for the SWAT meeting will be discussed with the site principal 
investigator to ensure appropriate people from each site are invited to participate in 
this meeting.   
3. On-demand SWAT meeting: On request, sites will have access to a follow-up 
SWAT meeting in person to discuss concerns and/or questions about 
implementation of CAB LA +RPV LA.   
4. Monthly Continuous Quality Improvement (CQI) calls: Sites within each country 
cluster randomized to this condition will attend monthly 1-hour CQI calls together 
if available.  If possible, the key staff at each clinic that participate in the day-to-
day injections, medical oversight, and management of CAB LA + RPV LA will 
attend this call, but a maximum of 2 staff from each site will be included on the 
calls.  This will be determined using information gathered during site selection and 
confirmed at the initial SWAT meeting.  If a barrier is identified that requires an 
additional staff member attend a CQI call(s), this will be considered on a case by 
case basis. These calls will be led by a CQI trained leader. During each call, study 
staff participants will be asked to identify barriers to implementing CAB LA + 
RPV LA that they identify and work through a Plan, Do, Study, Act (PDSA) cycle 
on the call.  They will then be asked to act on the PDSA cycle between CQI calls 
to test the success of their strategy at addressing the identified barriers.  
5. Face-to-Face injection training: Each site will be provided to an initial face-to-face 
injection training with the option of adding on virtual injection trainings if 
requested by the site during the study. Where new staff join the study the injection 
training should also be provided face-to-face where possible. 
6. Monthly FRAME assessment: each month the key stakeholder(s) from each site 
will be asked whether they made any adaptations to the implementation strategies 
at their site to assist in implementation of CAB LA + RPV LA.  This measurement 
will also be used to capture additional implementation strategies that were not 
identified by the study team. 
7. Access to toolkit: All sites will have access to both patient level and HCP level 
toolkits.  See Table 6 for list of anticipated toolkit components. 
8. Medical science liaison or CAB + RPV Medical Lead will visit each clinic per 
standard practice in the country. 
4.2.4.2. 
Standard Implementation Arm (arm-s) Description 
Following the investigator meeting each site will have a visit with either a medical 
science liaison or a medical lead (depending on the country) to address investigational 
product questions.  This might include, but is not limited to, discussing the treatment, 
answering medical questions, and utilization of toolkits components.  On-demand visits 
or calls with a medical representative will be available.   Injection trainings will be 
conducted virtually at the start of the study, with additional training options available as 

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needed.  To capture and understand a site’s successful implementation on their own doing 
a monthly FRAME-IS will be completed by key stakeholders and are intended to capture 
current successes and barriers.  Of note, this condition will not have access to the country 
specific implementation strategies developed for arm-e.  
 
The Arm-s will contain the following components:  
1. 
Investigator meeting: All site principal investigators and key staff (e.g., nurse, 
pharmacist) will attend the investigator meeting that will provide information 
on effectiveness of CAB LA+ RPV LA, study procedures, and an overview of 
safety information. 
2. Medical science liaison or CAB + RPV Medical Lead will visit each clinic per 
standard practice in the country.  These meetings will happen quarterly or at 
the discretion of the clinic. At this meeting, there will be the option of using 
the Implementation Slide kit, however, it is not a required part of this arm and 
is to be decided at the discretion of the Lead. 
3. 
Access to toolkit component: All sites will have access to both patient level 
and HCP level toolkits components.  See Table 6 for list of anticipated toolkit 
items. 
4. 
Virtual injection training:  All sites will have access to a virtual injection 
training at the start of the study and as needed throughout the study.   
5. 
Monthly FRAME assessment: each month the key stakeholder(s) for each site 
will identify whether they made any adaptations to the implementation 
strategies at their site to assist in implementation of CAB LA + RPV LA. 
 
4.2.5. 
Key Evaluation of Implementation Strategies & Insights 
FRAME: 
A measurement of implementation strategies in this study will be critical to fully 
understanding how sites capitalize on facilitators and overcome barriers to CAB LA + 
RPV LA implementation and make changes to prescribed strategies to best meet local 
needs.  These modifications are rarely systematically captured, ultimately limiting the 
generalizability of results to new clinical settings.  The framework for reporting 
adaptations and modifications to evidence-based interventions (FRAME; Stirman, 2019) 
allows the capture of important modifications and adaptations to interventions or 
implementation strategies occurring at each local site.  The FRAME-Implementation 
Strategy (FRAME-IS) is intended to be used to track changes made specifically to 
implementation strategies.  The FRAME-IS is a measure that can be completed monthly 
to provide a precise understanding of modifications, the process of modifying or 
adapting, and the relationship between different forms of modification and subsequent 
health and implementation outcomes.  Given sites are encouraged to figure out how to 
make CAB LA + RPV LA work for their given clinic, regardless of condition they are in, 
capturing the nuance for each site will be important for understanding optimal 
implementation across Europe moving forward.  Data from the FRAME-IS can inform a 
foundation for future optimal implementation in sites with similar characteristics.  The 
FRAME-IS will be used with providers in both arms.  
 

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Continuous Quality Improvement (CQI): 
CQI is a dynamic implementation strategy that is intended to improve evidence-based 
practice delivery and quality and will involve study staff participants (Colton, 2000).  It is 
an iterative process of monitoring performance, identifying barriers, generating possible 
solutions, and implementing changes.  The measure and impact of change will be 
assessed, and modifications can be made (in real time) if a desired outcome is not being 
achieved.  PDSA Cycle supports CQI and allows it to be individualized to the context 
within each clinic.  The participants will be taught how to utilize the CQI process to 
address these problems and perform mini-experiments to understand what change is most 
effective to achieve their goals.  This will start at the first CQI meeting during the initial 
SWAT meeting and will continue with hourly calls ~every month for 6 months, with the 
option to extend.  The CQI calls will start by helping identify problems/challenges, 
generate plans to address the challenges, and identify how to measure the change that 
results from the plan, so that at each call, staff study participants can discuss progress 
with the CQI leader and get support if additional iterations are needed.  With increased 
comfort, staff study participants will create PDSA cycles to test, independently of the 
CQI facilitator. 
 
Study Toolkit:  
The study toolkit is a collection of provider-facing and patient-facing materials intended 
to support the delivery of CAB LA + RPV LA in real-world clinical settings (Table 6).  
Contents include provider- and patient educational items, nurse/injector training aids, 
treatment scheduling and capacity planning tools, and patient-directed apps that will be 
made available as part of the study.   In the table below, the toolkit categories are 
identified.   Specific toolkit items will be shared at the investigator meeting.  At a 
minimum, they will be offered at the time pointed noted in the table.  However, the 
toolkit items are intended to be used throughout the study.     
 
Table 6 
Study Toolkit Components * 
Materials 
Objective 
Target 
Audience 
Timepoint Offered for 
Patients and Assessed 
by Providers 
Provider/ Staff 
Education 
Materials – Web 
based 
Staff Education 
Staff 
Month 1monthly 
through End of Study 
Provider/Staff 
Education 
materials – Hard 
copy 
Staff Education 
Staff 
Month 1 monthly 
through End of Study 
Patient Education 
Materials – Web-
based 
Patient Education 
Patient 
Oral Lead-in, Doses 1-
3, 5 

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Materials 
Objective 
Target 
Audience 
Timepoint Offered for 
Patients and Assessed 
by Providers 
Patient Education 
materials – Hard 
copy 
Patient Education 
Patient 
Oral Lead-in, Doses 1-
3, 5 
Web-based 
treatment planner 
Scheduling 
Staff 
Month 1, 2, 4, 6, 8 10 
Capacity Planning 
Tool 
Sustainability 
Staff 
Month 4, 6, 8, 10 
Implementation 
Slide kit 
Staff Education/ 
Capacity Planning 
Staff 
SWAT meeting or MSL 
meetings 
Patient video 
Patient Education 
Patient 
Oral Lead-in, Dose 1  
Injection Training 
Video 
Nurse/Injector 
Education 
Staff/Nurse or 
Injector 
Prior to first injection, 
throughout the study as 
needed 
In-person Injection 
Training 
Nurse/Injector 
Education 
Enhanced Arm 
only - 
Staff/Nurse or 
Injector 
Prior to first injection, 
throughout the study as 
needed 
Peer to Peer 
Education 
Provider/ Physician 
Education 
Physicians/staff 
During enrollment, 
throughout study as 
needed 
Chatbot 
Appointment 
Adherence and 
FAQs 
Patients (offered 
at some 
locations) 
Oral Lead-in-End of 
Study 
 
* Specific toolkits offered in the study will be flexible to ensure the study is offering toolkits consistent what the toolkits 
that are intended to be offered in routine care.   
 
While a “toolkit” of supporting elements will be provided in this study, clinical sites will 
be allowed to choose how they will implement CAB LA + RPV LA delivery in their 
clinical setting (i.e. nurse visit during clinic hours, pre-post clinic hours, weekend hours, 
Tues/Thursday clinics, in hospital settings, in pharmacies, at home etc.) as well as to 
create and use their own clinic-developed resources. The delivery models chosen will be 
tracked by study staff and captured in the questionnaires and SSIs. Modifications made to 
the implementation process or approach during the study, e.g. who administers the 
injection, timing of delivery of the injection, use of support materials, etc. are permissible 
and encouraged in order to facilitate successful delivery of the CAB LA + RPV LA 
regimen. Investigators will inform the study team of their change and document the 
reasons why, which will be formally captured by the FRAME-IS in both conditions. 
 
Staff Qualitative Staff Interviews and Quantitative Questionnaires: 
Questionnaires and interviews will be administered to the staff study participants at three 
timepoints: 

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• Month 1 (established by site activation): Before the first patient receives the 
first injections at the site 
• Month 5: within 4 weeks of the first patient receiving dose 3 at the site. 
• Month 12: within 4 weeks of the first patient receiving their last injection 
(Dose 7) at the site.  
 
Qualitative interviews will be conducted with study staff participants and to assess 
whether acceptability, appropriateness, fidelity, and sustainability are achievable within 
each site’s setting.  Interviews will probe for multilevel barriers to, and facilitators of, 
CAB LA+RPV LA implementation.  Key stakeholder interviews will elicit in-depth 
information as these individuals have first-hand knowledge of the factors influencing 
local implementation. The interviews are EPIS-based (Aarons, 2011) which allows for 
information about characteristics of the adopters, needs and resources of each site, impact 
of leadership, and factors that might impact the larger system including policy changes at 
a local and national level.   
The interviews for staff study participants will be conducted with up to approximately 4 
participants of various disciplines in each clinic that play a critical role (e.g., HIV care 
providers, nurse/person(s) administering the injections, clinic administrator/manager(s), 
pharmacists).  
 
An example of a baseline study staff participant qualitative interview can be found in 
Section 10.12. 
 
The first two questionnaires will take about 15 minutes to complete. The final 
questionnaire will take about 25 minutes to complete. Staff study participants will be 
asked to answer the questions at Month 1 based on their current expectations of 
administering the injection, and at the following timepoints based on their current 
experience administering the injection. The Month 12 assessment will include the CSAT, 
which may be scheduled in a separate assessment period to ensure thorough completion 
and support for sites following the conclusion of the study.  
With notification or approval by the study team, timing and format of interviews and 
questionnaires maybe adjusted during times of exceptional circumstances as a result of 
COVID-19, missed visit. etc.   
Details about concepts measured in the staff study participant questionnaires can be 
found Section 10.11.  
Patient Qualitative Interviews and Quantitative Questionnaires: 
Qualitative interviews result in valid data when thematic saturation is reached in a sample 
being examined.  Thematic saturation is estimated to occur with 6-12 interviews in the 
targeted study population (Hamilton, 2019).  The number of interviews is set at a 
minimum of 6 patients interviewed and up to 75% of PSPs enrolled per site to ensure 
thematic saturation.  This will allow for the ability to adjust the number of PSPs at a 

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given site to appropriately meet site specific saturation. Interviews will be administered 
to the PSP at two timepoints: before Dose 1 and within 4 weeks of receiving Dose 7. 
Selection for Interviews- Given the goal of qualitative data is to understand a specified 
topic area and gain in-depth contextual understanding rather than generalizability, 
purposive sampling will be utilized to select patient participants for interviews.  
Purposive sampling will ensure that the right patient participants are included, and the 
targeted information/questions can be answered and thematic saturation to be obtained at 
each site (Hamilton, 2019). 
An example of a baseline patient study participant qualitative interview can be found in 
Section 10.13. 
Quantitative Questionnaires.  The quantitative implementation data will be collected via 
questionnaire which will be administered to the patient study participants a Doses 1, 3, 
and 7 visits (questionnaires to be completed prior to receiving the injections).  
Each of the patient questionnaires will take 15-20 minutes to complete. Patient study 
participants will be asked to answer the questions at Dose 1 based on their current 
expectations of receiving the CAB LA+RPV LA injections, and at the Dose 3 and 7 
timepoints will ask participants to respond based on the current experience receiving the 
injection during the study. 
Details about concepts measured in the patient study participant questionnaires can be 
found Section 10.10.  
With notification or approval by the study team, timing and format of interviews and 
questionnaires maybe adjusted during times of exceptional circumstances as a result of 
COVID-19, missed visit. etc.   
4.2.6. 
Country Specific Challenges and Implementation Strategies  
Infectious Disease (ID) and HIV care providers were queried on their plan and ability to 
implement CAB LA + RPV LA effectively into their clinical settings across Europe. 
Mixed responses suggested that some sites might require more support and some sites 
many require less support to implement this new intervention well. The level of support 
may also vary within some countries.  However, the exact level of support remains an 
empirical question, which will be addressed through the two arms of the current study.  
Some of these unique factors will inevitably be addressed in the both conditions.   
 
Based on initial country feasibility and market research; key challenges by country and 
potential implementation strategies to address them are may be provided in 
implementation science handbook.   
 
4.2.6.1. 
France 
Research in France identified several steps for successful CAB LA + RPV LA 
implementation. First, creation of tools or support for HCPs to identify appropriate 
patients was noted as critical.  Some suggest without efficient transition of administration 

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of CAB LA + RPV LA to district nurses, there will be a capacity issues in hospitals.  If 
there is a clinic in this study that would be willing to explore the transition of delivering 
injectables from hospital to a district nurse, facilitating communication between hospitals 
and district nurses will be important. However, transition to district nurses will take time 
as they have no previous experience with this type of care, therefore may or may not 
occur during this study.  Last, research indicated that there was additional assessment 
needed around feasibility due to the ‘cold chain’ requirement. Both patients and nurses 
will need to pick up the medication from a pharmacy and transport it to their injection 
appointment location.   
 
4.2.6.2. 
Spain 
Research from Spain has identified eventual capacity issues post local approval once 
patient flow increases, and hospital wide resources will become stretched.  To address 
capacity issues resources within hospitals will need to be reallocated.  Additionally, 
communication between the HIV units and other hospital departments will need to be 
improved to ensure a good user experience.  Lastly, like France, HCPs were concerned 
about patient identification and need additional support. 
 
4.2.6.3. 
Belgium 
In Belgium there are several emerging areas to address for successful implementation of 
CAB LA + RPV LA.  First, a capacity issue is anticipated, and injections will need to be 
given by health-care providers other than nurses and alternative injection locations will 
eventually be required to ease capacity of the AIDS reference centers (ARCs). However, 
this will require a policy change and may happen during the study which will require 
flexibility of an implementation strategy that embraces dynamic processes for sustainable 
change.  It was also requested that the sponsor provide injection training and education to 
help with capacity constraints.  Patient support is needed to help support adherence, 
which is anticipated to be achieved through support tools.  Lastly, cold chain 
management is a consideration as the ideal storage scenario would involve dispensation 
and storage within ARCs. However, this will require legislative change in order to 
dispense CAB LA + RPV LA from a location other than a community pharmacy.  This 
model will likely involve multiple touchpoints to get the injections to the injector and 
injection to the patient. 
 
4.2.6.4. 
Germany 
In Germany, CAB LA +RPV LA will be in the outpatient setting with specialized 
services.   There are three models of HIV care in Germany: large private practices with 5-
8 physicians with multiple nurses and high capacity; small private practices with 1-3 
physicians and limited staffing; and university setting which see a small volume of 
patients but have a high level of resources. Medication will need to be picked up by 
patients a pharmacy with a paper prescription from their provider. Additionally, 
prescriptions are only valid for 30 days, which is anticipated to be a challenge for patients 
receiving CAB LA+ RPV LA every two-month dosing as the patient will need a 

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prescription written within 30 days of their injection appointment date.  As a result, the 
product journey will be challenging.  Additional potential challenges in Germany include 
providing appropriate education for clinic staff on CAB LA + RPV LA, as well as 
discussion about how to schedule appointments and support patient adherence. Lastly, 
study start will likely overlap with drug being locally available in Germany. 
 
4.2.6.5. 
Netherlands 
In the Netherlands CAB LA + RPV LA is expected to be delivered across hospital-based 
HIV clinics.  Some patients receive care from their general practitioners for related care 
like viral load tests and PrEP, but in general, care tends to be led by infectious disease 
physicians and specialist nurse practitioners, both can prescribe medication.  Stable 
patients typically only see their healthcare professionals twice a year, with one of these 
appointments potentially occurring virtually.  Additionally, prescriptions are typically 
written once every 6-months and patients collect their medication at the outpatient 
pharmacy every 3-months.  As a result, the introduction of CAB LA + RPV LA will 
require an increase in the frequency of visits (anticipated to impact clinic capacity and 
nurse time), prescription practices (including the potential of transporting CAB LA + 
RPV LA), and an economic impact on the hospitals as injection appointments are likely 
to be considered as an inpatient appointment effecting the hospitals budget. 
 
4.3. 
Treatment Groups and Duration 
4.3.1. 
Study sites  
Investigational sites or investigators that have not previously delivered the CAB LA + 
RPV LA regimen will be preferred for this study. Selection will be based on ability to 
recruit the desired number of study participants, clinic size, demographics, geographic 
diversity, and patient population. Sites will be selected in order to cover a wide variety of 
HIV care settings. Sites will be asked to operate through their regular clinic pathways 
rather than a research pathway wherever possible.   
 
Sites will be classified by the sponsor based on care delivery systems such as (but not 
restricted to) the following: 
• Hospitals 
• AIDS Reference Centers 
• Hospital-based ID clinics 
• Community Traveling Clinics (ex. district nurses) 
• Community-based  
• Sexual Health Clinics 
 
Clinics that include participants from multiple categories (public/private) will be 
categorized based on the Principal Investigator’s determination of most of their patient 
base. Each clinic selected will be categorized by country, archetype (defined above), 
number of providers/ staff, number of patients, and other clinical characteristics that may 
be considered confounders or influence implementation.    

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Number of Sites: 
Sites across the following countries: France, Spain, Netherlands, Germany and Belgium 
will be selected. Exact site number will be based on feasibility assessments and 
approximately18 sites will be selected. 
 
4.3.2. 
Study staff participants 
Study staff participants will be included that are central to best practices delivery of CAB 
LA +RPV LA within each local context. This will be decided based on the local clinical 
infrastructure and practices at each site. At least three staff participants, identified prior to 
study commencement, will be included at each site.  
 
Examples of Study Staff Participants whom may participate in the study: 
• HIV HCPs 
• Nurses 
• Staff performing injections 
• Clinic Managers 
• Administrators (staff involved in resourcing space/ staff or involved in patient 
scheduling, etc.) 
• Pharmacists 
 
Data will be collected from study staff participants per Table 2. Informed consent will be 
obtained prior to any study assessments for study staff participants (where applicable, as 
determined by local regulatory and compliance requirements).  
 
All study staff will attend an investigator meeting prior to study start. The purpose of this 
meeting is to educate healthcare staff on the CAB LA + RPV LA regimen, including the 
proper administration of the regimen, protocol requirements for all study participants, 
data collection methods and an overview of available study toolkit. Additionally, an 
overview of the key protocol objectives and relevant implementation science elements 
will be reviewed. 
 
Staff study participants will provide input by questionnaires, semi-structured interviews 
and, FRAME-IS questionnaires, and CQI calls, per the Schedule of Activities Table 2. 
Should there be turnover in staff study participants over the course of the study, the 
replacement staff member will undergo study training per standard practice and continues 
staff study activities per schedule of assessments.   
Number of staff study participants: 
Given the unique contexts across the 5 European countries the number and type of staff 
study participants will vary by site. The total number of staff study participants will be a 
minimum of approximately 3 per site (~n = 54). 

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4.3.3. 
Patient study participant  
Patient study participants are HIV-1-infected adults that fulfil the eligibility criteria. 
Each patient study participant will receive CAB LA + RPV LA and clinical assessments 
throughout the study per the Schedule of Activities (SoA). Data will be collected from 
patient study participants per Table 1.  
 
A goal of this study is to enroll 20% female participants, as this population is often 
underrepresented in clinical studies. 
 
Number of Patient Study Participants: 
Each site will be asked to recruit enough patient study participants to serve as a 
reasonable number in an environment reflective of a real-world situation. This will be 
based on feasibility assessment and site capacity to inform subject recruitment allocation 
ensuring a balance without compromising study subject safety. Additionally, this 
approach will allow sites adequate opportunity to describe the challenges and practical 
limitations experienced during initial implementation of CAB LA + RPV LA, as well as 
opportunity to evaluate the resources needed and alternative strategies for successful 
implementation. 
The enrolment period and rate will be monitored continuously and adjustments to the 
enrolment period and patient distribution may occur based on site feasibility and 
recruitment.  
The maximum number of patient participants included in this study is anticipated to be 
approximately 450. 
Patient study participants enrollment: 
All patient study participants will complete the screening phase of up to 35 days prior to 
enrollment.  Participants may be re-screened once. Participants who are enrolled into the 
trial and subsequently withdrawn from the study, for any reason, may not be re-screened. 
Participants may be enrolled as soon as all eligibility requirements have been confirmed 
at the site. Informed consent must be obtained prior to any study procedures for patient 
study participants, including any screening assessment. 
HIV-1 infected participants who meet all eligibility criteria will be switched from their 
pre-baseline regimen to an oral regimen (CAB 30 mg + RPV 25 mg once daily) during 
the oral lead-in phase. Participants will return to the clinic, and if laboratory and clinical 
evaluations continue to support progression into the injection treatment phase of the 
study, will take the last dose of their oral regimen (CAB 30 mg + RPV 25 mg) and 
receive the first dose of CAB LA (600 mg) + RPV LA (900 mg) injections on the same 
day (Month 1). The participant will receive the second injections CAB LA (600 mg) + 
RPV LA (900 mg) one month later (Month 2).   All subsequent injections will occur 
every two months thereafter (Month 4, Month 6, etc) for a total of 7 doses of CAB LA 

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and RPV LA (Table 7).  The total length of the treatment phase is approximately one 
year. 
Table 7 
Dosing Regimen 
Oral Lead-in to End of Study+ 
CAB + RPV Oral Lead-In 
Oral Lead-in (Day 1 to 
Month 1) 
two once daily tablets 
taken with food 
•  Take one tablet of CAB 30 mg + RPV 25 mg once daily  
CAB LA + RPV LA Injections 
Dose 1 (Month 1) 
• 
Receive last dose of oral CAB + RPV regimen 
• 
Receive CAB LA 600 mg given as 1 X 3 mL IM 
injection 
• 
Receive RPV LA 900 mg given as 1 X 3 mL IM 
injection  
Dose 2 to Dose 7  
(Month 2- End of Study+) 
 
two 3 mL injections every 
two months 
• 
Receive CAB LA 600 mg given as 1 X 3 mL IM 
injection 
• 
Receive RPV LA 900 mg given as 1 X 3 mL IM 
injection 
+Until after dose 7 (Month 12) when locally approved and commercially available, the participant no 
longer derives clinical benefit, the participant meets a protocol-defined reason for discontinuation or 
until development of CAB LA or RPV LA is terminated 
 
The dosing window for the second injections will be +0 / -7 days from the projected 
target date (target date is established at Month 1). All subsequent injection windows 
(starting with Dose 3) will be +7/-7 days from the projected target date. Doses outside of 
the window may be allowed with prior Medical Monitor approval. 
Participants will continue CAB LA + RPV LA until:  
• After dose 7 and when the study intervention is locally approved and available for 
the Investigator to prescribe. Note if  intervention is not locally approved at dose 
7 they will continue into the Extension Phase (see Section 6.8). 
• the participant no longer derives clinical benefit 
• the participant meets a protocol-defined reason for discontinuation   
• the development of CAB LA and/or RPV LA is terminated 
• participant withdraws consent 
• participant is withdrawn due to investigator discretion 
• participant is withdrawn due to participant or investigator non-compliance 

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• termination of the study by the Sponsor. 
Safety and efficacy assessments will be conducted as per the Schedule of Activities 
(Section 1.3).  
If the intramuscular (IM) dosing regimen is discontinued as a result of an independent 
data monitoring committee (IDMC) review from the ongoing Phase 3 studies, any 
subsequent analysis, or any other programmatic analysis, those participants who have not 
met any clinical management criteria for discontinuation will be discontinued 
permanently from the study and will enter into the long-term follow-up (LTFU) Phase of 
the study. 
4.3.4. 
LTFU Phase – Following the IM Regimen Only 
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason before CAB LA + RPV LA 
marketed product is locally available must enter the LTFU Phase. Participants must 
remain on suppressive HAART for at least 52 weeks after the last dose of CAB LA 
and/or RPV LA in order to prevent selective pressure on HIV during the period of 
declining drug exposures and the potential for selection of resistant mutants.  
• Where the CAB LA + RPV LA Marketed Product is Locally Available  
Only the participants that discontinue the CAB LA + RPV LA regimen for safety-
related reasons included in Section 7, must enter the LTFU Phase. Participants 
must remain on suppressive highly active antiretroviral therapy (HAART) for at 
least 52 weeks after the last dose of CAB LA and/or RPV LA in order to prevent 
selective pressure on HIV during the period of declining drug exposures and the 
potential for selection of resistant mutants.  
NOTE: Participants who transition to CAB+RPV LA, marketed product or 
alternative HAART (except due to safety-related reasons) do not need to enter the 
LTFU Phase. 
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant. HAART 
therapy should be initiated within one month (- 7 days) after the last dose if 
interruption is prior to Dose 2 and within 2 months ( 7days)  after the last injection 
if interruption is following Dose 2, however if withdrawn due to virologic failure, 
HAART should be initiated as soon as virologic failure is confirmed. Discuss with 
Medical Monitor. The Long-Term Follow Up period (LTFU) will begin the day of the 
last CAB LA and/or RPV LA dose and continue for 52 weeks.  

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Long term Follow up phase requirement  
Marketed product locally 
available 
Subject WD due to safety-
related reasons 
LTFU phase required? 
No 
Yes 
Yes 
No  
Yes 
Yes 
Yes 
No 
No, but Safety FU visit 
required to assess potential 
safety issues occurred after 
the last injection see Section 
4.5.1.2 Safety Follow-up 
Visit. 
 
Participants entering the LTFU phase will not complete a Withdrawal visit but will 
instead move directly into the LTFU Phase as per the schedule of activities. In addition, 
for participants who withdraw during the LTFU Phase, the final visit will be considered 
the study withdrawal visit.  
Participants will be assessed with clinic visits at months 3, 6, 9, and 12 during the LTFU 
Phase. Female participants of child bearing potential must continue to use adequate 
contraception methods for the entire year of follow up. 
In order to ensure that participants have access to HAART during the LTFU Phase, ViiV 
Healthcare may supply HAART or reimbursement may be provided as needed during this 
phase. The LTFU phase may be shortened or terminated at any time during the study for 
various reasons, e.g., better understanding of risks of development of resistance as CAB 
and RPV exposures decline, end of study timings, etc. 
 
4.4. 
Justification for Dose 
PSPs will evaluate the implementation of the every-2-month CAB LA + RPV LA 
regimen.  Specifically, subjects will receive oral CAB 30 mg once daily + oral RPV 25 
mg once daily for 1-month starting on Day 1 followed by CAB LA 600 mg (3mL) + RPV 
900 mg (3mL) at Month 2, Month 3 and every 2 months thereafter. 
4.4.1. 
Oral Lead-In Phase 
Participants in 213199 will enter the study virologically-suppressed on an oral SOC 
regimen and will receive oral CAB 30 mg + RPV 25 mg once daily for about one month 
during the oral lead-in (OLI) phase to confirm tolerability prior to receiving CAB LA + 
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Oral CAB has been co-administered with oral RPV in several studies of healthy subjects 
and HIV infected participants. No clinically relevant drug-drug interaction following 
repeat oral administration of CAB with RPV was observed in healthy subjects in 
LAI116181 [GlaxoSmithKline Document Number 2011N130484_00]. In the dose-
ranging Phase 2b study LAI116482 [(LATTE], oral CAB 10, 30, or 60 mg once daily 
was co-administered with 2NRTIs for 24 weeks in treatment naïve HIV infected subjects 
and with the marketed tablet formulation of RPV 25mg once daily as a 2-drug regimen 
after achieving virologic suppression for an additional 72 weeks; CAB 30 mg once daily 
and RPV 25 mg once daily was administered to all subjects after Week 96 for an 
additional 3 years. Rates of virologic suppression through Week 96 (Maintenance) were 
numerically higher than the EFV-based comparator regimen (Table 8).; GlaxoSmithKline 
Document Number 2014N216014_00].   Oral CAB 30 mg and RPV 25 mg once daily 
has been administered as 1-month OLI and 1-2 months oral bridging for planned missed 
injections in the Phase 2b Study 200056 [LATTE-2] (GlaxoSmithKline Document 
Number 2013N168152_05) and in Phase 3 studies 201585 [ATLAS] and 201584 
[FLAIR] which evaluated Q4W dosing of CAB LA + RPV LA and the Phase 3b Study 
207966 [ATLAS 2M] which evaluated both Q8W and Q4W regimens.  
Table 8 
Proportion (95% CI) of Participants with Plasma HIV-1 RNA <50 c/mL 
at Key Visits - Snapshot (MSDF) Analysis (ITT-E Population) in 
LATTE 
 
 
4.4.2. 
Long-Acting Injectable Phase 
Study 200056 (LATTE-2) is an ongoing, Phase 2b dose-ranging study evaluating the 
long-term efficacy and safety of a two-drug, two-class combination of CAB LA + RPV 
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regimen, for maintenance of virologic suppression in HIV-infected, treatment-naive 
adults. Following induction with16 weeks of oral CAB + 2 NRTIs, 4 weeks of CAB + 2 
NRTIs + oral RPV, eligible participants were randomized (2:2:1) to receive IM CAB LA 
every 4 weeks (800 mg Day 1 then 400 mg Q4W) or every 8 weeks (800 mg Day 1, 600 
mg Week 4, 600 mg Week 8, then 600 mg Q8W) in combination with IM RPV LA every 
4 weeks (600 mg Day 1 then 600 mg Q4W) or every 8 weeks (900 mg Day 1, 900 mg 
Week 8, then 900 mg Q8W), respectively, or to continue on their oral triple ART 
regimen. 
 
Both Q4W and Q8W regimens were continued throughout the Injection Phase as 
planned, and Week 96 results (Table 9) were supportive of further evaluation both the 
Q4W regimen in ATLAS and FLAIR as well as the Q8W regimen in the ATLAS-2M 
study. Subjects completing the 96-week Injection Phase remained on their randomized 
LA regimen (either Q4W or Q8W) during the Extension Phase (post Week 96), and those 
subjects randomized to the oral comparator arm were allowed transition to either LA 
regimen at Week 96. Forty-four subjects were transitioned from the oral comparator arm 
to LA treatments in the Extension Phase; 34 (77%) opted for the Q8W regimen and 10 
(23%) for the Q4W regimen. Initial LA injections were administered at Week 100 
following a 4-week oral lead-in where 2 NRTIs were discontinued and RPV 25 mg once 
daily was added to CAB 30 mg once daily. 
 
Table 9 
Summary of Study Outcomes (<50 copies/mL) at Weeks 48 and 96 – 
Snapshot (MSDF) Analysis (ITT-ME Population) in LATTE-2 
 
 
At week 160, 90% of patients receiving intramuscular CAB + RPV every eight weeks 
and 83% of patients receiving the same regimen every four weeks remained virally 
suppressed. Of the patients that switched from the comparator regimen of oral CAB + 
abacavir (ABC)/lamivudine (3TC) to the intramuscular regimen following week 96, 98% 
remained suppressed through to week 160 (Margolis, 2018). 
The monthly regimen of CAB LA + RPV LA was determined to be noninferior to 
standard of care in 2 Phase 3 studies – 201585 (ATLAS) and 201584 (FLAIR).  The 
every 2 month regimen was shown to be noninferior to the monthly regimen in Phase 3b 
Study 207966 (ATLAS 2M).   

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4.4.2.1. 
CAB LA Pharmacokinetics 
Observed pharmacokinetic data for both CAB LA regimens in LATTE-2 are presented in 
Figure 2 (Margolis, 2018). 
 
Figure 2 
Observed Mean (SD) Concentration-Time Data following CAB LA 
Q8W and Q4W and C following 30 mg PO QD through Week 96 
(200056, LATTE-2) 
 
 
Data Source: Figure 4.1003 
Subjects randomized to remain on oral CAB during the Maintenance Phase had predose CAB 
concentrations obtained on Day 1, Week 32 and Week 48. 
Subjects randomized to CAB LA in the Maintenance Phase received their final Induction Phase dose of 
oral CAB 30 mg once daily as well as their first CAB LA injection on Day1. 
CAB 2-h post-injection concentrations were obtained on Day 1 (largely reflecting oral dosing), Week 32 
and Week 48.   
CAB 1-week post-injection concentrations were obtained on Week 1, Week 25 and Week 41.   
CAB 4-week post-injection concentrations reflect either trough concentrations (Q4W) or troughs and mid-
cycle concentrations (Q8W) through W48.   
All concentrations shown from Week 56 to Week 96 represent troughs regardless of regimen.  
 
The CAB LA 600 mg Q2M regimen is predicted to achieve concentrations above 
1.35g/mL, the geometric mean trough concentration (C) following oral CAB 10mg 
once daily, which was shown to be efficacious in the LATTE study.  The lower bound of 
the 90% prediction interval is approximately 0.166g/mL, indicating that 95% of 
participants on this regimen should remain above the PA-IC90 throughout dosing (Figure 
3).  The CAB LA Q2M regimen consists of identical 600mg doses administered at Day 1, 
Month 2, and Q2M thereafter.  Observed data for the optimized Q2M regimen in 

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LATTE-2 Extension Phase were consistent with predictions, with a geometric mean CAB 
trough concentration of 1.58 g/mL 4 weeks following the reduced 600mg IM loading 
dose and of 2.03 g/mL following the fourth injection. 
 
Figure 3 
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q8W 
Regimen (600 mg IM Day 1, Week 4, Q8W Thereafter) 
 
*Note: current simulations based on interim plasma concentration dataset 
^Study Time and Events include a 4-week oral lead in for subjects transitioning to Q8W from oral SOC. 
Therefore, Day 1 (time zero) = date of first injections in 207966 
A one-week delay in CAB LA dosing for the Q2M regimen at steady state is predicted to 
result in ~92% rather than 95% of participants achieving trough concentrations above the 
PA-IC90, which is considered acceptable. 
4.4.2.2. 
RPV LA Pharmacokinetics 
Observed PK data for both RPV LA Q4W and Q8W regimens in LATTE-2 are presented 
in Figure 4. The RPV LA population PK model has been updated to include data from 
LATTE-2 and from Phase 1 studies in healthy volunteers (Margolis, 2018). 
 

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Figure 4 
Observed Mean (SD) Plasma Concentration-Time Data following 
RPV LA Q8W and Q4W through Week 96 and Day 1 C following RPV 
25 mg PO QD (LATTE-2) 
 
 
 
Data Source:  Figure 4.1004 
Subjects randomized to remain on oral CAB during the Maintenance Phase received their final Induction 
Phase/Oral lead-in dose of RPV 25mg once daily on Day 1 prior to resuming oral CAB + 2NRTIs. 
Subjects randomized to RPV LA in the Maintenance Phase received their final Induction Phase dose of oral 
RPV 25mg once daily as well as their first RPV LA injection on Day1. 
RPV 2-h post-injection concentrations were obtained on Day 1 (largely reflecting oral dosing), Week 32 
and Week 48.  
RPV 1-week post-injection concentrations were obtained on Week 1, Week 25 and Week 41.  
RPV 4-week post-injection concentrations reflect either trough concentrations (Q4W) or troughs and mid-
cycle concentrations (Q8W) through W48.  
All concentrations shown from Week 56 to Week 96 represent troughs regardless of regimen.  
The RPV LA Q2M regimen was selected based on safety and efficacy data from study 
200056 (LATTE-2) and supported by modeling and simulation of pharmacokinetic data 
obtained following administration RPV LA administration in healthy participants (Phase 
1 studies C158, and LAI115428 [GlaxoSmithKline Document Number 
2011N112455_03]) and in HIV-infected participants (Phase 2 study LATTE-2), the 
majority of the data coming from 200056 (LATTE-2) (Margolis, 2018).  
The RPV LA 900 mg Q2M regimen is predicted to achieve median (90% PI) steady-state 
C of 54 ng/mL (23-112ng/mL) (Figure 5). With this regimen, 100% of participants 
remain above the RPV protein-adjusted 90% inhibitory concentration (PA-IC90) during 
the whole dose interval at steady-state.  These data are similar to the observed Week 32 

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median steady-state C in LATTE-2 for Q8W which was also 54 ng/mL and the mean C 
was 58 ng/mL. The RPV LA Q2M regimen consists of identical 900 mg doses 
administered at Day 1, Month 2, and Q2M thereafter.  With the second RPV LA dose 
administered 1 month after the first dose, the anticipated median RPV C at Week 4 
(prior to second injection) is 40 ng/mL (versus 30 ng/mL observed prior to second 
injection at Week 8 in LATTE-2, where the RPV LA dose at Week 4 was not included), 
with >92% of participants above the RPV PA-IC90 of 12 ng/mL.  Observed data for the 
optimized Q2M regimen in LATTE-2 Extension Phase were consistent with predictions, 
with a geometric mean RPV trough concentration of 49.9 ng/mL 4 weeks following the 
900 mg IM loading dose and of 57.5 ng/mL following the fourth injection. 
Figure 5 
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q8W regimen (900 mg IM 
Day) 
 
* Note: current simulations based on interim plasma concentration dataset 
^Study Time and Events include a 4 week oral lead in for subjects transitioning to Q8W from oral SOC. 
Therefore, Day 1 = date of first injections for Study 207966 
 
At steady-state, a one-week delay in dosing for the RPV LA Q2M regimen is predicted to 
result in a median steady-state C that is approximately 11% lower (48 ng/mL) than for 
dosing that is administered on schedule, with >99% of subjects still remaining above the 
RPV PA-IC90.  This supports allowance of some flexibility in the dosing regimen similar 
to what is currently practiced in ongoing LATTE-2 and ATLAS 2M studies. 

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4.5. 
End of Study Definition 
4.5.1. 
Study Completion 
4.5.1.1. 
Study Staff Participants 
Study Staff participants will have completed the study upon completion of all 
questionnaires and qualitative interviews after Month 12 evaluations have been 
completed at their site, per the Schedule of Activities (Section 1.3). 
4.5.1.2. 
Patient Study Participants 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient study participant’s medical condition.  
Patient study participants are considered to have completed the study if they have 
completed all study visits and assessments up to and including Dose 7 (Month 12).  
Post Dose 7 (Month 12), they should remain on study (Extension Phase) until; 
Commercial supplies of the CAB LA + RPV LA regimen become locally available, they 
are required to initiate alternate antiretroviral therapy at the discretion of their HIV care 
provider, or until development of CAB LA + RPV LA is terminated. 
Until meeting the definition for study completion, participants will continue in the study 
until the participant no longer derives clinical benefit or the participant meets a protocol-
defined reason for discontinuation. 
Following commercial availability, patient study participants will exit the study and 
transition to commercial supplies of CAB LA + RPV LA, or alternate antiretroviral 
therapy at the discretion of their HIV care provider. 
Safety Follow-up Visit  
 
A safety follow-up visit is required for subjects completing the study when commercial 
supplies become available, (participant may or may not be transitioning to CAB + RPV 
LA marketed product). It should be conducted approximately 2-4 weeks after the last 
dose of IP to assess HIV associated conditions, AEs, Concomitant medications, ISR AEs 
after the last injection and the plan to transition to marketed product. This visit may be 
conducted by telephone. Ensure relevant eCRF forms (including the Study Conclusion 
form) are updated / completed. 
Participants who withdraw from CAB LA + RPV LA and go into the LTFU phase will be 
considered to have prematurely withdrawn from the study intervention.  
Follow-Up visits are not required for successful completion of the study. 
 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
A participant will be eligible for inclusion in this study only if all the following criteria 
are met: 
• 
Be able to understand and comply with protocol requirements, instructions, and 
restrictions; 
• 
Understand the long-term commitment to the study and be likely to complete the 
study as planned; 
• 
Be considered appropriate candidates for participation in an investigative clinical 
trial with oral and intramuscularly injectable medications (e.g., no active 
substance use disorder, acute major organ disease, or planned long-term work 
assignments out of the country, etc.).   
• 
For Germany also refer to country specific requirement Appendix 8 in Section 
10.8  
The following are study specific eligibility criteria unless stated otherwise. In addition to 
these criteria, Investigators must exercise clinical discretion regarding selection of 
appropriate study participants, taking into consideration any local treatment 
practices or guidelines and good clinical practice (GCP). All participants must be 
considered appropriate candidates for antiretroviral therapy in accordance with 
local treatment guidelines. 
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.  The use of local laboratory services to assess eligibility is only 
allowed with prior approval obtained by the study team with agreed guidance (before to 
initiating the study). In exceptional circumstances only, if a repeat lab is required because 
a central lab result cannot be generated, local lab results can be reviewed and approved 
by the Medical Monitor for consideration of participant eligibility. A repeat sample to the 
central lab will be submitted concurrently or at the next planned visit. 
Source documentation to verify entry criteria must be reviewed by the Principal 
Investigator or designee prior to enrolment. Source documents from other medical 
facilities must be located/received during the 35-day screening phase and under no 
circumstances may the participant be enrolled in the absence of source documentation.  

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All Participants eligible for enrolment in the study must meet all of the following 
criteria: 
AGE 
 
1. 
Aged 18 years or older at the time of signing the informed consent. 
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2.  HIV-1 infected and must be suppressed on a guideline recommended active HAART  
regimen for at least 6 months prior to Screening. Any prior switch, defined as a change of 
a single drug or multiple drugs simultaneously, must have occurred due to 
tolerability/safety, access to medications, or convenience/simplification, and must NOT 
have been done for virologic failure (on treatment HIV-1 RNA ≥200 c/mL).  
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 
12 months prior to Screening: at least one < 6 months prior to Screening and one 6-12 
months prior to screening; 
4. Plasma HIV-1 RNA <50 c/mL at Screening;  
SEX 
5. A female participant is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test at screen and at Day 1), not 
lactating, and at least one of the following conditions applies: 
a. Non-reproductive potential defined as: 
• 
Pre-menopausal females with one of the following: 
• 
Documented tubal ligation 
• 
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
• 
Hysterectomy 
 
• 
Documented Bilateral Oophorectomy 
• 
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating hormone 
(FSH) and estradiol levels consistent with menopause (refer to laboratory 
reference ranges for confirmatory levels)]. Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status prior to study enrolment.  
 

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b. Reproductive potential and agrees to follow one of the options listed in the Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) 
(Section 10.7) from 30 days prior to the first dose of study medication, throughout the study, and 
for at least 30 days after discontinuation of all oral study medications and for at least 52 weeks 
after discontinuation of CAB LA and RPV LA.  
The investigator is responsible for ensuring that participants understand how to properly use these 
methods of contraception. 
INFORMED CONSENT 
6. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol. Eligible 
participants or their legal guardians (and next of kin when locally required), must sign a 
written Informed Consent Form before any protocol-specified assessments are conducted. 
Enrolment of participants who are unable to provide direct informed consent is optional 
and will be based on local legal/regulatory requirements and site feasibility to conduct 
protocol procedures. 
OTHER 
7. French participants: 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. 

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ALL participants in the study should be counseled on safer sexual practices including 
the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk 
of HIV transmission to an uninfected partner. 
 
5.2. 
Exclusion Criteria 
Deviations from 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. 
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
HIV-1 RNA 
1. Within 6 months prior to Screening, plasma HIV-1 RNA measurement 50 c/mL; 
2. During the previous 12 months, any confirmed HIV-1 RNA measurement 200 c/mL 
Exclusionary medical conditions 
3. Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed 
during the study. 
4. Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3 
disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring systemic 
therapy, and historical or current CD4+ counts <200 cells/mm3are not exclusionary. 
5. Any pre-existing physical or mental condition (including substance use disorder) 
which, in the opinion of the Investigator, may interfere with the participant’s ability 
to comply with the dosing schedule and/or protocol evaluations or which may 
compromise the safety of the participant. 
6. Participants determined by the Investigator to have a high risk of seizures, including 
participants with an unstable or poorly controlled seizure disorder. A participant with 
a prior history of seizure may be considered for enrolment if the Investigator believes 
the risk of seizure recurrence is low. 
7. Participants who, in the investigator's judgment, pose a significant suicide risk. 
Participant’s recent history of suicidal behavior and/or suicidal ideation should be 
considered when evaluating for suicide risk 
8. The participant has a tattoo, gluteal implant/ enhancements or other dermatological 
condition overlying the gluteus region which may interfere with interpretation of 
injection site reactions 
9. 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 HBV DNA as follows: 
a. Participants positive for HBsAg are excluded; 

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b. Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg 
status) and positive for HBV DNA 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. 
10. 
Participants who are anticipated to require HCV treatment within 12 months 
must be excluded. Asymptomatic individuals with chronic hepatitis C virus (HCV) 
infection will not be excluded; investigators must carefully assess if therapy specific 
for HCV infection is required. (HCV treatment on study may be permitted, following 
consultation and approval of the DAA based therapy being considered with the 
medical monitor) 
11. 
Participants with HCV co-infection will be allowed entry into this study if:  
a. Liver enzymes meet entry criteria 
b. HCV Disease has undergone appropriate work-up, and is not advanced.  
Additional information (where available) on participants with HCV coinfection 
at screening should include results from any liver biopsy, Fibroscan, ultrasound, 
or other fibrosis evaluation, history of cirrhosis or other decompensated liver 
disease, prior treatment, and timing/plan for HCV treatment. 
c. In the event that recent biopsy or imaging data is not available or inconclusive, 
the Fib-4 score will be used to verify eligibility  
i. 
Fib-4 score >3.25 is exclusionary  
ii. 
Fib-4 scores 1.45 – 3.25 requires Medical Monitor consultation Fibrosis 
4 Score Formula:  
                        (Age x AST) / (Platelets x (sqr [ ALT ]) 
12. 
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) 
13. 
History of liver cirrhosis with or without hepatitis viral co-infection. 
14. 
Ongoing or clinically relevant pancreatitis 
15. 
Clinically significant cardiovascular disease, as defined by history/evidence of 
congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery 
bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty 
(PTCA) or any clinically significant cardiac disease. 
16. 
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell 
carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical 
intraepithelial neoplasia; other localized malignancies require agreement between the 
Investigator and the Study medical monitor for inclusion of the participant prior to 
inclusion 
17. 
Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study drugs or render the 
participant unable to receive study medication 

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18. 
History or presence of allergy or intolerance to the study drugs or their 
components or drugs of their class. 
19. 
Current or anticipated need for chronic anti-coagulation with the exception of 
the use of low dose acetylsalicylic acid (≤325 mg per day) or hereditary coagulation 
and platelet disorders such as haemophilia or Von Willebrand Disease. 
Exclusionary Laboratory Values or Clinical Assessments (a single repeat to determine 
eligibility is allowed) 
20. 
Any evidence of primary resistance based on the presence of any major known 
INI or NNRTI resistance-associated mutation, except for K103N, (International 
AIDS Society [IAS, 2015]) by any historical resistance test result (Wensing, 2019) 
21. 
Alanine aminotransferase (ALT)  5x the upper limit of normal (ULN) or ALT 
3x ULN and bilirubin  1.5 x ULN (with > 35% direct bilirubin) 
22. 
Any verified Grade 4 laboratory abnormality. A single repeat test is allowed 
during the Screening phase to verify a result 
23. 
Participant has estimated creatinine clearance <50 mL/min/1.73m2 via the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey, 
2009). 
Concomitant Medications 
24. 
Exposure to an experimental drug or experimental vaccine within either 28 days, 
5 half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to Day 1 of this study; 
25. 
Treatment with any of the following agents within 28 days of Day 1: 
• radiation therapy;  
• cytotoxic chemotherapeutic agents;  
• tuberculosis therapy except for isoniazid (isonicotinylhydrazid [INH]); 
• anti-coagulation agents; 
• Immunomodulators that alter immune responses such as chronic systemic 
corticosteroids, interleukins, or interferons. Note: Participants using short-term 
(e.g. ≤21 days) systemic corticosteroid treatment; topical, inhaled and intranasal 
corticosteroids are eligible for enrolment.  
26. 
Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of 
Screening. 
27. 
Use of medications which are associated with Torsade de Pointes must be 
discussed with the Medical Monitor to determine eligibility. (See SRM for a list of 
relevant medications) 
28. 
Participants receiving any prohibited medication and who are unwilling or 
unable to switch to an alternate medication. Note: Any prohibited medications that 
decrease CAB or RPV concentrations should be discontinued for a minimum of four 
weeks or a minimum of three half-lives (whichever is longer) prior to the first dose 
and any other prohibited medications should be discontinued for a minimum of two 
weeks or a minimum of three half-lives (whichever is longer) prior to the first dose 

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COVID-19 
29. 
A participant with 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 10.14.7) 
 
 
5.2.1. 
Additional Eligibility Criteria 
To assess any potential impact on participant eligibility with regard to safety, the 
Investigator must refer to the most current 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 drugs. 
Note: Patient study participants with  Grade 1 LFTs at screening and or day 1 
must be discussed with the Medical Monitor prior to initiation of LA dosing; 
continuation in the study or progression onto LA dosing may require additional 
evaluations, including labs drawn after a period of oral dosing with CAB + RPV. 
5.3. 
Lifestyle Considerations 
No restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as patient study participants who consent to participate in the 
clinical study but are not subsequently entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened one time within 4 weeks of the original screening; informed consent 
will need to be reviewed and re-signed for each rescreen. Subjects will be issued a new 
subject number for every screening/re-screening event. 
Staff study participants will not be captured for screen failure reporting. 

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6. 
STUDY INTERVENTION 
6.1. 
Study Intervention(s) Administered 
The term ‘study intervention’ is used throughout the protocol to describe any 
combination of products received by the participant as per the protocol design. Study 
intervention is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study intervention may therefore refer to the 
individual study interventions or the combination of those study interventions. 
Investigational product (IP) in this protocol refers to the investigational study drugs Oral 
Cabotegravir, Cabotegravir LA, Oral Rilpivirine and Rilpivirine LA. These will be 
supplied by GlaxoSmithKline/ViiV Healthcare and Janssen Pharmaceuticals, 
respectively. 
Participants entering the Long-Term Follow-Up Phase will not have their selected 
HAART provided as clinical trial material. The selected HAART will be recorded on the 
Concomitant Antiretroviral Therapy (ConART) eCRF page. 
Dosing and Administration 
Oral Lead-in to End of Study+ 
CAB + RPV Oral Lead-In 
Oral Lead-in (Day 1 to 
Month1) 
two once daily tablets taken 
with food 
•  Take one tablet of CAB 30 mg + RPV 25 mg once daily  
CAB LA + RPV LA Injections 
Dose 1 (Month 1) 
• 
Receive last dose of oral CAB + RPV regimen 
• 
Receive CAB LA 600 mg given as 1 X 3 mL IM 
injection 
• 
Receive RPV LA 900 mg given as 1 X 3 mL IM 
injection  
Dose 2 to Dose 7  
(Month 2- End of Study+) 
 
two 3 mL injections every 
two months 
• 
Receive CAB LA 600 mg given as 1 X 3 mL IM 
injection 
• 
Receive RPV LA 900 mg given as 1 X 3 mL IM 
injection 
+Until after dose 7 (Month 12) when locally approved and commercially available, the participant no 
longer derives clinical benefit, the participant meets a protocol-defined reason for discontinuation or until 
development of CAB LA or RPV LA is terminated 

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6.1.1. 
Formulations of CAB + RPV 
6.1.1.1. 
Cabotegravir Tablets (CAB) 
CAB is manufactured by GlaxoSmithKline and is formulated as white to almost white 
oval shaped film coated 30 mg tablets for oral administration, packaged in high density 
polyethylene (HDPE) bottles with desiccant and child-resistant closure that include an 
induction seal. CAB tablets will be packaged in bottles of 30 tablets. Participants must 
keep all IP in its original pack container. GSK will notify sites if and when data are 
available to support the use of pill boxes. The recommended storage conditions, and 
expiry date where required, are stated on the product label. 
CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline 
cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white 
filmcoating. The white film-coating contains hypromellose, titanium dioxide and 
polyethylene glycol. 
6.1.1.2. 
Rilpivirine Tablets (RPV) 
RPV is provided by Janssen Research & Development, LLC, a division of Janssen 
Pharmaceuticals, as 25 mg tablets that are off-white, round, biconvex, film-coated and 
debossed on one side with “TMC” and the other side with “25”. RPV is manufactured by 
Janssen-Cilag S.p.A, Latina, Italy. RPV will be provided as a globally marketed product 
which includes approvals in the US and Europe. RPV will be overlabeled and packaged 
in bottles of 30 tablets. The recommended storage conditions, and expiry date where 
required, are stated on the product label. 
Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of 
RPV. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose 
monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified 
microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, 
lactose monohydrate, PEG 3000, titanium dioxide and triacetin. 
6.1.1.3. 
Cabotegravir Injectable Suspension (CAB LA) 
CAB LA (GSK1265744 LA) is manufactured by GlaxoSmithKline and is a sterile white 
to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for 
administration by intramuscular (IM) injection. The product is packaged in a glass vial 
with a 13 mm stopper and aluminum seal. Each vial is for single-dose use containing a 
withdrawable volume 3.0 mL (600 mg) and does not require dilution prior to 
administration. The recommended storage conditions, and expiry date where required, 
are stated on the product label. 
CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene 
glycol 3350, mannitol, and water for injection. 

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6.1.1.4. 
Rilpivirine Injectable Suspension (RPV LA) 
RPV LA (TMC278, also named JNJ-16150108-AAA), 300 mg/mL Extended Release 
Suspension for Injection (G001), is provided by Janssen Research & Development, LLC, 
a division of Janssen Pharmaceuticals, as a sterile white suspension containing 300 
mg/mL of RPV as the free base. The route of administration is by intramuscular (IM) 
injection. RPV LA is packaged in a single use 4 mL glass vial with a 13 mm stopper and 
aluminum seal. Each vial contains a nominal fill of 3.0 mL (900 mg), and does not 
require dilution prior to administration. The recommended storage conditions, and expiry 
date where required, are stated on the product label. 
RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate 
monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water 
for injection. 
6.1.1.5. 
CAB LA Packs 
CAB LA may be packaged in a pharmacy pack or provided in separate components:  
 
• 3mL fill of CAB LA vial 
• Vial adapters, used to draw IP out of the vials into the injection syringes 
• Syringes  
• Needles (23-gauge, 1.5 inch) 
• Printed instructions for use 
6.1.1.6. 
RPV LA Packs 
RPV LA may be packaged in a pharmacy pack or provided in separate components:  
• 3mL fill of RPV LA vial 
• Vial adapters, used to draw IP out of the vials into the injection syringes 
• Syringes  
• Needles (23-gauge, 1.5 inch) 
• Printed instructions for use 
6.2. 
Preparation/Handling/Storage/Accountability 
• 
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
• 
In accordance with local regulatory requirements, the investigator, institution, or the 
head of the medical institution (where applicable) is responsible for study 

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intervention accountability, reconciliation, and record maintenance (i.e. receipt, 
reconciliation and final disposition records).  The amount of IP dispensed and/or 
administered to study participants, the amount returned by study participants, and the 
amount received from and returned to GSK must be documented. 
• 
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
• 
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. 
• 
Product accountability records must be maintained throughout the course of the 
study. 
IP accountability will be evaluated using pill counts of unused IP for participants 
receiving oral treatment (oral CAB and oral RPV). This assessment will be conducted 
each time the participant receives a new (refill) supply of IP through the withdrawal or 
study completion. 
IP accountability for participants receiving CAB LA + RPV LA will be performed at the 
‘vial’ level (e.g., correct number of vials were used for each injection). There may be a 
small amount of solution remaining in the vial which does not require quantification.  
Used vials may be discarded at the site once accountability is complete. 
6.2.1. 
Dosing Considerations for CAB LA + RPV LA 
Vials of CAB LA and RPV LA are each supplied as a suspension and need no further 
dilution or reconstitution. Since RPV LA requires refrigeration, sites should allow the 
vial(s) to come to approximately room temperature prior to injecting. The vials should be 
gently inverted a few times to re-suspend sediments and allow bubbles to subside, and 
then use a syringe or provided vial adapter to withdraw the required volume of 
suspension for IM injection. 
All injections must be given intramuscularly in the gluteus medius. Sites may use their 
discretion as to where in the gluteus muscle each injection is given according to 
individual participant circumstance. If possible, injections should be spaced 
approximately 2 cm from one another, from the site of any previous injection or any 
injection site reaction. The time and location of injection will be captured in the eCRF. 
Intermuscular injections should be administered at a 90-degree angle into the gluteus 
medius muscle using a needle of appropriate gauge and length (In most participants, a 
1.5” 23-gauge needle for CAB LA and a 1.5” 23-gauge needle for RPV LA is 
recommended). The needle should be long enough to reach the muscle mass and prevent 

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study drug from seeping into subcutaneous tissue, but not so long as to involve 
underlying nerves, blood vessels, or bone. Variable needle lengths and/or needles with 
different gauge (CAB LA: 21 to 25-gauge; RPV LA: 21 to 23-gauge) are permitted if 
needed to accommodate individual body types. Longer needle lengths may be required 
for participants with higher body mass indexes (BMIs, example > 30), to ensure that 
injections are administered intramuscularly as opposed to subcutaneously. BMI, needle 
gauge and length used will be collected in the eCRF. Additional details of the injection 
device used by sites for IM administration including, but not limited to functional 
performance (ie patient study participant’s body position at the time of administration, 
etc) may also be collected within the eCRF. 
At the first dose (injection), participants transitioning from oral CAB + RPV should be 
dosed with the IM regimen within 2 hours  taking the last oral regimen dose where 
possible. 
Additional dosing instructions and considerations can be found in the SRM. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
For drug distribution purposes, the study will be single-arm, open-label study where all 
patients who pass screening will be assigned to CAB LA + RPV LA regimen.  
For the purposes of implementation science/strategy, this study will be a two-arm study 
and sites will be either randomized to the Enhanced or Standard implementation strategy.  
Cluster randomization will be applied because:  
• Evaluation of intervention will be implemented at site level.  
• For logistical convenience, and to avoid any contamination that could occur if 
implementation science interventions were provided for some subjects and not 
others within each site 
 
Cluster randomization will be used to randomize sites in each country to either arm-e or 
arm-s. To achieve balanced implementation strategies across the sites, randomization 
may be stratified by clinic features. This will ensure data can identify whether a certain 
implementation strategy performs differently within a country or not, as well as between 
different countries. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the participant’s source records and the 
eCRF. The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. 
When participants self-administer oral study interventions at home, compliance with 
CAB + RPV dosing will be assessed through querying the participant during the site 
visits and documented in the source documents and CRF. IP accountability will be 
evaluated using pill counts of unused IP (CAB + RPV tablets). This assessment will be 

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conducted each time the participant receives a new (refill) supply of oral study 
medication or any oral bridging phase. A record of the number of CAB + RPV tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Treatment start and stop dates will also be recorded 
in the eCRF. 
Due to the long-acting nature of the CAB LA and RPV LA it will be imperative that the 
participant is compliant with dosing instructions and study visits. As part of the screening 
and participant selection process, it is imperative that Investigators discuss with potential 
participants the long-term commitments for the trial (including the long-term follow-up 
phase), and the importance of adhering to treatment regimens. Sites are to have plans in 
place for adherence counselling for the duration of the study including the LTFU Phase. 
In addition, Investigators must have plans in place to verify the participant’s contact 
information at each visit. Investigators should contact participants directly if a participant 
misses any scheduled visit. 
6.5. 
Dose Modification 
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study beyond what is allowed within the 
protocol or directly approved by the study Medical Monitor. Protocol waivers or 
exemptions are not allowed. Therefore, adherence to the study design requirements is 
essential and required for study conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information. 
6.5.1. 
Protocol Permitted Substitutions 
6.5.1.1. 
Oral Bridging- Oral CAB LA + RPV LA 
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, in consultation with the medical monitor, Investigators may provide daily oral 
CAB 30 mg and RPV 25 mg as a short-term (3 months) “bridging” strategy for 
participants who have begun CAB LA + RPV LA. In certain circumstances (e.g., prior to 
steady state dosing and following a >8 weeks since last injection) repeating the loading 
doses of CAB LA and RPV LA may be required. Should a participant require “oral 
bridging”, sites must contact the study Medical Monitor for guidance with treatment and 
dosing strategies prior to a missed CAB LA + RPV LA dose. 
6.5.1.2. 
Oral Bridging- Standard of Care Antiretroviral Therapy (SOC ART) 
For patient participants who are unable to attend an IM injection visit nor obtain oral 
CAB + RPV from the site, oral bridging with any commercially available, guideline-
recommended, SOC ART regimen is permitted. The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit.  Sites must contact the study 
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instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. 
It is important to collect relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 
6.5.2. 
COVID-19 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participant’s ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, clinics are operating with only emergency staff. 
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 meet this challenge, there are recommendations in 
Section 10.14 to address access to medicine, staff shortage, shipment of oral medications 
to patients, and alternative sites of care, etc. 
6.5.3. 
IM Dosing 
Participants receiving CAB LA and/or RPV LA are anticipated to be at risk for 
development of virologic resistance if antiretroviral therapy is interrupted. The time 
period during which participants are at risk for development of virologic resistance may 
be determined by the period between when drug levels fall below therapeutic values and 
when they fall below levels which exert selective pressure on HIV. This time period will 
vary by ART agent and is dependent upon effective concentration, inhibitory 
concentration, and half-life.  Plasma concentrations of both LA drugs may be measurable 
for more than one year following IM injections. Any interruption in IM dosing should be 
discussed with the Medical Monitor. Investigators should ensure that the participant 
initiates alternative highly active ART to minimize the risk of developing resistance as 
concentrations of and RPV decline over time. 
CAB LA + RPV LA dosing for participants transitioning from oral CAB + RPV is 
as follows: 
All injections should be planned as single injections per drug. 

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Target Date 
The patient’s ‘target date’ is determined by their first injection date and ideally is the 
same date for every injection. For example, if the1st dose (Month 1) is January 15th, then 
dose 2 (Month 2) will be February 15th, and dose 3 (Month 4) will be April 15th, etc. 
Since the first injection visit (Month 1) will determine the future injection visit schedule 
for participants and ideally be between the 1st and 28th day of the month.  Planning for 
the first injection visit date (within allowed visit windows) should take into consideration 
the availability of the participants to adhere to future visit windows (planned vacations, 
business trips, etc.).   
Treatment Injections- Months 1 and 2 –one month apart 
Participants will take the last dose of their oral (CAB 30 mg + RPV 25mg) and receive 
the first CAB LA (600mg) + RPV LA (900mg) injections (within 2 hours of the final oral 
dose of CAB + RPV).  
The second dose (CAB LA 600mg + RPV LA 900mg) will be administered one month 
later (preferable on the same target date as Dose 1).  The dosing window for Dose 2 
allows administration -7days of the proposed visit date but not later. 
 
Treatment Injections- Months 4- Q2M dosing 
 
Subsequent injections (Dose 3 through 7: CAB LA 600mg + RPV LA 900mg) occur 
every 2 months.  The dosing window is 7days. The Medical Monitor must be contacted 
to discuss individual participant case management if a dose must be administered outside 
of the window.   
 
Nursing Visits for IM Dosing 
Qualified healthcare professionals (HCPs) trained on study procedures can administer IM 
injections outside of the study clinic setting (e.g. home, nursing facility, hospital), 
assuming this can be done safely, without compromising investigational product 
preparation/handling/storage/accountability requirements and done in accordance with 
local requirements. Approval by the medical monitor, the study team and IRB/EC RA as 
locally required are needed for nursing visits.  In cases of nursing visits, where feasible, 
all assessments should also be performed as per schedule of activity Section 1.3 (Table 
1). See the Home-visit Handbook for procedural detail on home visits. 
 
6.5.4. 
Oral Dosing 
Any interruption in therapy (ie due to scheduling conflicts, life circumstances, etc.) 
during any oral dosing period that is greater than 3 consecutive days must be noted on the 
eCRF Bridging Oral/Oral Study Treatment page. Interruptions greater than 7 consecutive 
days must also be discussed with the Medical Monitor prior to resumption of therapy. 

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The Medical Monitor must be contacted upon site staff becoming aware of resumption in 
therapy, if therapy was resumed without prior approval. 
Visits for participants in LTFU are expected to occur as projected according to the last 
injection.   
6.6. 
Concomitant Therapy 
Participants must be advised to notify their Investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
for interactions between such treatments and the study medications. Concomitant 
medications (prescription and non-prescription) will be permitted during the course of the 
study at the investigator’s discretion (except for prohibited medications described in 
Section 6.6.2 and should be administered only as medically necessary during the study. 
All concomitant medication, blood products, and vaccines taken during the study will be 
recorded in the eCRF. The minimum requirement is that the drug name, route, and the 
dates of administration are to be recorded. 
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. 
6.6.1. 
Permitted Medications and Non-Drug Therapies  
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 may cause a temporary increase in the level of plasma HIV-1 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn. This approach will 
minimize the risk of non-specific increases in the level of plasma HIV-1 RNA at the next 
scheduled assessment. 
Other IM injectables (with exceptions below) are permitted but must be administered 
away from the site of IP administration (should be spaced 2 cm or more away from site 
of IP injection). 
Antacid and H2 Antagonist Use: 
While both oral CAB and RPV have dosing requirements with antacid products 
containing divalent cations, only oral RPV has requirements for dosing with H2 

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antagonists.  Since co-administration of oral CAB and RPV is required in this study, the 
most restrictive dosing requirements must be taken into consideration.  
CAB oral administration only: Antacid products containing divalent cations (e.g., 
aluminium, calcium and magnesium) must be taken at least 2 hours before or at least 4 
hours after CAB. 
Concurrent administration of multivitamins is acceptable. 
RPV oral administration only: Antacid products must be taken at least 2 hours before 
or at least 4 hours after RPV. H2-Receptor antagonists (e.g. cimetidine, famotidine, 
nizatidine, ranitidine) may cause significant decreases in RPV plasma concentrations.  
H2-receptor antagonists should only be administered at least 12 hours before or at least 4 
hours after RPV. RPV should not be co-administered with proton pump inhibitors, such 
as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. 
RPV: Administration of clarithromycin, erythromycin and telithromycin is not 
recommended with RPV due to possible increase in plasma concentration of RPV due to 
CYP3A enzyme inhibition. Where possible, alternatives such as azithromycin should be 
considered. Please refer to the local rilpivirine prescribing information for guidance 
regarding other drugs that are prohibited, should be used with caution, require dose 
adjustment, or increased clinical monitoring if taken with rilpivirine. 
Drugs with a known risk of Torsade des Pointes (TdP) should be used with caution when 
on rilpivirine.  A list of drugs associated with TdP is available in SRM and can be 
administered to subjects after consultation with the medical monitor. 
6.6.2. 
Prohibited Medications and Non-Drug Therapies 
The following 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, cytotoxic chemotherapy, or radiation therapy may 
not be administered (see Exclusion Criteria, Section 5.2).  
• 
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 participants with acute viral 
hepatitis (James, 2009). 
• 
Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided 
due to their immunosuppressive effect; however, short treatment courses with 
oral prednisone/ prednisolone/methylprednisolone (e.g. adjunctive treatment 
of Pneumocystis pneumonia with ≤ 21 days of tapering prednisone) are 
allowed. A single dose of systemic dexamethasone is permitted (more than a 
single dose in a treatment course may cause significant decrease in RPV 

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plasma concentration and is prohibited). Topical, inhaled or intranasal use of 
glucocorticoids will be allowed. 
• 
Hepatitis C infection therapy is allowed, however, interferon-based HCV 
therapy or use of any drugs that have a potential for adverse drug:drug 
interactions with study intervention is prohibited throughout the entire study. 
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information. 
6.6.2.1. 
Concurrent with CAB and/or RPV  
For participants receiving either formulation of CAB and RPV, the following 
medications could significantly decrease the levels of CAB and/or RPV due to enzyme 
induction and therefore must not be administered concurrently: 
• 
Carbamazepine 
• 
Oxcarbazepine 
• 
Phenobarbital  
• 
Phenytoin 
• 
Rifabutin 
• 
Rifampicin / Rifampin 
• 
Rifapentine 
• 
St. John’s wort (Hypericum perforatum) 
6.6.2.2. 
Concurrent with oral RPV 
In addition to the medications listed in Section 6.6.2, participants must discontinue the 
following (or change to an allowable alternative) while receiving treatment with oral  
RPV: 
• proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole; 
• systemic dexamethasone (more than a single dose) 
If the participant cannot discontinue use or change to an allowable alternative while 
receiving treatment with RPV, the participant should not be randomized into the study. 
6.6.3. 
Concurrent with either CAB LA or RPV LA 
In addition, for participants receiving CAB LA and RPV LA, use of anticoagulation 
agents for greater than 14 days is prohibited, except for the use of anticoagulation for 
deep vein thrombosis (DVT) prophylaxis (e.g., postoperative DVT prophylaxis) or the 
use of low dose acetylsalicylic acid (≤325 mg). Systemic anticoagulation (including 
prophylaxis doses) on the day of an IM injection should be avoided. 
Note: Any prohibited medications that decrease cabotegravir or rilpivirine concentrations 
should be discontinued for a minimum of four weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose and any other prohibited medications should 

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be discontinued for a minimum of two weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose. 
6.6.4. 
Prohibited Medications for Participants Receiving HAART during 
the Long-Term Follow-Up Phase 
For participants taking HAART during the Long-Term Follow-Up Phase, refer to local 
prescribing information for details regarding concurrent therapies. 
6.7. 
Treatment of Study Treatment Overdose 
For participants receiving Oral CAB, any tablet intake exceeding a total daily dose of 30 
mg will be considered an overdose.  For participants receiving oral RPV, any dose 
exceeding a total daily dose of 25 mg will be considered an overdose.  
For CAB LA and RPV LA, any single dose in excess of the studied doses will be 
considered an overdose. 
Should IM maladministration, specifically overdose or inadvertent IV dosing, be 
suspected at any time, the participant will stay onsite for approximately 2-3 hours post 
dose for safety monitoring and an ECG will be performed at 2 hours post dose. If the visit 
is being performed in the home and further observation or treatment is required at a 
healthcare facility, the patient study participant should be transported to a clinic or a 
hospital as required.  The Medical Monitor will be notified in the event of a suspected 
maladministration. Refer to Home-visit Handbook for procedural detail on home visits, 
where home-visits are locally approved. 
In the event of suspected maladministration, additional PK samples will be drawn at 2 
hours post dosing for evaluation of CAB and/or RPV concentrations. 
For the purposes of this study, an overdose is not an AE (refer to Section 10.5.1) unless it 
is accompanied by a clinical manifestation associated with the overdose.  If the clinical 
manifestation presents with serious criteria, the event is a SAE (see Section 10.5.2). 
If an overdose occurs and is associated with an adverse event requiring action, all study 
medications must be temporarily discontinued until the adverse event resolves.  
The Investigator should use clinical judgement in treating overdose, as ViiV Healthcare 
is unable to recommend specific treatment. 
In the event of an overdose the Investigator or treating physician should: 
1. Contact the Medical Monitor immediately 
2. Closely monitor the participant for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until the IP can no longer be detected 
systemically, (number of days will vary by compound – Medical Monitor / study 
team can advise). 

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3. Obtain a plasma sample for pharmacokinetic (PK) analysis if possible within 2 days 
from the date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
 
6.8. 
Intervention after the End of the Study or Extension Phase 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study intervention. Participants who have successfully completed Dose 7 
will continue to have access to both CAB LA and RPV LA until study intervention is 
either locally approved and commercially available, the participant no longer derives 
clinical benefit, the participant meets a protocol-defined reason for discontinuation or 
until development of either CAB LA or RPV LA is terminated, this period is termed the, 
‘Extension Phase.’. Refer to the Schedule of Activities for details on the requirements for 
these visits (footnote for visit Month 8 and 10) 
6.9. 
Medical Devices 
The medical devices to be used in this study are: vial adaptor, syringe and needle. 
Instructions for medical device use are provided in the Study Reference Manual.  
All device deficiencies, (including malfunction, use error and inadequate labelling) shall 
be documented, and reported by the investigator throughout the clinical investigation (see 
Section 10.16) and appropriately managed by the sponsor. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
A participant may withdraw consent and discontinue participation in this study at any 
time at his/her own request. The investigator may also, at his or her discretion, 
discontinue the participant from participating in this study at any time (e.g., safety, 
behavioral or administrative reasons). If a participant withdraws from the study, he/she 
may request destruction of any samples taken, and the Investigator must document this in 
the site study records. Withdrawn participants will not be replaced. 
Participants may stop study treatment permanently at any time during the study.  The 
primary reason study treatment is permanently stopped will be collected in the eCRF.   
If commercial product is not available when participants complete the Dose 7 visit, they 
should continue in the CAB LA + RPV LA Extension phase of the study.  Should a 
participant permanently stop study treatment at any time during the study and prior to 

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commercial product being locally available, they should be advised that it is strongly 
recommended they enter the Long-Term Follow-Up phase of the study, in the interest of 
continued safety monitoring. Participants who enter the Extension Phase but permanently 
discontinue participation when the CAB LA + RPV LA marketed product is locally 
available must enter the Long Term Follow-Up Phase if they withdraw from the study 
due to safety-related reasons only. 
Any participant not participating in the Long-Term Follow-Up phase after CAB LA + 
RPV LA study treatment is stopped permanently, will attend a withdrawal visit and be 
withdrawn from the study. Participants are not obligated to state the reason for 
withdrawal. However, the reasons for withdrawal, or failure to provide a reason, must be 
documented by the Investigator on the Completion/Withdrawal section of the electronic 
case report form (eCRF). Every effort should be made by the Investigator to follow-up 
participants who withdraw from the study. 
Participants may have a temporary interruption to their study intervention for 
management of toxicities. 
Participants may be prematurely discontinued from the study intervention for any 
of the following reasons: 
• 
Adverse event / Serious adverse event 
• 
Protocol deviation 
• 
Intolerability of injections 
• 
Participant lost to follow-up 
• 
Participant or Investigator non-compliance; 
• 
Termination of the study by the Sponsor 
• 
At the request of the participant, Investigator, GSK or ViiV Healthcare; 
• 
The participant requires concurrent prohibited medications during the course of the 
study. The participant may remain in the study if in the opinion of the Investigator 
and the medical monitor; such medication will not interfere with the conduct or 
interpretation of the study or compromise the safety of the participant. 
Participants must be discontinued from study intervention for any of the following 
reasons: 
• 
Virologic withdrawal criteria as specified in Section 7.1.6 are met; 
• 
Participant requires substitution of ART;  
• 
Participant requires substitution or dose reduction of CAB LA, RPV LA (oral 
bridging supply and potential for a second loading dose may be permissible 
following discussion with the Medical Monitor)  
• 
Liver toxicity where stopping criteria are met and no compelling alternate cause is 
identified (see Section 10.6.5.1); 

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• 
Renal toxicity is met and no compelling alternate cause is identified; 
• 
Corrected QT interval (QTc) >550msec from three or more tracings separated by at 
least 5 minutes and considered causally related to IP.  Note: ECGs are not routinely 
conducted in this study. 
• 
Grade 4 clinical AE considered causally related to study drug;  
• 
Participant has a Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement and no compelling alternative cause is identified 
• 
Participant withdrew consent 
Safety data for all participants who receive any amount of study drug, including 
participants who withdraw from the study, will be included in evaluations of safety. 
If a participant is prematurely or permanently withdrawn from the study, and not 
continuing into the LTFU, the procedures described in the Schedule of Activities Table 
for the in-clinic Withdrawal visit are to be performed. Where a participant does not 
complete a withdrawal visit or enter the LTFU, an in-clinic or remote Safety Follow-Up 
visit will be conducted 4 weeks after the last dose of study medication when there are 
ongoing AEs serious adverse events (SAEs) related & not related to study drug and also 
any laboratory abnormalities that are considered to be AEs or potentially harmful to the 
participant, at the last on-study visit.  
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study. 
The following actions must be taken and documented in relation to a participant who fails 
to attend the clinic for a required study visit: 
a. 
The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible.  
b. The site must 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.  
c. 
In cases where the 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.  
d. Should the participant continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”.  
A participant may withdraw from study intervention 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 administrative reasons. If a participant withdraws from the study, he/she may request 
destruction of any samples taken, and the Investigator must document this in the site 
study records.  

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7.1. 
Discontinuation of Study Intervention 
Participants unable to manage drug toxicity or tolerate investigational product (either 
formulations of CAB or RPV), or meet a protocol-defined withdrawal criterion must 
have IP discontinued. Where the CAB LA + RPV LA marketed product is not locally 
available, any participant receiving at least one dose of CAB LA and /or RPV LA who 
discontinue IP / Withdraw will initiate treatment with HAART and enter the LTFU phase 
for an additional 52 weeks of follow up. The start of the 52-week follow-up period begins 
the day of the last CAB LA and/or RPV LA dose with the first visit at Month 3. When 
the CAB+RPV LA marketed product is locally available participants must enter the 
LTFU Phase if withdrawing for safety related reasons only.  
7.1.1. 
Liver monitoring event – Increased monitoring  
A liver monitoring event is an occurrence of predefined liver chemistry changes that 
triggers increased monitoring of the participant’s liver chemistries, but no action is taken 
with study treatment unless liver chemistry stopping criteria are met. 
Liver monitoring event criteria:  
 
• Baseline ALT ≤1.5x ULN: ALT ≥5x ULN and <8x ULN and bilirubin <2x ULN 
without symptoms believed to be related to liver injury or hypersensitivity. 
 
• Baseline ALT >1.5x ULN: ALT ≥3x baseline and <5x baseline and bilirubin <2x 
ULN without symptoms believed to be related to liver injury or hypersensitivity 
Actions: 
• Notify the medical monitor within 24 hours of learning of the abnormality to 
discuss participant safety.  
• Participant can continue study intervention   
• Participant must return every 2 weeks for repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until resolution or stabilisation (ALT <5x ULN on 
2 consecutive evaluations) 
• If at any time participant meets the liver chemistry stopping criteria, proceed as 
described above  
7.1.2. 
Asymptomatic Liver Enzyme Elevations 
For asymptomatic subjects 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 subject did not meet 
any liver monitoring or liver stopping criteria. 

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7.1.3. 
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). 
 
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 Section 10.3.1 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the Investigator believes study intervention discontinuation is in 
the best interest of the participant. 
 
Liver Safety Required Actions and Follow up Assessments can be found in Section 10.3. 
7.1.4. 
Temporary Discontinuation 
Participants may have a temporary interruption to their study intervention when on oral 
therapy (oral lead or oral bridging) for management of toxicities. Such interruption of 
study intervention does not require withdrawal from the study. However, consultation 
with the Medical Monitor is required. 
 
7.1.5. 
Restart 
If participant meets liver chemistry stopping criteria do not restart the participant with 
study intervention unless: 
 
• ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted, 
 
• Ethics and/or IRB approval is obtained, if required, and 
 
• Separate consent for treatment restart is signed by the participant. 
Refer to Section 10.3.2 for full guidance. 
 
Background 
• Restarts should be limited to cases in which there is clear evidence that the 
underlying cause of the liver event is not related to study drug.  
• For long-acting agents, a restart may actually be continuation of therapy rather 
than a true re-start due to the timeframe between dose administration relative to 
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• If protocol defined stopping criteria for liver chemistry elevations are met 
(Section 10.3), study drug must be stopped. Subjects who meet liver chemistry 
stopping criteria should not be retreated with investigational product unless an 
exemption has been approved by the VSLC.  The algorithm for restart is 
described in Section 10.3.2 and summarised in Figure 8. 
• If the restart is approved by the VSLC in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, 
including the possibility of recurrent, more severe liver injury or death.  
• Ethics Committee or Institutional Review Board approval of drug restart must be 
obtained, as required. 
• The subject must also provide signed informed consent specifically for the IP 
restart. Documentation of informed consent must be recorded in the study chart. 
• Study drug must be administered at the dose specified by the VSLC. 
• Subjects approved by the VSLC for restart of IP must return to the clinic once a 
week for liver chemistry tests for a minimum of one month and thereafter for as 
long as clinically indicated and then laboratory monitoring may resume as per 
protocol. Longer durations of close monitoring may be required for long-acting 
IP. 
Refer to Section 10.3.2 for full guidance. 
 
7.1.6. 
Virologic Failure 
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. The use of local laboratory services to assess virologic failure is 
only allowed with prior approval (before to initiating the study) obtained by the study 
team with agreed guidance. 
7.1.7. 
Definition of Protocol-Defined Confirmed Virologic Failure 
For the purposes of clinical management in this study, CVF is defined as:  
Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL. 
7.1.8. 
Managing Virologic Failure 
Following study entry, no changes, or intensification of ART will be permitted prior to 
protocol-defined virologic failure, outside of the planned protocol regimens. Only plasma 
HIV-1 RNA values determined by the central laboratory will be used to assess virologic 
failure (except where the use of a local laboratory for study-specific assessments has 
been reviewed and approved by the sponsor prior to study start). Baseline plasma HIV-1 
RNA is the assessment completed on study Day 1. The definition of confirmed virologic 
failure does not apply to participants in the LTFU Phase. These participants will be 
followed for the emergence of viral resistance. 

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Inadequate adherence or maladministration may be a cause for virologic failure and 
should be explored as a first step in the management of study participants (e.g., at the 
first indication of inadequate virologic response or rebound). Upon notification that a 
participant’s HIV-1 RNA plasma level qualifies him/her as a suspected virologic failure 
(SVF), the Investigator should query the participant regarding intercurrent illness, recent 
immunization, or interruption of oral therapy. 
7.1.8.1. 
HIV-1 RNA Blips 
HIV-1 RNA “blips” are not usually associated with subsequent virologic failure (DHHS, 
2019). Although the implications of persistent HIV-1 RNA levels between the lower 
level of detection and <200 c/mL are unclear, the risk of emerging resistance is believed 
to be relatively low. 
Participants with transient increases in HIV-1 RNA (‘blips’ HIV-1 RNA <200 c/mL) are 
not considered suspected virologic failures and do not require a change in therapy. 
Participants who have a HIV-1 RNA ≥50 c/mL at the key analysis timepoints (Month 12, 
End of Study visit) should return for a repeat HIV-1 RNA as soon as possible but no later 
than 4 weeks after the date of the Month 12, respectively such that the result falls within 
the same analysis window. 
In order to better characterize HIV-1 RNA ‘blips,’ if there is a known reason / 
explanation for the blip (e.g., immunization, allergies, concomitant medication, 
intercurrent illness, etc), the study team should be notified of the reason and case context. 
If the Investigator has concerns regarding persistent low-level viremia (HIV-1 RNA ≥50 
c/mL and <200 c/mL), the Medical Monitor should be contacted to discuss participant 
management. Following discussion with the Medical Monitor, additional viral load 
testing may be performed between visits to determine the appropriate participant 
disposition for the next scheduled visit. 
7.1.8.2. 
Suspected Virologic Failure 
Upon notification that a participant’s HIV-1 RNA plasma level meets the definition of 
suspected virologic failure (plasma HIV-1 RNA ≥200c/mL), the Investigator should 
confirm the definition is met by initiating a repeat of the HIV-1 RNA assessment. 
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing to avoid false-positive results: 
• 
Confirmatory testing should be scheduled within 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 at least 4 weeks following any 
immunization, during which time the participant should receive full dose of all IP. 

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• 
If therapy is interrupted* due to toxicity management, 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 dose of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA testing is done. 
*Note: treatment interruption guidelines above may not apply for participants on CAB 
LA + RPV LA treatment. The study team should be contacted to discuss any treatment 
interruptions for participants meeting the definition of virologic failure. 
In addition, the Investigator should query the participant regarding intercurrent illness, 
recent immunization, or interruption of therapy. 
Sites should contact the Medical Monitor to discuss individual participants, 
whenever necessary. 
7.1.8.3. 
Confirmed Virologic Failure 
Participants with CVF must be discontinued from study treatment. However, participants 
who have received at least one dose of CAB LA or RPV LA prior to confirming virologic 
failure will remain in the study on oral HAART in the LTFU Phase. 
A plasma sample from the suspected virologic failure visit as well as Day 1 (if baseline 
HIV-1 RNA level 200 c/mL) will be sent for genotypic and phenotypic resistance 
testing and the result made known to the Investigator when available. Baseline proviral 
genotyping on Day 1 PBMCs and other genotyping techniques may also be attempted for 
patient study participants with CVF.  A plasma sample from the confirmation visit will be 
obtained for storage. This sample may be used for possible future analyses, e.g., for 
genotypic and phenotypic analyses etc. 
For all participants who meet CVF, baseline and suspected virologic failure plasma 
samples with HIV-1 RNA level 200 c/mL will be analyzed in an attempt to obtain 
genotype/phenotype data on as many samples as possible. Plasma samples for storage 
will also be obtained at unscheduled visits including confirmation of CVF. Participants 
may continue to receive study drug at the discretion of the Investigator until results of 
resistance testing are available at which time the participant must be discontinued from 
the study. Even if genotype/phenotype data cannot be generated, participant must be 
discontinued from the study intervention. 
If a participant is prematurely discontinued from the study intervention, the Investigator 
must make every effort to perform the Withdrawal Visit evaluations outlined in the 
Schedule of Activities Table. These data will be recorded as they comprise essential 
evaluations needed to be done before discharging any participant from the study. 
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, 

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behavioral, compliance or administrative reasons. This is expected to be 
uncommon. 
• 
At the time of discontinuing from the study, if possible, an early 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).  
• 
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 data for further research, 
the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent for the study primary research but data will not be used 
for further research. 
• 
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 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 are handled as part of Section 10.1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed except for urgent actions to address 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the Schedule of Activities Table, are essential and required 
for study conduct. 

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This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Schedule of Activities, Section 1.3. 
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility and scheduled assessments.  The use of local laboratory services to 
assess eligibility is only allowed with prior approval (before to initiating the study) 
obtained by the study team with agreed guidance.  
The following points must be noted:  
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order: 
1. 
vital signs 
2. 
blood draws 
•The IRB/independent ethics committee (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the Informed 
Consent Form. 
8.1. 
Screening Assessments 
Eligibility criteria must be carefully assessed at the Screening visit. Physical 
examinations should be conducted as part of normal routine clinical care. Background 
information to be collected at Screening includes demography and prior ART history. 
Eligible participants may be enrolled immediately as soon as all Screening assessments 
are complete, and the results are available and documented. All participants will 
complete the screening period of approximately 35 days prior to Oral Lead-in during 
which all clinical and laboratory assessments of eligibility must be performed and 
reviewed. All Screening results must be available prior to enrollment. 
All information about the participant’s current regimen must be available for 
review by the Principal Investigator or designee prior to enrollment. Source 
documents from other medical facilities must be located/received during the 35-day 
screening period and under no circumstances may the participant be enrolled in the 
absence of source documentation even if there are delays in receipt of this 
information. 
Participants who meet all entry criteria and are enrolled will be assigned a participant 
number. A single repeat of a procedure/lab parameter can determine eligibility (unless 
otherwise specified). Participants not meeting all inclusion and exclusion criteria at initial 
screen may be rescreened one time within 4 weeks and receive a new participant number. 
Participants who are enrolled into the trial and subsequently withdrawn from the study 
for any reason may not be rescreened. 

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8.2. 
Baseline Assessments 
8.2.1. 
Patient Study Participants 
At Day 1, any changes to the eligibility parameters must be assessed and any results 
required prior to enrollment (e.g., Day 1 urine pregnancy test for women of childbearing 
potential) must be available and reviewed. The following demographic parameters will 
be captured: year of birth, sex, race and ethnicity. Medical/medication/family history will 
be assessed as related to the inclusion/exclusion criteria listed in Section 5.1. 
Baseline information to be collected at Day 1 includes general medical history and 
current medical conditions. Laboratory assessments will also be assessed.  
Questionnaire are recommended to be administered at the beginning of the visit before 
any other assessments are conducted, in the order specified. 
In addition to a full routine medical history at Baseline, more detailed information will be 
collected for some disease processes such as: 
• 
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at Baseline and assessments will include height, weight, blood pressure, 
smoking status and history, pertinent medical conditions (e.g., hypertension, 
diabetes mellitus), and family history of premature cardiovascular disease. In 
addition, medical history/risk factors for renal disease such as nephropathy, renal 
failure, and nephrolithiasis will be assessed. 
• 
history of illicit drug use [e.g., cocaine, heroin, and methamphetamine use]); 
• 
intravenous drug use history; 
• 
gastrointestinal disease (e.g., gastrointestinal [GI] bleeding, peptic ulcer disease 
[PUD], etc); 
• 
metabolic (e.g., Type I or II diabetes mellitus); 
• 
psychiatric (e.g., depression); 
• 
renal (e.g., nephrolithiasis, nephropathy, renal failure); and, 
• 
neurologic disorders 
Procedures conducted as part of the participant’s routine clinical management [e.g., 
laboratory assessments] and obtained prior to signing of informed consent may be 
utilized for baseline purposes provided the procedure meets the protocol-defined criteria 
and has been performed in the timeframe of the study. Where possible local lab results 
should be confirmed by submission of samples to the central lab. 

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8.2.2. 
Staff Study Participants 
Questionnaires and Interviews for staff study participants should be completed prior to 
the first Patient Study Participant CAB LA + RPV LA injection. 
8.3. 
Efficacy Assessments- Patient Study Participants 
8.3.1. 
Plasma HIV-1 RNA 
Plasma for quantitative HIV-1 RNA will be collected according to the Schedule of  
Activities (Section 1.3). Methods to be used may include but are not limited to the Abbott  
RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL. In some cases, (e.g., 
where the HIV-1 RNA is below the lower limit of detection for a given assay) additional 
exploratory methods may be used to further characterize HIV-1 RNA levels. 
8.3.2. 
Lymphocyte Subsets, CD4+ and CD8+ 
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ and CD8+ lymphocyte counts, ratios) 
according to the Schedule of Activities (Section 1.3) and Laboratory testing 
specifications (Section 8.4.4). 
8.3.3. 
HIV-Associated Conditions 
HIV-associated conditions will be recorded and will be assessed according to the CDC, 
2014 Revised Classification System for HIV Infection. 
8.4. 
Safety Assessments- Patient Study Participants 
8.4.1. 
Clinical Evaluations 
The following clinical evaluations will be performed according to the schedule of 
activities: 
• 
Monitoring and recording of all AEs and SAEs. Additional information on the 
Time Period and Frequency of Detecting AEs and SAEs is provided in Section 
1.3. 
• 
Physical exams should be conducted as part of normal routine clinical care. 
Abnormalities noted during any exam must be recorded in the eCRF (e.g., in the 
current medical conditions or AE logs). 
• 
Height and weight will be measured and recorded. Height collected on the Day 1 
(Baseline) only. 
• 
Vital signs will include systolic and diastolic blood pressure and heart rate 
collected after resting for about 5 minutes. Temperature will also be collected. 
• 
Past medical history, family history, social history, medication history. Targeted 
history on cardiovascular risk (smoking history, family and personal history). 

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• 
HIV-associated conditions will be recorded. 
• 
Regular monitoring of hematology, blood chemistry and glucose (parameters to 
be tested listed below). 
• 
Pregnancy testing.  A negative urine pregnancy test is required prior to initiation 
of IP, any dose of CAB LA or RPV LA or as required by the Medical Monitor 
following a treatment interruption(s). If serum testing is required locally, the 
results should be available prior to the visit where urine testing is indicated per 
the Schedule of Activities. 
o Participants who are enrolled in the study and have a positive pregnancy 
test during the course of the study, will be allowed to remain in the study, 
provided a pregnancy specific ICF addendum is signed by the participant. 
No IP can be continued (oral or LA) in any pregnant participant until the 
benefit/risk assessment is discussed with the participant and the pregnancy 
specific ICF addendum has been signed. See details in Appendix 15: 
Information and Guidance for Managing Pregnant Participants.  
o Pregnant participants who remain in the study do not need pregnancy 
testing during the study, for the duration of their pregnancy.  
• 
Evaluation and documentation of all concomitant medications and blood 
products. 
• 
Injection Site Reactions (ISRs) will be assessed clinically during the study for the 
following: 
Pain, tenderness, pruritis, warmth, bruising, discoloration, infections, rash, 
erythema, swelling, induration, and nodules (granulomas or cysts).   
• 
A clinical assessment (using Division of Acquired Immunodeficiency Syndrome 
[DAIDS] grading scale) should be performed both before and after an injection to 
identify resolving and new ISRs. All injection site reactions are considered 
adverse events. The clinical assessment and interpretation of any ISR, will be 
documented in the ISR AE eCRF. 
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments. 
8.4.2. 
Physical Examinations 
Physical exams should be conducted as part of normal routine clinical care.  
Abnormalities noted during any exam must be recorded in the eCRF (e.g., in the current 
medical conditions or AE logs). 
• 
A complete physical examination will include, at a minimum, assessment of 
the Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems. 
Height and weight will also be measured and recorded as per the Schedule of 
Activities (Section 1.3). 

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• 
A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
The site of IM injection administration should be assessed at every visit for 
signs of any possible reaction. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.4.3. 
Vital Signs 
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate. These will be recorded 
as per the Schedule of Activities (Section 1.3). 
8.4.4. 
Clinical Safety Laboratory Assessments 
Hematology 
Platelet count  
Automated WBC differential: 
RBC count 
Neutrophils 
WBC count (absolute)  
Lymphocytes 
Hemoglobin 
Monocytes 
Hematocrit 
Eosinophils 
MCV 
Basophils 
Clinical Chemistry 
BUN 
Potassium 
AST  
Total bilirubina 
Creatinine 
Chloride 
ALT  
Albumin  
Glucosec 
Total CO2 
Alkaline phosphatase 
Creatine phosphokinase 
Sodium 
Lipase 
Phosphate 
Creatinine clearanceb 
Other Tests 
Plasma HIV-1 RNAd 
CD4+ and CD8+ cell counts [CD4/CD8 ratio]e 
Peripheral Blood Mononuclear Cells (PBMCs):  Day 1 and Withdrawal only 
Rapid Plasma Reagin (RPR) (Screening) 
Prothrombin Time (PT)/International Normalized Ratio (INR)/ Partial Thromboplastin Time (PTT) 
(screening) 
Pregnancy test for women of childbearing potential 
Urinalysis (screening, withdrawal/LTFU), urine albumin/creatinine ratio, and urine protein/creatinine 
ratio, urine phosphate 
Follicle stimulating hormone (FSH) and estradiol (only for instances when postmenopausal status is 
questionable) 
PK samples maybe collected for maladministration, liver events, pregnancy long-term follow-up or as 
directed by the medical monitor. Pregnant participants who elect to remain in the study will have 
additional pre-dose trough PK samples for both CAB and RPV obtained, to be collected within 15 
minutes prior to the LA dose, on the day of the study visit see Section 10.15.6.2. 

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MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells, BUN = Blood urea 
nitrogen, AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon dioxide, 
PT/INR = prothrombin time/international normalized ratio. 
a) Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN. 
b) Glomerular filtration rate (GFR) will be estimated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) [Levey, 2009]. 
c) Glucose can be done in a non-fasting or fasted state. 
d) For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt 
to obtain genotype/phenotype data. 
e) CD8+ cells will only be reported at Baseline and Month 12 
f) 
Urine pregnancy test/ serum pregnancy test will be performed according to the Schedule of 
Assessments (Table 1).  
 
Where lab samples are missed in error, including not analysed by the central lab, see the 
Study Reference Manual (SRM) for guidance on which samples should have subjects 
brought back in for a central lab retest (local lab only sites require a local retest only). 
Should a patient be required to return to site provide a re-test lab sample the lab date 
should entered in the eCRF under an unscheduled visit, if the re-test is conducted on a 
day that is different to the scheduled visit. 
8.4.5. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants with HIV infection may occasionally present with symptoms of depression 
and/or 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. Additionally, depression and anxiety has been reported in some 
participants being treated with RPV. Therefore, it is appropriate to monitor and closely 
observe participants prospectively before and during treatment for suicidal ideation 
and/or behavior, or any other unusual changes in behavior. It is recommended that the 
Investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior. 
Participants presenting with new onset/treatment emergent depression should be advised 
to contact the Investigator immediately if symptoms of severe acute depression 
(including suicidal ideation/attempts) develop, because medical intervention and 
discontinuation of the study medication may be required. 
The investigator will collect information using the Possible Suicidality-Related AE  
(PSRAE) eCRF form in addition to the Adverse Event (non-serious or Serious Adverse 
Events) eCRF form on any participant that experiences a possible suicidality-related 
adverse event 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 
behavior, 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 ViiV/GSK within one week 
of the Investigator diagnosing a possible suicidality-related adverse event. All sites 
should have a plan in place for managing possible risks for suicide related events. 

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8.5. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.5. 
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 IP. (see Section 7).  
Please refer to Appendix 14 in Section 10.14 for study management information during 
the COVID-19 pandemic.  
Reporting for medical device deficiencies are covered in Section 10.16 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE  
Information 
• 
All SAEs will be collected from the signing of the informed consent form until 
the follow-up visit at the time points specified in the SoA (Section 1.3).   
• 
All AEs will be collected from Day 1 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 on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Section 
10.5.6. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
• 
All AEs and SAEs associated with medical device deficiencies for associated 
persons (i.e. healthcare professionals) will be collected. The associated person 
will be provided with a safety reporting information and an authorisation letter, 
as indicated in Section 8.5.8 
• 
Investigators are not obligated to actively seek 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. 
8.5.2. 
Method of Detecting AEs and SAEs 
• 
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 10.5.6. 

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• 
Care will be taken not to introduce bias when detecting AE and/or SAE. 
Openended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
8.5.3. 
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. Further 
information on follow-up procedures is given in Section 10.5. 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the sponsor of a 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. 
• 
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. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) 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. 
 
8.5.5. 
Pregnancy 
8.5.5.1. 
Pregnancy Testing 
Women of childbearing potential must have a negative pregnancy test at Screening, and 
at Baseline (Day 1). Pregnancy testing will also be conducted as per the Schedule of 
Activities (Section 1.3) and at any time during the trial when pregnancy is suspected. 
If pregnancy is confirmed, a discussion with the pregnant study participant assessing the 
benefit/risk assessment of continuing in the study will be undertaken. If, after this 
discussion, the participant would like to continue in the study, this will be allowed, 
provided the pregnant participant signs the pregnancy specific ICF addendum. See 
Section 10.15 for details. 

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Pregnant participants who remain in the study do not need pregnancy testing during the 
study, for the duration of their pregnancy. Additionally, the Medical Monitor may request 
that a urine pregnancy test be performed in the event of a treatment interruption greater 
than 7 days. 
8.5.5.2. 
Rationale for Continued Use in Pregnancy 
Additional data regarding the use of CAB + RPV LA during pregnancy, and management 
of pregnant participants remaining in the study are found in Appendix 15: Information 
and Guidance for Managing Pregnant Participants 
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering a unique opportunity to 
overcome such adherence challenges. LA therapy may also help with nausea (50 % mild 
to moderate) or hyperemesis (2%) that is frequently seen, especially during the first 
trimester of gestation. 
Participants on LA dosing who become pregnant will have exposures throughout 
pregnancy due to the long half-life and PK tail of CAB/RPV. Prior to this protocol 
amendment, pregnant participants would have been withdrawn from the study, and 
initiated on an alternative oral ART regimen. Alternative regimens consist of either 2 or 3 
antiretrovirals to protect the life of the mother and for the prevention of MTCT. This 
regimen, combined with the long half-life and PK tail of CAB/RPV, would potentially 
expose the fetus to additional ARVs during gestation (in some cases upwards of 5 
antiretrovirals). 
Given the risk/benefit ratio for cabotegravir and rilpivirine LA dosing in WOCBP, 
coupled with concerns of increasing fetal exposure to several additional antiretrovirals 
upon participant withdrawal, this amendment to the protocol will allow pregnant 
participants to remain in the study after a pregnancy specific ICF addendum is signed by 
the participant. 
8.5.5.3. 
Time Period for Collecting Pregnancy Information 
Pregnancy information will be collected from Day 1 until the last follow-up assessment.  
This includes the entirety of the LTFU Phase. Pregnant study participants who consent to 
remain in the study during pregnancy will continue to have all clinical assessments (with 
the exception of pregnancy test) performed as per the Schedule of Activities Table 
(Section 1.3), including the collection of additional PK samples for CAB and RPV. See 
Section 10.15 for details.  
Pregnant participants who have received at least one dose of CAB LA or RPV LA and 
decide NOT to continue in the study during pregnancy will enter the LTFU Phase of the 
study and will be monitored for 52 weeks after the last LA dose. Moreover, an alternative 
oral HAART will be initiated, at the discretion of the PI and in discussion with the 
Medical Monitor. If a participant becomes pregnant within 52 weeks of the last dose of 
study drug the participant should notify the study site. 

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8.5.5.4. 
Action to be Taken if Pregnancy Occurs 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. The investigator should inform GSK within 24 hours of learning of 
the pregnancy and should follow the procedures outlined in Section 10.15.  
Pregnant participants who elect to continue in the study and receive CAB + RPV LA 
must sign a pregnancy specific ICF addendum. Cabotegravir and rilpivirine are detected 
in systemic circulation for up to 12 months or longer after discontinuing injections of 
CAB + RPV LA; therefore, consideration should be given to the potential for fetal 
exposure during pregnancy and should be discussed between the study participant and the 
study PI.  
Participants who become pregnant during the study and elect to continue in the study and 
receive CAB+RPV LA, will have additional PK samples collected to monitor 
cabotegravir and rilpivirine exposure levels throughout the pregnancy (see Section 10.15) 
and at the time of delivery.   
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child(ren). Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Abnormal 
pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the participant has completed the study and considered by the Investigator 
as possibly related to the study intervention, must be promptly reported to ViiV/GSK. 
GSK’s central safety department will also forward this information to the Antiretroviral  
Pregnancy Registry. The international registry is jointly sponsored by manufacturers or 
licensees of ARV products. Additional information and a list of participating 
manufacturers/licensees are available from http://apregistry.com/ 

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8.5.6. 
Cardiovascular and Death Events 
Investigators will be required to fill out the specific CV event page of the eCRF 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 
• 
Revascularisation 
For any cardiovascular events detailed above 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. 
8.5.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
Disease related events (DREs) or outcomes listed in the CDC Classification System for 
HIV-1 Infections (Section 10.4) can be serious/life threatening and 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. However, if either of the following conditions applies, then 
the event must be recorded and reported as an SAE (instead of a DRE): 
• 
The investigator determines that the event or outcome qualifies as an SAE 
under part ‘other situations’ of the SAE definition (see Section 10.5.2), or 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, 
or duration than expected for the individual participant, or 
• 
The investigator considers that there is a reasonable possibility that the 
event was related to treatment with the investigational product, or 

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• 
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 DRE on the SAE page rather than 
the HIV Associated Conditions eCRF page and report promptly (i.e., expedited reporting, 
see Section 10.5.2) to GSK. 
8.5.8. 
Medical Device Deficiencies 
The vial adaptor, syringe, and needles used in the study are classed as medical devices by 
the US Food and Drug Administration (FDA). To fulfill regulatory reporting obligations 
worldwide, the investigator is responsible for the detecting and documentation of events 
meeting the definitions of device deficiency that occur during the study with such 
devices.  
The definition of a medical device deficiency can be found in Section 10.16 
NOTE: Medical device deficiencies associated with an SAE will be reported together 
with an SAE form. AEs associated with a medical device deficiency must be documented 
in the eCRF. 
8.5.8.1. 
 Time period for Detecting Medical Device Deficiencies 
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.  
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such device deficiency is considered reasonably related to 
a medical device provided for the study, the investigator will notify the sponsor within 24 
hours. 
Medical device deficiencies and any associated AE/SAEs for associated persons (i.e. 
healthcare professionals) will be collected. The associated person will provided with a 
safety reporting information and authorisation letter. 
The method of documenting Medical Device Incidents is provided in Section 10.16.  
8.5.8.2. 
Follow-up of Medical Device Deficiencies 
Follow-up applies to all participants, including those participants who discontinue study 
treatment or the study, and associated persons. 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 

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New or updated information will be recorded on the original completed form with all 
changes signed and dated by the investigator. 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
Device deficiencies will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a device deficiency. 
The medical device deficiency report form will be sent to the sponsor by email.  
The sponsor will be the contact for the receipt of device deficiency reports. 
Regulatory Reporting Requirements for Medical Device Deficiencies 
The investigator will promptly report all deficiencies occurring with any medical device 
used for CAB+RPV in the study, as described in Section 10.16 in order for the sponsor to 
fulfil the legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical studies. 
The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
8.6. 
Pharmacokinetics 
Pharmacokinetic samples may be collected in cases of maladministration, liver events, to 
follow-up pregnancy, at plasma HIV 1 RNA retest of SVF, or as directed by the medical 
monitor. 
Pregnant participants will have additional PK samples collected during the duration of the 
pregnancy. See Appendix 15: Information and Guidance for Managing Pregnant 
Participants 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Genetics 
Genetics are not evaluated in this study. 
8.9. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10. 
Viral Genotyping and Phenotyping 
Whole venous blood samples will be obtained from each participant to provide PBMCs 
and plasma for storage samples according to the Schedule of Activities Table (see 
Section 1.3) for potential viral genotypic and phenotypic analyses. 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
1 2 7  
 
Ge n ot y pi c a n d p he n ot y pi c a n al yses ma y b e carrie d o ut b y M o n o gra m Bi os cie nces usi n g, 
b ut n ot li mite d t o, t heir Sta n dar d P he n o Se nse a n d Ge n o S ure testi n g met h o ds f or pr oteas e 
( P R O), re verse tra ns cri pt ase ( R T), a n d i nte grase assa ys. 
8. 1 0. 1.  
HI V -1 P ol y m er a s e  Vir al G e n ot y pi n g a n d P h e n ot y pi n g  
Partici pa nts meeti n g c o nfir me d vi r ol o gic fail ure will ha ve plas ma sa m ples teste d f or 
HI V -1 P R O a n d R T ge n ot y pe a n d p he n ot y pe a n d HI V -1 i nte grase ge n ot y p e a n d 
p he n ot y p e fr o m sa m ples c ollecte d at t he ti me of m eeti n g s us p ecte d vir ol o gi c fail ure; 
t hese res ults will be re p orte d t o t he I n vesti gat or as s o o n as a vaila ble t o pr o vi de g ui da nce 
f or ele cti o n of a n alter nati ve re gi me n. 
8. 1 1.  
H e alt h E c o n o mi c s  
Healt h Ec o n o mics/ Me dic al Res o urce Utilizati o n a n d Healt h Ec o n o mics para meters are 
n ot e val uate d i n t his st u d y.  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1.  
St ati sti c al  H y p ot h e s e s  
T he h y p ot h eses o n t he q u a ntitati ve as pects of t his st u d y is t hat e n ha n ce d i m ple me ntati o n 
strate g y is s u peri or t ha n t he sta n dar d i m ple me ntati on strate g y  i n ter ms of m ea n staff 
st u d y partici p a nt ( S S P) AI M/I A M/ FI M s c ores. i. e., 
H 0: µ(e n ha nce d) = µ(sta n dar d) vs. H1: µ(e n ha nce d) > µ(sta n dar d) 
9. 2.  
S a m pl e Si z e  D et er mi n ati o n  
T he st u d y siz e is base d o n practical c o nsi derati o ns i n ter ms of feasi bilit y of e nr olli n g a n 
a de q uate n u m b er of sites o n eac h i m ple me ntati o n strate g y bala nce d wit h t h e desire t o 
ha ve i nter ve nti o ns teste d acr oss se v eral t y pes of i n vesti gati ve sites; as well as e nr olli n g 
a n a de q u ate n u m ber of patie nt st u d y partici pa nts i n eac h site .  
 
C CI

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Approximately 24 sites (from feasibility process) will be selected from the feasibility 
process to achieve 18 sites randomly assigned to study implementation strategies and 
approximately 54 evaluable staff study participants for an estimated total of 27 
evaluable study staff participants per implementation strategy group. 
Assuming 10% screen failures, it is estimated that with 18 sites approximately 527 
patient study participants will be screened to achieve 474 subjects enrolled and 450 
evaluable patient study participants completing the study (assumes 5% of patient 
study participants would be non-evaluable) for an estimated total of 225 evaluable 
patient study participants per implementation strategy group. 
Power to Show Superiority in mean SSP AIM/IAM/FIM scores 
Table 10 shows preliminary AIM/IAM/FIM data from the ongoing U.S. implementation 
study CUSTOMIZE (209493). 
Table 10 
Staff Study Participants Scores at Month 4 in CUSTOMIZE (209493) 
 
N 
Mean 
SD 
Median 
Observed 
Range 
(min-max) 
Floor 
n (%) 
Ceiling 
n (%) 
Skewness 
Kurtosis 
AIM 
Scale 
(Total 
Sample) 
24 
4.39 
0.61 
4.13 
3.25-5.00 
0 
(0.0%) 
11 
(45.8%) 
-0.16 
-1.58 
IAM 
Scale 
(Total 
Sample) 
24 
4.45 
0.59 
4.50 
3.25-5.00 
0 
(0.0%) 
12 
(50.0%) 
-0.34 
-1.39 
FIM 
Scale 
(Total 
Sample) 
24 
4.32 
0.71 
4.25 
3.00-5.00 
0 
(0.0%) 
11 
(45.8%) 
-0.47 
-1.09 
 
Based on these preliminary data from CUSTOMIZE study, and the given sample size (the 
number of study participants) , the power to detect a difference of 0.5 between the 
implementation arms in terms of AIM, IAM and FIM are shown in Table 11. 
Table 11 
Power to Detect a 0.5 Difference in AIM/IAM/FIM 
Endpoint 
ARM-S 
ARM-E 
Delta 
SD 
Alpha 
N(S) 
N(E) 
Power* 
AIM 
4.39 
4.89 
0.5 
0.61 
0.05 
27 
27 
84% 
36 
36 
93% 

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Endpoint 
ARM-S 
ARM-E 
Delta 
SD 
Alpha 
N(S) 
N(E) 
Power* 
IAM 
4.45 
4.95 
0.5 
0.59 
0.05 
27 
27 
86% 
36 
36 
94% 
FIM 
4.32 
4.82 
0.5 
0.71 
0.05 
27 
27 
72% 
36 
36 
84% 
*Power calculation using two-sided t-test assuming equal variance. 
 
As shown in Table 11, with 27 study staff participants (3 per site) surveyed on each arm, 
the study would have 72%-86% power to detect a 0.5 difference in FIM, AIM and IAM 
endpoints between ARM-E (Enhanced implementation strategy arm) and ARM-S 
(Standard implementation arm) assuming data from Table 10 (CUSTOMIZE study) for 
ARM-S. 
And with 36 study staff participants (4 per site) surveyed on each arm, the study would 
have 84% - 94% power to detect a 0.5 difference in FIM, AIM and IAM endpoints 
between ARM-E and ARM-S. 
Sample Size for Provider Population 
An overall average number of 9 sites, per arm, would produces a two-sided 95% 
confidence interval with a distance from the mean paired difference (e.g. site level mean 
change from baseline in AIM, IAM or FIM score) to the limits (half-width) that is equal 
to 0.497 when the estimated standard deviation of the paired differences is 1.0, across 
sites. 
Table 12 
Sensitivity Analysis for Sample Size versus Half-Width (Precision)- 
Two-Sided 95% Confidence Interval (For Number of Sites) 
Sample Size 
Actual Distance from Mean 
Difference to Limits (Precision) 
SD=0.5 
SD=1.0 
10 
0.358 
0.715 
11 
0.336 
0.672 
12 
0.318 
0.635 
13 
0.302 
0.604 
14 
0.289 
0.577 
15 
0.277 
0.554 
16 
0.266 
0.533 
17 
0.257 
0.514 
18 
0.249 
0.497 
19 
0.241 
0.482 
20 
0.234 
0.468 
 

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A sample size of 27 providers, per arm, produces a two-sided 95% confidence interval 
with a distance from the mean paired difference to the limits (half-width) that is equal to 
0.396 when the estimated standard deviation of the paired differences is 1.0. 
Table 13 
Sensitivity Analysis for Sample Size versus Half-Width (Precision)- 
Two-Sided 95% Confidence Interval (for Number of Providers) 
Sample Size 
Actual Distance from Mean 
Difference to Limits (Precision) 
SD=0.5 
SD=1.0 
 
 
 
21 
0.228 
0.455 
22 
0.222 
0.443 
23 
0.216 
0.432 
24 
0.211 
0.422 
25 
0.206 
0.413 
26 
0.202 
0.404 
27 
0.198 
0.396 
28 
0.194 
0.388 
29 
0.190 
0.380 
30 
0.187 
0.373 
Figure 6 
Sensitivity Analysis for Sample Size versus Half-Width (Precision)- 
Two-Sided 95% Confidence Interval (for Sites and Providers) 
 
Sample Size for Patient Population 
A sample size of 225 patient subjects per implementation strategy group produces a two-
sided 95% confidence interval with a distance from the mean paired difference to the 
limits that is equal to 0.131 when the estimated standard deviation of the paired 
difference is 1. 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
1 3 1  
 
T a bl e 1 4  
S e n siti vit y A n al y si s  f or S a m pl e Si z e v er s u s H alf-Wi dt h ( Pr e ci si o n) - 
T w o -Si d e d 9 5 % C o nfi d e n c e I nt er v al (f or P ati e nt s ) 
S a m pl e Si z e  
A ct u al Di st a n c e fr o m M e a n 
Diff er e n c e t o Li mit s ( Pr e ci si o n)  
S D = 0. 5  
S D = 1. 0  
1 0 0  
0. 0 9 9  
0. 1 9 8  
1 2 5  
0. 0 8 9  
0. 1 7 7  
1 5 0  
0. 0 8 1  
0. 1 6 1  
1 7 5  
0. 0 7 5  
0. 1 4 9  
2 0 0  
0. 0 7 0  
0. 1 3 9  
2 2 5  
0. 0 6 6  
0. 1 3 1  
2 5 0  
0. 0 6 2  
0. 1 2 5  
 
Fi g ur e 7  
S e n siti vit y A n al y si s f or S a m pl e Si z e v er s u s H alf -Wi dt h ( M e a n Dif f t o 
Li mit) v er s u s S a m pl e Si z e - P ati e nt s ( M ulti pl e C o nfi d e n c e L e v el s)  
 
 
As e x plai ne d i n ot her parts of t his pr ot oc ol, la u nc hi n g C A B L A + R P V L A i n t he real 
w orl d ma y pres e nt c halle n ges t hat were n ot o bs er ve d i n a cli ni cal trial setti n g. T heref ore,  
i n a d diti o n t o t he pri mar y a nal ys es w hic h f oc uses o n st u d y staff partici pa nts data, 
statistical a nal ys es of patie nt o utc o me e n d p oi nts will be perf or me d t o e val uate c ha n ges i n 
st u d y patie nts’ satisf acti o n sc ore res ults, t o all o w a f or mal c o m paris o n b et w ee n  t he t w o 
i m ple me ntati o n strate gies.    
 
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
1 3 2  
 
9. 3.  
P o p ul ati o n A n al y s e s  
T he f oll o wi n g k e y p o p ul ati o ns are defi ne d.  A n y f urt her p o p ulati o n defi niti o ns will be 
detaile d i n t he R A P:  
P o p ul ati o n  
Defi niti o n / Criteri a  
I nte nt-T o -Treat -
E x p ose d (I T T -E)  
•  
All assi g ne d patie nt partici pa nts w h o recei ve d at least o ne d ose 
of st u d y treat me nt.  
•  
T his p o p ulati o n will be base d o n t he treat me nt t he s u bject was 
ra n d o mize d t o ( All s u bjects were assi g ne d t o t he sa me dr u g 
re gi me n i n t his st u d y) 
•  
A n y partici pa nt w h o recei ves a partici pa nt n u m ber will be 
c o nsi dere d t o ha ve bee n assi g ne d.  
Safet y  
•  
All assi g ne d partici pa nts w h o recei ve d at least o ne d ose of C A B 
Oral + R P V Oral or C A B L A + R P V L A.  
•  
All patie nts recei ve t he sa me dr u g re gi me n, C A B L A + R P V L A  
 
9. 4.  
St ati sti c al A n al y s e s  
T here will be t w o mai n re p orti n g a n d a nal ysis ti mefra m es.  First, will be t h e pri mar y 
c o m plete a nal yses w hic h will be c o n d ucte d w h e n t he last st u d y partici p a nt has c o m plete d 
t heir C A B L A + R P V L A st u d y treat me nt u p t o D ose 7.  All st u d y staff partici pa nt (site-
le vel) q uesti o n naire a n d i nter vie w data, pl us all st u d y partici pa nt (s u bject -le vel) data will 
be i ncl u de d i n t his re p orti n g a n d a nal ysis eff ort.  
O nce all st u d y partici p a nts ha ve c o m plete d t he st u d y, fi nal a nal yses of t h e data will als o 
be c o n d ucte d  
T he statistical a nal ysis pla ns will be fi nalize d pri or t o D B L a n d it will i ncl u de a m ore 
tec h nical a n d d etaile d descri pti o n of t he statistical a nal ys es descri be d i n t his secti o n. T his 
secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of e n d p oi nts. A nal ysis o n patie nt 
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study participant data will account for sites that patients are nested in. The reporting 
analysis plan will provide further details of the analyses. 
As mentioned above, this study has both site- and subject-level outcomes and each 
outcome will be analyzed and summarized accordingly. 
Qualitative interview data will be summarized by a third party and reported as part of the 
overall study results (CSR). Details of these analyses will be described in a separate 
analysis plan provided by the CRO partner under GSK’s oversight. 
Qualitative Analytic Strategy and Data Integration. The EPIS-informed qualitative data 
collected from both the study staff participants and the providers are embedded within the 
quantitative outcome of the study for expansion, development, and convergence. All 
qualitative data will be recorded, transcribed, translated if necessary, cleaned.  Data will 
be entered into a qualitative data management software and any notes from calls made to 
study staff team that are related to study outcomes will be compiled and analyzed.  The 
Clinical Research Organization or an identified expert consultant will be responsible for 
coding all qualitative assessments for use in the evaluation of feasibility, acceptability, 
appropriateness, barriers and facilitators of future implementation, and potential 
modification suggestions to implementation strategies. Established procedures to enhance 
validity will be used, including development of an audit trail documenting analytical 
decisions.  All coding decisions will be noted for further review. Rater agreement will be 
assessed through a second rater coding a subset of the data, and agreement will be 
reported. We will also use a check-coding model where the primary coder will code and 
recode a percentage of the same material to ensure there is over a 90% consistency.  
A theory-driven approach to explore the relationship between the findings and the EPIS 
framework will be followed. The goals, objectives and key research questions will guide 
all aspects of the qualitative analyses. Using content analysis, we will identify analytical 
categories to describe and explain observations. Our work will occur in five stages 
outlined in Mays et al. framework approach to qualitative analysis: 1) Familiarization, 2) 
Identifying a Thematic Framework, 3) Indexing, 4) Charting, and 5) Mapping and 
Interpretation. Codes will be derived deductively by identifying categories at the 
beginning of the research (e.g., elements of the EPIS framework) and inductively by 
identifying those that emerge gradually from the data. Operational definitions of each 
code will be used and through constant comparison, updates to the coding model will 
occur throughout to support efforts to index the data and lead to further refinement. In the 
charting and mapping phases, we will integrate the qualitative and quantitative data for 
expansion, development, and convergence, and based on our research questions, themes, 
commonalities and variations in themes, and findings related to training, feasibility, 
acceptability, and fidelity-related issues will be examined. Data integration will assist a 
fine-grained understanding of processes and characteristics that may influence 
effectiveness and implementation outcomes of CAB LA+ RPV LA in sites across 
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9.4.1. 
Primary Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Staff Study Participants (SSP):  
 
Change from baseline at Month 12 
in Acceptability of Intervention 
Measure (AIM), Intervention 
Appropriateness Measure (IAM), 
and Feasibility of Intervention 
Measure (FIM) 
 
 
Acceptability of Implementation Measure (AIM), 
Implementation Appropriateness Measure (IAM), 
and Feasibility of Implementation Measure (FIM) 
will be summarized using descriptive statistics 
including 95% confidence intervals.  Data will be 
summarized by month of study/injection visit and 
by implementation strategy as actual values and 
change from baseline. Mean AIM, IAM and FIM 
scores will be compared between the two 
implementation arms. In addition, distribution of 
AIM, IAM and FIM items scores will also be 
compared. P-values will be reported for these 
comparisons. 
 
Responses will also be summarized overall and by 
site type. Exploratory analyses will be undertaken 
to assess the variability of responses by factors 
including but not limited to site type, setting and 
for subject level outcomes markers of 
demographic and baseline characteristics. 
 

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9.4.2. 
Secondary Endpoint(s) 
Endpoints 
Statistical Analysis Methods 
Staff Study Participants (SSP)  
Change of Implementation 
Leadership Scale (ILS), Change 
and Implementation Climate Scale 
(ICS) over time assessed 
quantitatively via questionnaires 
through Month 12 
 
 
 
 
 
 
FRAME-IS outcome Months 2 – 
12 (monthly) 
 
Implementation Leadership Scale (ILS), and 
Implementation Climate Scale (ICS) will be 
summarized using descriptive statistics including 
95% confidence intervals.  Data will be summarized 
by month of study as actual values and change from 
baseline. 
 
Responses will also be summarized overall and by 
site type. Exploratory analyses will be undertaken 
to assess the variability of responses by factors 
including but not limited to site type, setting and for 
subject level outcomes markers of demographic and 
baseline characteristics. 
 
Responses from the FRAME-IS outcome will be 
summarized by month. 
Patient Study Participants (PSP)  
 
Length of patient study participant 
visit from arrival until departure 
from clinic assessed at Dose 
1,Dose 2, Dose 4, and Dose 5. 
 
Change in Acceptability of 
Intervention Measure (AIM) Score, 
Intervention Appropriateness 
Measure (IAM) Score, and 
Feasibility of Intervention Measure 
(FIM) Score over time. Assessed 
via questionnaires at Dose 7. b 
 
 
The length of patient study participant visit will be 
determined from the time of arrival to time of 
departure and summarized using descriptive 
statistics including 95% confidence intervals. 
 
Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM), and 
Feasibility of Intervention Measure (FIM) will be 
summarized using descriptive statistics including 
95% confidence intervals.  Data will be summarized 
by month of study/injection visit and by 
implementation strategy as actual values and 
change from baseline. Mean AIM, IAM and FIM 
scores will be compared between the two 
implementation arms. In addition, distribution of 
AIM, IAM and FIM items scores will also be 
compared. P-values will be reported for these 
comparisons. 
 
Responses will also be summarized overall and by 
site type. Exploratory analyses will be undertaken 
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Endpoints 
Statistical Analysis Methods 
including but not limited to site type, setting and for 
subject level outcomes markers of demographic and 
baseline characteristics. 
Study Staff Participants: 
 
Total score of the Clinical 
Sustainability Assessment Tool 
(CSAT) at Month 12 
 
 
Total score of the Clinical Sustainability 
Assessment Tool (CSAT) will be summarized using 
descriptive statistics including 95% confidence 
intervals.  Data will be summarized by month of 
study as actual values and change from baseline. 
 
 
Percentage of injections occurring 
within target window from the 
target date. 
 
Percentage of injections occurring within target 
window from the target date, will be summarized at 
Month 12, including 95% confidence intervals 
 
The patient’s ‘target date’ is determined by their 
first injection date 
 
Proportion of participants with 
plasma HIV-1 RNA <50 c/mL over 
time  
 
 
 
Proportion of participants with 
confirmed virologic failure (CVF) 
over time  
 
Incidence of treatment-emergent 
genotypic and phenotypic 
resistance to CAB and RPV in 
patient study participants with CVF 
Incidence and severity of AEs and 
SAEs over time and the proportion 
of participants who discontinue 
treatment due to AEs over time  
The proportion of participants with HIV-1 RNA 
<50 c/mL, based on the snapshot algorithm, will be 
summarized at Dose 7, with 95% confidence 
intervals 
The proportion of participants with HIV-1 RNA >= 
50c/mL, respectively, based on the snapshot 
algorithm, will be summarized at Dose 7, with 95% 
confidence intervals.  
Summary of proportion of participants with 
confirmed virologic failure (CVF) over time using 
the FDA Snapshot algorithm in the ITT-E 
population 
Incidence of treatment-emergent genotypic and 
phenotypic resistance to CAB and RPV in patient 
study participants with CVF will be summarized at 
Dose 7, with 95% confidence intervals 
Incidence and severity of AEs and SAEs over time, 
will be summarized, with 95% confidence intervals. 
Proportion of participants who discontinue 
treatment due to AEs over time will be summarized. 

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Endpoints 
Statistical Analysis Methods 
Preference between CAB + RPV 
LA and daily oral ART medication 
(received prior to entering the 
study) quantitatively assessed via 
preference questionnaire at Dose 7 
The proportion of participants preferences between 
CAB + RPV LA and daily oral ART medication 
(received prior to entering the study) with be 
summarized at Dose 7.  
 
Reported injection site reactions 
over time  
 
Absolute values and changes in 
laboratory parameters over time 
 
Reported injection site reactions over time will be 
summarized 
 
Absolute values and changes in laboratory 
parameters over time will be summarized, with 95% 
confidence intervals 
 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
1 3 8  
 
9. 4. 4.  
Ot h er A n al y s e s  
T he i m pact of de m o gra p hic para met ers i ncl u di n g, b ut n ot li mite d t o, a ge, ge n der, race, or 
ot her de m o gra p hi c fact ors as p ote ntial pre dict ors of i nter - a n d i ntra-partici pa nt varia bilit y 
f or acce pta bilit y, a d o pti o n, a p pr o priate ness, a n d s ustai na bilit y m a y be e x pl ore d if 
s ufficie nt data are a vaila ble fr o m patie nts.  
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For clinics, baseline clinic characteristics will be collected and analyzed for potential 
confounders.  Additionally, endpoints may be analyzed by study arm, by country, clinic 
archetype and by provider type. 
9.5. 
Interim Analyses 
One or more interim analysis will be conducted to provide early evaluation of the 
implementation science primary and key secondary objectives. No changes to the study 
conduct will occur. 
Completed staff and patient participant questionnaire and interview data collected at the 
time of the interim data cut, will be included in the analyses. In addition, a limited 
number of eCRF datasets will be included in order to describe the characteristics of the 
patient study participants enrolled. 
The timing of the interim/s will be based on when a sufficient number of staff study 
and/or patient study participant questionnaires and interviews have been completed. 
No formal criteria for stopping or amending the study based on interim analysis results 
will be made.  
An interim Reporting and Analysis Plan will describe the planned analyses in greater 
detail.  
9.6. 
Data Monitoring Committee 
No data monitoring committee will be assigned to this study as all subjects are receiving 
the same regimen (open-label) and appropriate safety medical and laboratory monitoring 
is included in the study. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight  
10.1.1. 
Regulatory and Ethical Considerations 
Prior to initiation of a site, ViiV/GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements. 
• 
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, Investigator Brochure, 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.  
• 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC 
• 
Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence 
to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities.  

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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her 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 the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
• 
Participants who become pregnant while in the study and who elect to continue 
to receive CAB + RPV LA injections must sign the pregnancy specific ICF 
addendum. 
• 
If follow-up information from a treating physician or other licensed medical 
practitioner is required for a medical device incident with an AE/SAE involving 
an associated person(s), the Associated Person Safety Reporting Information 
and Authorization Letter must be signed by the associated person to obtain 
consent.  
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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by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.5. 
Quality Control (Study Monitoring) 
• 
In accordance with applicable regulations including GCP, and GSK 
procedures, GSK monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements. 
• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of participants are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
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. 
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 
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• 
GSK will also provide the Investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the  
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
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 (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 data management 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. 
• 
Guidance on completion of CRFs will be provided in CRF completion 
guidelines. 
• 
Quality tolerance limits (QTLs) will be pre-defined in the quality tolerance 
limits plan to identify systematic issues that can impact participant safety and/or 
reliability of study results. These pre-defined parameters will be monitored 
during the study and deviations from the QTLs and remedial actions taken will 
be summarized in the clinical study report. 
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 

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• 
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.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the 
final Clinical Study Report (CSR)/ equivalent summary unless local regulations 
or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
10.1.9. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the Investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 

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Investigator or the head of the medical institution, where applicable, of the 
impending action. 
• 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the Investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
• 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.   
• 
If required by applicable regulations, the Investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 

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10.2. 
Appendix 2: Division of AIDS Table for Grading the Severity 
of Adult and Paediatric Adverse Events Version 2.1, March 
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 utilized 
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. 
 
 

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DAIDS, 2017 

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10.3. 
Appendix 3: Liver Safety: Required Actions, Follow-up 
Assessments and Study Intervention Restart Guidelines 
Study treatment refers to all drugs evaluated in the study and therefore includes ViiV 
study intervention and non-ViiV ART therapies that can be used in combination with 
ViiV products or other ART interventions. 
 
A liver stopping event is an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that trigger discontinuation of study treatment and requirement of 
additional actions and follow up assessments to be performed. 
 
A liver monitoring event is as an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that triggers increased monitoring of the participant’s liver 
chemistries, but no action is taken with study treatment unless liver chemistry stopping 
criteria are met. 
 
10.3.1. 
Liver chemistry stopping criteria and Required Actions and 
Follow-up Assessments 
Study treatment or Investigational Product must stop immediately when participant meets 
one of the criteria described in below: 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
If baseline ALT ≤ 1.5x ULN 
ALT-absolute ALT  8x ULN 
ALT Increase ALT  5x ULN but <8x ULN persists for 2 weeks (with bilirubin 
<2x ULN and no signs or symptoms of acute hepatitis or 
hypersensitivity) 
Bilirubin1, 2 
ALT  3x ULN and bilirubin  2x ULN (>35% direct bilirubin)  
Cannot 
Monitor 
ALT  5x ULN but <8x ULN and cannot be monitored every 1 - 2 
weeks 
Symptomatic3 ALT  3x ULN with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
If baseline ALT > 1.5x ULN 
ALT-absolute 
ALT ≥ 5x baseline OR > 500 U/L (whichever occurs first) 
ALT Increase 
ALT ≥ 3x baseline but <5x baseline persists for ≥2 weeks (with 
bilirubin <2x ULN and no signs or symptoms of acute hepatitis or 
hypersensitivity) 

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Liver Chemistry Stopping Criteria - Liver Stopping Event 
Bilirubin1, 2 
ALT ≥ 3x baseline OR > 300 U/L (whichever occurs first) and 
bilirubin ≥ 2x ULN 
Cannot 
Monitor 
ALT ≥ 3x baseline but <5x baseline 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. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study intervention for that participant if 
ALT 3x ULN and bilirubin 2x ULN.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 3x ULN and bilirubin 2x ULN (>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). 
 
 
Required Actions and Follow up Assessments following ANY Liver Stopping 
Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study 
intervention. 
• Report the event to the Medical 
Monitor within 24 hours. 
• Complete the liver event eCRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2. 
• Complete the liver imaging and/or liver 
biopsy eCRFs if these tests are 
performed. 
• Perform liver event follow up 
assessments.  
• Monitor the participant until liver 
chemistries resolve, stabilise, or return 
to within baseline (see MONITORING 
below). 
Make every attempt to carry out liver 
event follow-up assessments at the 
central laboratory as described below: 
• 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). 

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Required Actions and Follow up Assessments following ANY Liver Stopping 
Event 
Actions 
Follow Up Assessments 
• Do not restart participant with study 
intervention unless allowed per protocol 
and VSLC approval is granted (refer to 
Section 10.3.2.2). 
• If restart is not allowed or not 
granted, permanently discontinue study 
intervention and may continue 
participant in the study for any protocol 
specified follow up assessments. 
 
 
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.  
• Monitor participants twice weekly until 
liver chemistries resolve, stabilise or 
return to within baseline. 
• A specialist or hepatology consultation 
is recommended. 
• Syphilis screening. 
• Drugs of abuse screen, including 
alcohol. 
• 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). 
• Fractionate bilirubin, if total 
bilirubin ³1.5x ULN. 
• 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). 
• 
Gamma glutamyl transferase 
[GGT], glutamate dehydrogenase 
[GLDH], and serum albumin 
• 
International normalized ratio (INR) 
• Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and 
/or liver biopsy to evaluate liver 
disease; complete Liver Imaging 

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Required Actions and Follow up Assessments following ANY Liver Stopping 
Event 
Actions 
Follow Up Assessments 
and/or Liver Biopsy eCRF 
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. 
CPK - creatine phosphokinase 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation 
is not immediately available, discontinue study intervention for that participant if ALT 3x ULN and 
bilirubin 2x ULN. 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 3x ULN and bilirubin 2x ULN (>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. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to blood sample draw on the eCRF. 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. 
 
10.3.2. 
 Study Intervention Restart after Stopping for Liver Criteria 
Drug Restart refers to resuming study treatment following liver events meeting stopping 
criteria in which there is a clear underlying cause (other than DILI) of the liver event (e.g. 
cholecystolithiasis, acute viral hepatitis, leptospirosis; syphilitic hepatitis). Furthermore, 
there should be no evidence of alcoholic hepatitis or hypersensitivity, and the drug should 
not be associated with HLA markers of liver injury. (Figure 8, Table 16) 
 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
1 7 4  
 
Rest arts s h o ul d be li mite d t o c ases i n w hic h t here is cle ar e vi de nce t h at t he 
u n de rl yi n g c a use of t he li ver e ve nt is n ot rel ate d t o st u d y dr u g.  
If partici pa nt me ets li ver c he mistr y st o p pi n g criteria d o n ot restart partici pa nt wit h st u d y 
treat me nt u nless: 
•  
Vii V  Healt hcare Safet y a n d La b elli n g C o m mittee ( V S L C) a p pr o val is gr a nte d 
•  
Et hics a n d/ or I R B a p pr o val is o btai ne d, if re q uir e d, a n d  
•  
Se parate c o nse nt f or tr eat me nt restart is si g n e d b y t he partici pa nt  
If V S L C a p pr o val t o restart s u bject wit h st u d y tr eat me nt is n ot gr a nte d , t he n 
s u bject m ust per ma ne ntl y disc o nti n ue st u d y treat me nt a n d ma y c o nti n ue i n t he 
st u d y f or pr ot oc ol-s pecifie d f oll o w u p assess me nts ( Secti o n 1 0. 3 ). 
1 0. 3. 2. 1.  
Dr u g  R e st art  
 “ Dr u g restart” ca n be a p pr o ve d b y t he V S L C f or tr a nsie nt, defi ne d n o n-dr u g -i n d uce d 
li ver i nj ur y if n o e vi de nce of: 
• 
 i m m u n oaller gic i nj ur y / H L A ass ociati o n wit h i nj ur y 
• 
alc o h olic he patitis  
St u d y dr u g m ust be hel d w hile la bs a n d e val u ati o n are c o m plet e d t o assess dia g n osis.  
C CI

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

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

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

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10.4. 
Appendix 4: CDC Classification for HIV-1 Infection (CDC, 
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 
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  
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  
• 
No information on CD4+ T-lymphocyte count or percentage, and  
• 
No information on presence of AIDS-defining conditions. 
Stage-3-defining opportunistic illnesses in HIV infection 
• 
Candidiasis of bronchi, trachea, or lungs  

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• 
Candidiasis of oesophagus  
• 
Cervical cancer, invasive 
• 
Coccidioidomycosis, disseminated or extrapulmonary  
• 
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. 
Reference 
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014.  
MMWR 2014; 63 (RR-03);1-10. 
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, Version 
2.1. [March 2017]. Available from: https://rsc.tech-res.com/docs/default-
source/safety/daids-ae-grading-table-mar2017.pdf 

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10.5. 
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
10.5.1. 
Definition of Adverse Events 
Adverse Event Definition: 
• 
An AE is any untoward medical occurrence in a patient or clinical investigation 
participant, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
• 
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 medicinal product. 
Events meeting AE definition include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator. 
• 
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 treatment administration even though it 
may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication (overdose per se will not be reported as an AE/SAE unless 
this is an intentional overdose taken with possible suicidal/selfharming intent.  This 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.  However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE. 

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Events NOT meeting definition of an AE include: 
• 
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 an AE. 
• 
Situations where 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. 
10.5.2. 
Definition of Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc.). 
 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
Results in death 
Is life-threatening 
NOTE: 
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. 

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Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
In general, hospitalization signifies that the participant has been detained (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 out-patient setting.  
Complications that occur during hospitalization are AEs.  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.  
Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 

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Is associated with liver injury and impaired liver function defined as: 
• ALT  3xULN and total bilirubin*  2xULN (>35% direct), or 
• ALT  3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT  3xULN 
and total bilirubin  2xULN, then the event is still to be reported as an SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
 
10.5.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the eCRF 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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10.5.4. 
Recording of AEs and SAEs 
AEs 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) relative to 
the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in the eCRF 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
GSK.  In this instance, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records prior to submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms. 
10.5.5. 
Evaluating AEs and SAEs 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and will assign it to one of the following categories: 
Mild:  An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday activities 
Severe:  An event that prevents normal everyday activities. - an AE that is assessed as severe will 
not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; 
and both AEs and SAEs can be assessed as severe. 
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. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" is meant to convey that there are facts/evidence 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. 

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• 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated. 
• 
The investigator will also consult the Investigator Brochure (IB) and/or Product Information, 
for marketed products, in the determination of 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 when 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 prior to the initial 
transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE data collection tool accordingly. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as 
fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health  

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10.5.6. 
Reporting of SAEs to GSK 
 
SAE reporting to GSK via electronic data collection tool 
• 
Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use the paper 
SAE data collection tool and fax it to the Medical Monitor. 
• 
Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available. 
• 
The investigator will be required to confirm review of the SAE causality by ticking the 
‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the SAE. 
• 
After the study is completed at a given site, the electronic data collection tool (e.g., InForm 
system) 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, 
the site can report this information on a paper SAE form or to the Medical Monitor by 
telephone. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page. 
SAE reporting to GSK via paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Medical Monitor or the SAE coordinator 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable, with a copy of the SAE data collection tool sent by overnight mail 
• 
Initial notification via the telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page. 

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10.6. 
Appendix 6: Toxicity Management 
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (See Section 10.2 
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events”).  Additional information regarding detecting, documenting and reporting AEs 
and SAEs are available in Section 10.5 and Section 8.5. 
10.6.1. 
Treatment Interruption Due to an Adverse Event 
IP may be interrupted at the discretion of the Investigator and according to the severity of 
the AE. If one or more antiretroviral medications is held due to toxicity or adverse 
events, all antiretroviral medications must be held to reduce the risk of development of 
resistance considering both the length of the planned interruption and the 
pharmacokinetic half-life of each antiretroviral of the regimen, in a way to minimize the 
risk of development of resistance. 
No toxicity-related dose reductions of IP will be allowed. IP should be restarted as soon 
as medically appropriate; in general, for oral dosing, this should be no longer than 14 
days after discontinuation (unless Grade 3 or 4 toxicities persist). Any interruption in 
therapy during the Treatment Phase, oral dosing, of greater than 7 consecutive days must 
be discussed with and agreed by the Medical Monitor prior to resumption of therapy. The 
Medical Monitor must be contacted upon becoming aware of resumption in therapy, if 
therapy was resumed without prior approval. IM dosing is expected to occur during the 
week in which the participant’s projected visit falls (as according to the date of the 
first injection visit [Month 1] or called Target Date). A +0 / -7 day window is 
stipulated around the target date for dosing injections at Month 2. A +7 / 7 day 
window, from the projected target date, is allowable from the third injections 
forward. Any interruption outside of this guidance MUST be discussed with the Medical 
Monitor prior to reinitiating IM IP. 
Guidance is provided below on general participant management and IP interruptions 
based on the severity of the AE. All changes in the IP regimen must be accurately 
recorded in the participant’s eCRF. 
10.6.2. 
Grade 1 or Grade 2 Toxicity/Adverse Event 
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the Investigator. (NOTE: See Section 10.6 Specific Toxicities/Adverse 
Event Management” for exceptions to this guideline). Participants who choose to 
withdraw from study due to a Grade 1 or 2 AE should have study withdrawal and 
followup evaluations completed. 
Participants who develop ALT ≥3 times ULN while on study must consult with 
Medical Monitor prior to starting or continuing of CAB LA and RPV LA. 

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10.6.3. 
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 IP, dosing may continue after discussion with the Medical 
Monitor. 
• 
Participants who develop a Grade 3 AE or toxicity, which the Investigator 
considers related or possibly related to the IP, should have the IP withheld and be 
rechecked each week until the AE returns to Grade 2.  Once the AE is Grade 2, 
IP may be re-started.  
• 
Should the same Grade 3 AE recur within 28 days in the same participant, the IP 
should be permanently discontinued and the participant withdrawn from study.  
• 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and to have withdrawal 
study evaluations completed. A follow-up visit should be performed 2-4 weeks 
after the last dose of IP.  Any participant receiving at least one dose of CAB LA 
and /or RPV LA who discontinue IP / Withdraw will initiate treatment with 
HAART and enter the Long-Term Follow-Up Phase for 52 weeks of follow up.  
• 
Participants with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue IP if the Investigator has compelling 
evidence that the toxicity is not related to IP, with the exception of liver chemistry 
stopping criteria (See Section 10.6.5.1). Isolated Grade 3 lipid abnormalities do 
not require withdrawal of IP. 
10.6.4. 
Grade 4 Toxicity/Adverse Event 
• 
Participants who develop a Grade 4 AE or toxicity must have IP permanently 
discontinued.  However, if the Investigator has compelling evidence that the AE 
is not causally related to the IP, dosing may continue after discussion with and 
assent from the Medical Monitor.  Participants should be rechecked each week 
until the AE returns to Grade 2. 
• 
Participants experiencing Grade 4 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and encouraged to complete 
the withdrawal and follow-up study evaluations as noted above.  Any participant 
receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART and enter the Long-Term 
FollowUp Phase for 52 weeks of follow up.  
• 
Participants with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue therapy if the Investigator has 
compelling evidence that the toxicity is not related to IP, with the exception of 
liver chemistry stopping criteria. An in-clinic follow-up visit will be performed 
approximately 2-4 weeks after the last dose of study medication if AEs, SAEs, or 

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laboratory abnormalities considered potentially harmful to the participant are 
ongoing at the last on-study visit.  Isolated Grade 4 lipid abnormalities do not 
require withdrawal of IP. 
Participants should permanently discontinue study drug [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the etiology of the rash has been definitively diagnosed as NOT 
attributable to study drug (see below), and the participant should be withdrawn from the 
study.  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. 
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 – see Section 10.2). 
However, if the etiology of the rash has been definitively diagnosed as being unrelated to 
study drug and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed and 
documentation of the diagnosis provided.  In this situation, the study drug should be 
continued.  
Participants in the Follow-Up Phase who are receiving ABC as part of their regimen 
should be evaluated for the possibility of a clinically suspected ABC HSR and managed 
appropriately as outlined in the local prescribing information for ABC. 
Any participant receiving at least one dose of CAB LA and /or RPV LA who 
discontinue IP / Withdraw will initiate treatment with HAART and enter the LTFU 
phase for 52 weeks of follow-up. 
10.6.5. 
Specific Toxicities/ Adverse Event Management 
General guidelines for the management of specific toxicities that are considered to be 
associated with treatment of HIV patients. 
 
Participants who permanently discontinue study drug for reasons of toxicity should be 
followed weekly until resolution of the AE and encouraged to complete the withdrawal 
and Follow-up study evaluations as noted in Section 8.5.3 
10.6.5.1. 
Liver Chemistry Stopping and Follow-up Criteria 
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event etiology during administration of study drug and the 
follow-up phase.  
For a complete listing of stopping and follow-up criteria refer to Section 10.3.1. 

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10.6.5.2. 
Diarrhea 
Participants with Grade 1 or 2 diarrhea may continue study treatment without 
interruption.  Participants with diarrhea of any toxicity grade may be treated 
symptomatically with anti-motility agents; however, the recommended daily dose of the 
chosen anti-motility agent must not be exceeded.  If symptoms persist or get worse on the 
recommended daily dose of the chosen anti-motility agent then the anti-motility agent 
must be discontinued and consultation made with the Medical Monitor. 
For participants with Grade 3 diarrhea that is unresponsive to the recommended dose of 
the anti-motility agents and for which an alternative etiology (e.g., infectious diarrhea) is 
not established, the treatment with the anti-motility agent and IP must be interrupted until 
resolution of diarrhea to Grade 2 or Baseline, after which IP and background ART may 
be resumed after discussion and agreement with the Medical Monitor.  If Grade 3 
diarrhea recurs within 28 days upon the resumption of IP, the IP should be permanently 
discontinued and the participant withdrawn from the study.  Any participant receiving at 
least one dose of CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate 
treatment with HAART and enter the LTFU phase for 52 weeks of follow up. 
If loperamide is used for treatment of diarrhea, local prescribing information should be 
followed with respect to dose and frequency of administration.  Loperamide dosing 
should not exceed local prescribing information. 
10.6.5.3. 
Seizures 
Several cases of seizure have occurred during the cabotegravir program. These cases 
have alternate explanations for their occurrence. ViiV Healthcare has reviewed these 
cases in detail and does not believe they constitute a reasonable likelihood of causation 
associated with CAB. This assessment is supported by the lack of preclinical signal, class 
effect or known CNS mechanism, the relatively low frequency of seizures relative to 
expected rates in both healthy and HIV positive participants and clinical confounders in 
each case. The Sponsor considers the risk of developing seizures on the study as being no 
higher than that of the rest of the HIV-1 infected population.  
Overall, there is not convincing evidence that cabotegravir exposure may be causally 
associated with seizure or with reduction of seizure threshold, due to the low frequency 
of reports, the confounders present in the cases received to date and lack of any 
preclinical signal or identified plausible mechanism. However, seizure and seizure-like 
events are considered as AEs of special interest for close monitoring in studies. Subjects 
with an unstable or poorly controlled seizure disorder will be excluded from study 
participation. 
Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, septic workup and excluding underlying structural abnormalities 
with neuroimaging. 

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Where seizures occur, the Sponsor would like to better characterize these occurrences to 
enable systematic analyses. 
Investigators are requested to document and report seizure or possible seizure events 
promptly (within 24 hours of learning of the event) to the Sponsor for evaluation and 
onward reporting.  Data should be documented on the appropriate eCRF seizure page. 
10.6.5.4. 
Creatine Phosphokinase (CPK) Elevation 
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4 
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 IP, IP should be discontinued, and the 
participant withdrawn from the study.  Any participant receiving at least one dose of 
CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate treatment with 
HAART enter the LTFU phase for 52 weeks of follow-up. 
10.6.5.5. 
Lipase Elevations and Pancreatitis 
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely 
for the development of symptoms. 
Participants with asymptomatic Grade ≥3 elevations in lipase that are considered possibly 
or probably related to IP should have IP interrupted until serum lipase returns to Grade 
≥2.  The lipase assay should be repeated within 2 weeks of any Grade ≥3 result.  
Participants with persistence of Grade ≥3 lipase in the absence of other diagnoses or 
reoccurrence of lipase elevation (at Grade ≥2) following reintroduction of IP should 
permanently discontinue IP. 
Participants with a confirmed diagnosis of clinical pancreatitis that is considered possibly 
or probably related to IP should have IP held.  After complete resolution of the episode, 
participants may be re-challenged with IP after discussion with the Medical Monitor, 
only if the Investigator has compelling evidence that the event was not caused by IP.  
Upon re-challenge, lipase determinations should be performed every 2 weeks for at least 
6 weeks after re-initiation of treatment.  With any elevation of lipase of Grade ≥2 or any 
recurrence of symptoms, the participant should discontinue IP and be withdrawn from 
study. 
Any participant receiving at least one dose of CAB LA and /or RPV LA who discontinue 
IP / Withdraw will initiate treatment with HAART and enter the LTFU phase for 52 
weeks of follow up. 

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10.6.5.6. 
Decline in Renal Function 
Participants who experience an increase in serum creatinine from Baseline of 45 
micromoles/liter (Mol/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 total protein/albumin ratios should also be done at this 
confirmatory visit.  If the creatinine increase is confirmed, the Investigator should 
contact the study medical monitor to discuss additional follow-up and medical 
management. 
Participants who have a decline in the estimated GFR (using the CKD-EPI method) of  
>50% from Baseline must return for a confirmatory assessment as soon as possible 
[Levey, 2009]. A urinalysis and urine albumin/creatinine and urine protein/creatinine 
ratios should also be done at this confirmatory visit. If the estimated GFR has declined by 
>50% (confirmed), then study drug should be withheld and the Investigator should 
contact the study medical monitor to discuss the rationale for restarting study drugs (if 
appropriate).  Consideration for confounding factors (e.g., background therapy, other 
medications, dehydration, concurrent conditions) should be taken into account, and a 
nephrology consult may be obtained.   
10.6.5.7. 
Proximal Renal Tubule Dysfunctions (PRTD) 
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: 
Glycosuria (≥250 mg/dL) in a non-diabetic; 
Low serum potassium (<3 mEq/L); 
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 should have study drug 
withheld and the Investigator should contact the Study medical monitor to discuss the 
rationale for restarting study drugs (if appropriate). Consideration for confounding 
factors (e.g., NRTI backbone, other medications, dehydration, concurrent conditions) 
should be taken into account, and a nephrology consult may be obtained.  If study drug is 
reinitiated, it should have been withheld for no more than 4 weeks. 
 
10.6.5.8. 
Injection Site Reactions (ISRs) 
Injection site reactions will be managed through investigator assessment throughout the 
study.  All ISRs that are either serious, Grade 3 or higher, or persisting beyond 2 weeks 

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must be discussed with the Medical Monitor to determine etiology and assess appropriate 
continued study participation.   
Digital photographs may be documented where possible on all participants who have an 
injection site reaction, with observable findings, that is either serious or Grade 3 or 
higher, or that persists beyond 2 weeks.  Dermatology will be consulted on all 
participants who have an injection site reaction considered serious, Grade 3 or above, or 
if clinically significant and persistent beyond 30 days and others if the Investigator or 
Medical Monitor feels it is medically necessary. 
Details regarding photo collection and any other follow up will be given by the Medical 
Monitor at the time of assessment. 
ISR discomfort can be managed symptomatically (e.g., cold/warm compress, 
acetaminophen, ibuprofen) if the reaction is interfering with the participant’s ability to 
perform activities of daily living.  The required intervention should be documented on the 
appropriate eCRF page. 
10.6.5.9. 
Allergic reaction 
Participants may continue study drug 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 drug should permanently discontinue the CAB LA + RPV 
LA regimen and the participant should be withdrawn from the study.  Participants should 
be treated as clinically appropriate and followed until resolution of the AE. 
10.6.5.10. Rash Without HSR Symptoms 
Including serious skin reactions such as Stevens-Johnson Syndrome, Toxic 
Epidermal Necrolysis, Erythema Multiforme or rash with significant liver 
dysfunction.  
Participants should be instructed to contact the Investigator as soon as possible if they 
develop a rash on study. 
As many products also cause rash and/or serious skin reactions, all other medicinal 
products that the participant is receiving should also be reviewed and discontinued as 
appropriate. 
The following guidance is provided for clinical management of participants who 
experience rash alone in the absence of systemic or allergic symptoms or signs of 
mucosal or target lesions. 
CAB is an analogue of DTG and mild to moderate rash is an expected adverse reaction 
for DTG-containing ART.  Episodes generally occur within the first 10 weeks of 

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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 
characterization of HSR and rash observed with DTG-containing ART, please see the 
current version of the CAB IB. Rash is an adverse drug reaction (ADR) for RPV.  In 
clinical trials, most rashes emerged during the first 4 weeks of treatment, were transient, 
and usually mild (Grade 1) to moderate (Grade 2).  There were no Grade 4 rashes and 
none were serious.  Treatment related Grade 3 rash was reported in 0.1% of participants 
in the RPV group.  Treatment related rash led to permanent discontinuation in 0.1% of 
participants in the RPV group.  No cases of erythema multiforme, SJS or TEN have been 
reported during clinical development of RPV. 
Participants with an isolated Grade 1 rash may continue study drug 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. 
Participants may continue study drug for an isolated Grade 2 rash.  However, study drug 
(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 an increase in ALT.  The participant should be advised to contact the physician 
immediately if rash fails to resolve (after more than 2 weeks), if there is any worsening of 
the rash, if any systemic signs or allergic symptoms develop, or if mucosal involvement 
develops. 
 
10.7. 
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
• 
Premenarchal 
• 
Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
• 
Postmenopausal female 

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• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-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. 
Contraception Guidance 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 17.  

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Table 17 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
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  
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If  
not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. 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.) 
NOTES:  
a. Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies. 
b. A highly effective method of contraception should be utilized from 30 days prior to the first dose 
of study medication, throughout the study, and for at least 52 weeks after discontinuation of CAB 
LA and RPV LA. 
Pregnancy Testing 
o WOCBP should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test  

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o Additional pregnancy testing should be performed as per the study Schedule of 
Activities Table. 
o Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected  
o Pregnancy testing will be performed and assayed in the central laboratory OR 
using the test kit provided by the central laboratory / provided by the sponsor 
/approved by the sponsor and in accordance with instructions provided in its 
package insert. 
o If pregnancy is confirmed, please see Appendix 15 for details regarding allowing 
pregnant participants to remain in the study 
10.7.1. 
Collection of Pregnancy Information 
• The Investigator will collect pregnancy information on any participant who 
becomes pregnant while participating in this study. See Appendix 15 and Section 
10.15.1 for information to be collected for participants who become pregnant 
while participating in this study. 
• 
Participants who become pregnant while in the study may remain in study and 
continue scheduled dosing with CAB + RPV LA, once a pregnancy specific ICF 
addendum is signed by the participant. See Section 10.15 for additional data and 
information regarding the management of participants who remain in the study 
while pregnant. 
• 
Information will be recorded on the appropriate form and submitted to GSK 
within 24 hours of learning of a participant's pregnancy. 
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported 
as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 
GSK as described in this section.  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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10.8. 
Appendix 8: Country-specific requirements 
Germany 
This requirement has been included based on request from the lead Ethics committee to 
specify that participants would have an expected individual benefit from enrollment in 
the study 
• 
A participant will be eligible for inclusion in this study if he/she meets all 
eligibility criteria and for whom an individual benefit can be expected.  
 

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10.9. 
Appendix 9: Abbreviations and Trademarks 
Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AIM 
Acceptability of intervention measure 
ALT 
Alanine aminotransferase 
Anti-HBc 
Hepatitis B core Antibody 
Anti-HbsAg 
Antibodies against Hepatitis B surface Antigen 
ARV 
Antiretroviral 
ART 
Antiretroviral therapy 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC(0-) 
Area under the concentration curve from 0 hours to the time of 
next dosing 
AZT 
Azidothymidine (zidovudine) 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CAB 
Cabotegravir 
CAB LA 
Cabotegravir long-acting 
c/mL 
Copies/milliliter 
cART 
Combination antiretroviral therapy 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CDC 
Centers for Disease Control and Prevention 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration 
ConART 
Concomitant Antiretroviral Therapy 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CSAT 
Clinical Sustainability Assessment Tool 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
CVF 
Confirmed Virologic Failure 
CQI 
Continuous Quality Improvement  
DAA 
Direct-Acting Antivirals 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
DRE 
Disease-Related Events 
DVT 
Deep vein thrombosis 

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ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FIM 
Feasibility of intervention measure 
FDA 
Food and Drug Administration 
FRAME 
Framework for Reporting Adaptations and Modifications-
Enhanced 
FRAME-IS  
FRAME-Implementation Strategy 
FRP 
Female of reproductive potential 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HAART 
Highly active antiretroviral therapy 
HBV 
Hepatitis B virus 
HCP 
Healthcare practitioner 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HIV 
Human immunodeficiency virus  
HLA 
Human leukocyte antigen 
HSR 
Hypersensitivity reaction 
IAM 
Intervention appropriateness measure 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICS 
Implementation Climate Scale 
ID 
Infectious Disease 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
ILS 
Implementation Leadership Scale 
IM 
Intramuscular 
INI 
Integrase inhibitor 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT-E 
Intent-to-treat exposed 
IUD 
Intrauterine device 
ISR 
Injection Site Reaction 
LA 
Long-Acting 
LFTs 
Liver function tests 
LTFU 
Long-Term Follow-UP 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
Milligram 
Mg/dL 
Milligram per deciliter 
MRHD 
Maximum Recommended Human Dose 

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NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NRS 
Numeric Rating Scale 
NRTI 
Nucleoside reverse transcriptase inhibitor 
OLI 
Oral lead-in 
PDSA 
Plan, Do, Study, Act 
PK 
Pharmacokinetic 
PLHIV 
Persons living with HIV 
PREP 
Pre-exposure prophylaxis  
PRO 
Protease 
PRTD 
Proximal Renal Tubule Dysfunction 
PSP 
Patient study participant 
PSRAE 
Possible suicidality-related adverse event 
QTc 
Corrected QT interval  
Q2M 
Every 2 months 
Q8W 
Every 8 weeks 
Q4W 
Every 4 weeks 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RPR 
Rapid plasma reagin 
RPV 
Rilpivirine, Edurant 
RPV LA 
Rilpivirine long-acting 
RT 
Reverse transcriptase 
SAE 
Serious adverse event 
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of activities 
SOC 
Standard of Care 
SRM 
Study Reference Manual 
SSI 
Semi-structured interview 
SSP 
Staff study participants 
SWAT 
Skilled Wrap-Around Team  
TEN 
Toxic epidermal necrolysis 
TOC 
Table of Contents 
TMC278 
Tibotec Medicinal Compound 278 
ULN 
Upper limit of normal 
US 
United States 
VSLC 
ViiV Safety and Labeling Committee 
WBC 
White blood cell 
WOCBP 
Woman of Childbearing Potential 
 

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Trademark Information 
Trademarks of ViiV Healthcare 
None 
Trademarks not owned by ViiV 
Healthcare 
Edurant 
Genosure 
InForm 
MedDRA 
Monogram Biosciences 
PhenoSense 
 

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 0 3  
 
1 0. 1 0.  
A p p e n di x 1 0 : P ati e nt  St u d y P arti ci p a nt Q u e sti o n n air e s  
T he f oll o wi n g c o nce pts are meas ure d i n t he patie nt st u d y partici pa nt q u esti o n naire s: 
•  Acce pt a bilit y of t he C A B + R P V i njecti o n ( AI M)  
•  A p pr o priate n ess of t he C A B + R P V i njecti o n (I A M)  
•  Feasi bilit y of t he C A B L A + R P V L A i njecti o n ( FI M)  
•  Utilit y of patie nt s pecifi c t o ol kit res o urces  
•  
•  Facilitat ors a n d b arri ers t o C A B L A + R P V L A relate d t o ti me s pe nt i n 
a p p oi nt me nts t o recei ve t he i njecti o ns will be meas ure d at D ose 1, 3 , a n d 7 . 
•  Prefere nce  
 
Acce pt a bilit y, a p pr o priat e ness, a n d feasi bilit y will be meas ure d b y t hree bri ef 4 -ite m 
meas ures ( Wei ner , 2 0 1 7): t he Acce pt a bilit y of I nt er ve nti o n Meas ure ( AI M), the 
I nter ve nti o n A p pr o priate ness Meas ure (I A M) a n d t he Feasi bilit y I nter v e nti o n Meas ure 
( FI M).  T he AI M, I A M, a n d FI M access i m ple me ntatio n o utc o mes i de ntifie d i n t he  
Pr oct or Fra me w or k w hic h are c o nstr ucts of a 5 -p oi nt Li kert sc ale  vali date d fr o m t he 
Pr oct o r Fra me w or k. R e p o nses are meas ure d usi n g a 5-p oi nt Li k ert  scal e 
A d diti o nal q uesti o ns are i ncl u de d t o e val uate facilitat ors a n d barri ers fr o m t he patie nt 
pers pecti ve, a n d t o e val u ate t he usef ul n ess of t he patie nt s pecific t o ol kit res o urces.  
 
C CI
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 0 4  
 
 
 
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI

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

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 0 6  
 
C o nstr uct  
E x a m ple Q uesti o n  
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 0 7  
 
C o nstr uct  
E x a m ple Q uesti o n  
O uter C o nte xt  
C CI

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 0 8  
 
C o nstr uct  
E x a m ple Q uesti o n  
N ote: c o nstr ucts are t ake n fr o m t he pre p ar ati o n a n d i m ple me nt ati o n p h ase.  All c o nstr ucts fr o m 
i m ple me nt ati o n p h ase are n ote d wit h *.  
 
C CI

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

T M F -1 3 7 9 4 0 9 2  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
2 1 0  
 
C o nstr uct  
E x a m ple Q uesti o ns  
C CI

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10.14. 
Appendix 14: COVID-19 Pandemic and Clinical Trial 
Continuity 
Background 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, research clinics are operating with only emergency 
staff. 
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 patient safety and to ensure 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 to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19.  
10.14.1. 
Changes to Study Visits and Study Procedures 
• Where site staff resource is constrained due to COVID-19, IM dosing visits may 
proceed with limited or no other protocol-defined assessments (e.g. lab tests, 
questionnaires, etc.). If lab tests will be missed for more than one consecutive 
visit, the medical monitor must be contacted, to provide guidance for safety 
monitoring.  
• For WOCBP, point of care pregnancy testing should be performed, prior to IM 
dosing. 
• If central laboratory testing cannot be performed at a particular visit, and 
monitoring for safety is required, tests 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 site should 
proactively inform the sponsor about such instances. Local laboratory results may 
be used to inform safety decisions. Results should be retained in source records. 
• When on-site visits are reduced, it is important that the Investigator continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 

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• There may be cases where the current principal investigator (PI) of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
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. 
 
10.14.2. 
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 participant sending a picture of his/her written consent to the investigator, or the 
Investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.   
Any updated informed consent form or other subject-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. 
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval. 
 
10.14.3. 
Permissible Use of Antiretroviral Therapy 
In order to minimize the risk of gaps in HIV-1 antiretroviral therapy (ART) for 
participants impacted by COVID-19 in the clinical trial, the following options can be 
considered with regards to ART dosing, in order of preference: 
1. Where possible, and safe to do, please continue to prioritize IM dosing visits in 
order to keep the participants on the protocol-defined regimen 
 
a. Qualified healthcare professionals (HCPs) trained on study procedures can 
administer IM injections outside of the study clinic setting (e.g. home, 
nursing facility, hospital), assuming this can be done safely, without 
compromising investigational product 
preparation/handling/storage/accountability requirements and done in 

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accordance with local requirements. Please seek approval by the study 
team on a case-by-case basis. 
 
 
2. If a participant is not able to attend an IM injection visit due to COVID-19 related 
restrictions, the gap in IM dosing should be covered with oral ART, until IM 
dosing can resume. Participants should be reminded of the importance of adhering 
with daily oral dosing. Two options can be approved for oral bridging therapy in 
consultation with the Medical Monitor, listed in order of preference: 
 
a. Oral CAB + RPV  
i. Investigator should request availability of oral CAB + RPV supplies, 
prior to pursuing option b. 
b. Oral standard of care (SOC) commercial ART (prescribed locally) 
 
Oral bridging with CAB + RPV 
The protocol permits oral bridging to cover planned missed injections with oral CAB + 
RPV, only until IM dosing can be resumed.  The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit. This recommendation can be 
used to accommodate requests for oral dosing due to COVID-19. Oral bridging 
recommendations should be followed as per protocol Section 6.5.1. The process and 
required information for requesting oral bridging can be found in your Study 
Reference/Procedure Manual.  Please continue to reach out to your study medical 
monitor for approval of oral bridging, in order to document use and to ensure expeditious 
shipment of oral CAB + RPV to your site.  
Participants who use oral CAB + RPV as short-term oral bridging are permitted to return 
to IM dosing, on protocol, once the COVID-19 conditions permit resumption of site 
activities.  
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with CAB/RPV is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy. Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 

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Oral bridging with Standard of Care Antiretroviral Therapy (SOC ART) 
For participants impacted by COVID-19, where the participant is unable to receive IM 
injections, and oral CAB + RPV is not available for use, oral bridging with any 
commercially available, guideline-recommended, SOC ART regimen is permitted. The 
start date of oral bridging should be within the dosing window for the missed IM dosing 
visit.  Please reach out to your study medical monitor for approval of SOC ART as oral 
bridging, in order to document the use of commercially available SOC ART within the 
study. 
Participants who use oral SOC ART as short-term oral bridging as a result of COVID-19 
will not be considered formally withdrawn insofar as they wish to continue on the study.  
Individuals who bridge with SOC ART will be permitted to return to IM dosing, on 
study, once the COVID-19 conditions permit resumption of site activities.   
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with SOC ART is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy.  Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
10.14.4. 
Direct-To-Patient (DTP) Shipment of Oral Study IP  
If a participant is unable to travel to the clinic, either to receive IM injections or to be 
dispensed oral bridging, sites are encouraged to consider DTP shipments of drug, from 
the site, to the participant, to ensure access to medicines.  
• If the study site is considering DTP shipment of oral CAB + RPV investigational 
product (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 should 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 should be documented in 
source records. 
• Oral CAB + RPV IP can be shipped at ambient temperatures via ground transport 
without a temperature monitoring device, with low risk of temperature excursions. 
Sites are encouraged to use discretion in determining the need for in-transit 
temperature monitoring based on the labelled storage requirements and the 
planned mode of transport and apply this as appropriate.  Shipment of oral CAB + 
RPV via air courier continues to require appropriate temperature monitoring.  For 
shipment conditions of oral medications other than oral CAB + RPV, please 
consult the product labelling. 
• In all cases IP accountability must be maintained, and all DTP dispensing 
documentation should be reflected in source records and dispensing logs per GCP. 

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• 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 IMP directly to participants. 
 
10.14.5. 
COVID-19 Experimental 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. 
10.14.6. 
COVID-19 Specific Data Capture 
10.14.6.1. Capturing COVID-19 Specific Protocol Deviations 
Please refer to your study procedure manual for specific details on capturing protocol 
deviations as a result of COVID-19. 
 
10.14.6.2. Capturing COVID-19 Specific AEs and SAEs 
It is important for the study team to describe COVID-19 related adverse events/serious 
adverse and their impact on study data and outcomes. Standardization of case definitions 
will facilitate future data analysis.  
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. 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 drug 
continuation.  

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5. 
A new COVID-19 infection Case Report Form will be added to the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important to collect the correct information from each participant reporting a 
COVID-19 AE or SAE.  Therefore, please use the CRF templates to help you 
collect this information, once available. 
 
10.14.7. 
WHO Case Definitions  
March 20, 2020 Version (https://www.who.int/publications-detail/global-surveillance-
for-human-infection-with-novel-coronavirus-(2019-ncov)) 
 
Suspected case:  
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset;  
OR  
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset;  
OR  
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation.  
 
Probable case:  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory).  
OR  
B. A suspect case for whom testing could not be performed for any reason.  
 
Confirmed case:  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms.  

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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.  
 
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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10.15. 
Appendix 15: Information and Guidance for Managing 
Pregnant Participants 
10.15.1. 
Collection of Pregnancy Information 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in the protocol in Section 8.5.  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. 
• 
Females who become pregnant while in the study may remain in study, and continue 
scheduled dosing with CAB + RPV LA, once a pregnancy ICF addendum is signed 
by the participant. 
10.15.2. 
Introduction 
Pregnancy increases the risk of HIV progression, while HIV increases the risk for 
maternal complications from pregnancy and poses the risk of perinatal HIV transmission 
to the unborn fetus.  Mother to child transmission (MTCT) of HIV can occur during 
pregnancy, labor, delivery or postpartum through breastfeeding.  In the absence of any 
interventions, vertical HIV transmission rates approximate 35%, but fall below 5% with 
effective interventions [WHO, 2010].  In the United States and other developed countries, 
the risk of perinatal infection has decreased from 25% without intervention to less than 
2% with intervention [WHO, 2012].  The HIV-infected mother who breastfeeds her 
infant while taking ARVs herself or giving ARVs to her infant reduces the risk of 
transmission to about 2% after 6 months of breastfeeding, or 4% over 12 months 
[UNAIDS , 2011]. 
The WHO, 2013 Guidelines thus recommend (strong recommendation, moderate-quality 
evidence) all pregnant and breastfeeding women with HIV should initiate triple ARVs 

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(ART), which should be maintained at least for the duration of mother-to-child 
transmission risk. Women meeting treatment eligibility criteria should continue lifelong 
ART [WHO, 2013]. The global benefits anticipated from ART in pregnant women who 
are eligible for treatment include treatment of the mother’s underlying HIV disease, 
eliminating pediatric transmission/infection and reducing sexual transmission of HIV 
Recent recommendation updates to treatment guidelines have included objectives to 
increase HIV screening of patients, including pregnant women (noting the importance of 
adopting HIV screening to be a part of prenatal care). 
The ART recommendation for pregnant females prioritizes the health of women over 
potential risks and increased cost.  For females who are on ARV therapy at the time that 
they become pregnant, the World Health Organization recommends that they continue 
such therapy if they are responding to the ARV. 
In line with this recommendation, this study will allow those females participating in 
CARISEL 213199 who are receiving CAB + RPV LA but become pregnant on study, to 
continue in the study in order to maintain their effective regimen with minimal 
disruption.  The PK of CAB + RPV LA, characterization of the safety of CAB + RPV LA 
administered during pregnancy, and characterization of maternal, birth and infant 
outcomes following treatment with CAB + RPV LA will be examined.  
10.15.3. 
Background 
At the time of finalizing this protocol, there have been 25 pregnancies reported during the 
CAB/RPV LA Phase 3 development program (including 6 during PK tail and 5 during 
OLI) with 8 pregnancies leading to live births (including 3 pregnancies exposed during 
the PK tail of treatment and 1 pregnancy exposure occurring during CAB oral lead-in) 
and 5 on-going pregnancies. 
• 
A total of 12 pregnancy losses (11 of these occurring during the first trimester) 
• 
Missed abortions: 2 (one of these was a twin anembryonic pregnancy) 
• 
Elective abortions (no medical indication): 5 
• 
Elective abortion for nausea and vomiting: 1 
• 
Spontaneous abortions: 4 (one late spontaneous abortion at 23/40; severe IUGR, 
placental insufficiency; presence of risk factors) 
No reported congenital anomalies 
10.15.4. 
Benefit/Risk Assessment 
Investigator to discuss with pregnant participant the benefit-risk of continuing in the 
study and continuing to receive CAB + RPV LA injections, or being withdrawn from 
study, as a result of her pregnancy. All participants who chose to stay in the study during 
pregnancy, and who choose to continue to receive CAB + RPV LA injections will need 
to sign a pregnancy specific ICF addendum. 

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There is a pregnancy exposure registry that monitors pregnancy outcomes in women 
exposed to CAB + RPV LA (CABENUVA) during pregnancy. Healthcare providers are 
encouraged to register all pregnant study participants, whether or not they choose to 
remain in the study, by calling the Antiretroviral Pregnancy Registry [Antiretroviral 
Pregnancy Registry (APR) Steering Committee, 2013] at 1-800-258-4263. 
10.15.4.1. Cabotegravir 
Cabotegravir use in pregnant females has not been evaluated and there are insufficient 
human data on the use of during pregnancy to adequately assess a drug-associated risk of 
birth defects and miscarriage.  
The rate of miscarriage is not reported in the APR. The background risk for major birth 
defects and miscarriage for the indicated population is unknown. The background rate for 
major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital 
Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in 
clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR 
uses the MACDP as the U.S. reference population for birth defects in the general 
population. The MACDP evaluates women and infants from a limited geographic area 
and does not include outcomes for births that occurred at less than 20 weeks’ gestation. 
Animal Data (pre-clinical) 
Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day 
from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. 
There were no effects on fetal viability when fetuses were delivered by caesarean 
although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (greater 
than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were 
observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) 
and no drug-related fetal malformations were observed at any dose. 
Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 
mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 
2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). 
In a rat pre- and postnatal development study, cabotegravir was administered orally to 
pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. 
A delay in the onset of parturition and increases in the number of stillbirths and neonatal 
deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the 
exposure in humans at the RHD); there were no alterations to growth and development of 
surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early 
postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were 
nursed from birth by control mothers. There was no effect on neonatal survival of control 
pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 
times the exposure at the RHD) was not associated with delayed parturition or neonatal 
mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta 
and can be detected in fetal tissue. 

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During the pre-clinical development of CAB, there were no positive genotox findings. 
Embryo-fetal studies also showed no adverse findings including neural tube defects.  In a 
pre and postnatal study, there were some test article-related decreases in F1 pup survival 
(87.4% vs 98.9% in control) in the highest dose (1000 mg/kg/day) during postnatal days 
1-4.  No findings in the 0, 0.5 and 5 mg/kg/day doses).  
The clinical significance of these finding in humans is unknown. 
Human Data 
Cabotegravir use in pregnant females has not been evaluated and there are insufficient 
human data on the use of CAB + RPV LA during pregnancy to adequately assess a drug-
associated risk of birth defects and miscarriage.  
While there are insufficient human data to assess the risk of neural tube defects (NTDs) 
with exposure to CAB + RPV LA during pregnancy, preliminary findings from an 
unscheduled analysis of a birth outcomes surveillance study conducted in Botswana 
(Tsepamo Study) and presented in May 2018 showed a higher than expected number of 
neural tube defects (NTDs) among newborns whose mothers were exposed to DTG based 
ART at conception. DTG is a different molecule in the same integrase class of 
medications as CAB. As of May 2018 four cases of neural tube defects were identified in 
426 infants born to mothers who were exposed to DTG-containing regimens from the 
time of conception. In the same study, no infant born to a woman who started DTG 
during pregnancy had a neural tube defect, out of 2,824 women. Updated analysis of 
interim data from the Tsepamo study became available in 2019 and more recently in 
2020. Subsequently, the study team presented an updated analysis, including data through 
to 30 April 2020, at the 23rd International AIDS Society (IAS) Meeting [Zash, 2020].  
The latest data from the Tsepamo study included additional data accrued between 1 April 
2019 (the cut-off for the last formal analysis) and 30 April 2020. Over this 13-month 
period, 39,200 additional births were recorded, including 1908 additional exposures to 
DTG at conception. Two additional NTDs were detected in 1908 (0.10%) deliveries to 
mothers taking DTG at conception, compared with six NTDs in 4569 (0.13%) deliveries 
in mothers taking non-DTG regimens at conception, of which five NTDs in 2999 (0.17%) 
deliveries were to mothers taking efavirenz at conception. The incidence in HIV negative 
mothers over the 13-month period was 17/30,258 (0.06%).  
As of the Tsepamo April 2020 analysis, seven cases of neural tube defects were reported 
in 3,591 deliveries (0.19%) to mothers taking dolutegravir -containing regimens at the 
time of conception, compared with 21 cases in 19,361 deliveries (0.11%) to mothers 
taking non- dolutegravir containing regimens at the time of conception (Prevalence 
Difference 0.09%; 95% CI -0.03, 0.30).  Since the first analysis the estimated prevalence 
of neural tube defects with DTG exposure at conception has decreased in magnitude from 
0.94% to 0.19%. In the same study, no increased risk of neural tube defects was reported 
in women who started dolutegravir 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. 

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A causal relationship of these events to the use of DTG 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. There are insufficient human data on the use of CAB + RPV LA during 
pregnancy to adequately assess a drug-associated risk of miscarriage or birth defects, 
including NTDs. 
10.15.4.2. Rilpivirine 
Animal Data 
Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and 
rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, 
and 6 through 19, respectively). No significant toxicological effects were observed in 
embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 
15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and 
postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day 
through lactation. No adverse effects were noted in the offspring at maternal exposures 
up to 63 times the exposure in humans at the RHD 
Human Data 
Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-
containing regimens during the first trimester of pregnancy and over 170 during 
second/third trimester of pregnancy, the prevalence of birth defects in live births was 
1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and 
second/third trimester exposures. 
Available data from the APR show no difference in the overall risk of birth defects for 
rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. 
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) 
In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy 
compared with the postpartum period. Refer to the current Edurant Prescribing 
Information for additional information on rilpivirine. 
10.15.5. 
Clinical Considerations 
10.15.5.1. Exposure 
Lower exposures with oral rilpivirine were observed during pregnancy. Cabotegravir and 
rilpivirine are detected in systemic circulation for up to 12 months or longer after 
discontinuing injections of CAB + RPV LA; therefore, consideration should be given to 
the potential for fetal exposure during pregnancy. 
With the change in volume of distribution associated with pregnancy, drug concentrations 
of CAB and RPV during pregnancy will be assessed in pregnant participants who 
contiune to receive LA therapy while on study. For these participants, plasma PK 

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samples of CAB and RPV will be obtained at every study visit for Q8W and Q4W during 
the pregnancy. Additionally, all other scheduled assessments, including viral load 
monitoring, will continue as reflected in as described in the protocol in the Time and 
Events Table (see Section 1.3 ) 
Figure 9 
LTFU PK in Female and Pregnant Participants 
(LATTE-2, ATLAS) 
 
 
 
 
Weeks Post Final Injection
0
12
24
36
48
60
Plasma CAB ( g/mL)
0.01
0.1
1
10
L2 512
A 5911
L2 592
A 5487 (+HCG)
A 5485 (-HCG)
A 7224 (-HCG)
A 6595 (-HCG)

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10.15.5.2. Use of Supplements with CAB + RPV LA 
During pregnancy, additional supplements including vitamins, minerals and other 
mediations including OTC meds may be prescribed to the pregnant woman. It is 
important for all female participants who remain in the study to be aware of any potential 
DDIs that may occur with study medications and other agents used during pregnancy. 
Oral Cabotegravir Only 
Antacid products containing divalent cations (e.g., aluminium, calcium and 
magnesium) must be taken at least 2 hours before or at least 4 hours after CAB. 
Concurrent administration of multivitamins is acceptable. 
10.15.5.3. Overall Benefit: Risk Conclusion  
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment.  Additional considerations when using CAB + RPV 
LA can be found in the protocol in Section 2.3 
There is limited data regarding the use of CAB + RPV LA in pregnant females. Based on 
animal data, the use of CAB + RPV LA is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans.  Available data from the APR show 
no difference in the overall risk of birth defects for rilpivirine compared with the 
background rate for major birth defects of 2.7% in a U.S. reference population of the 
Metropolitan Atlanta Congenital Defects Program (MACDP). 
Refer to Section 10.15.4.1 for additional data. 
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering an opportunity to overcome 
such adherence challenges. LA therapy may also help with nausea (50 % mild to 
moderate) or hyperemesis (2%). Female participants on LA dosing who become pregnant 
will have exposures throughout pregnancy due to the long half-life and PK tail of 
CAB/RPV. Pregnant participants who are withdrawn from study and are initiated on an 
alternative oral ART regimen consisting of either 2 or 3 antiretrovirals to protect the life 
of the mother and for the prevention of MTCT, potentially expose the fetus to additional 
ARVs during gestation (in some cases upwards of 5 antiretrovirals). 
In summary, taking into account the measures taken to minimize risk to participants 
participating in this study, the potential risks identified in association with CAB + RPV 
LA are justified by the anticipated benefits that may be afforded to pregnant participants 
with HIV infection. 
Given the risk/benefit ratio for CAB + RPV LA dosing in WOCBP, coupled with 
concerns of increasing fetal exposure to several additional antiretrovirals upon participant 
withdrawal, pregnant participants will be allowed to remain in the study and continue to 

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receive CAB + RPV LA injections, once the new pregnancy ICF addendum is signed by 
the participant.  
10.15.6. 
Study Assessments and Procedures: specific assessments for 
pregnant participants 
Participants who become pregnant while in the study, and who sign the informed consent 
pregnancy addendum may remain in the study and continue to receive CAB + RPV LA.  
Please note: The HIV provider is responsible for HIV care and will collaborate and share 
information with the subject’s obstetric care provider, discuss the subject’s participation 
in this study, the necessary procedures at delivery, to share HIV information, and to 
collect birth and infant outcomes from the subject’s obstetric care provider and/or the 
pediatric health provider for the infant. 
Because obstetric and/or pediatric care will not be specifically provided via this study, the 
subject must also establish appropriate obstetric and pediatric care (including prenatal 
care) per local standard of care (SoC) in parallel.  It will be necessary for the subject to 
provide a release of medical information to facilitate collection of pregnancy and 
pregnancy outcomes by the investigator. 
All assessments will be conducted in accordance with the protocol, as described in the 
protocol in the Schedule of Activities Table (see Section 1.3) 
Viral Load Assessments 
Women who become pregnant while on study and consent to stay on study will have VL 
testing obtained at every study visit during pregnancy and at the first post-partum visit. 
Timing of subsequent VL assessments are performed, as described in the protocol in the 
Schedule of Activities Table (see Section 1.3) 
 
10.15.6.1. Safety Assessments 
Pregnancy related complications and diagnoses, and outcomes will be captured as AEs 
and SAEs as outlined in the protocol in Section 8.5. 
Pregnancy complications (e.g., preeclampsia or eclampsia, prolonged hospitalization after 
delivery, for wound infections etc, seizures) and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
In the event of a pregnancy loss, after the loss is confirmed the subject may continue to 
receive CAB + RPV LA unless they meet the criteria for confirmed virologic withdrawal.  
They may continue to CAB + RPV LA until study medications are locally approved and 
commercially available or until they no longer receive benefit.  In this case the subject 
must agree to use contraception to avoid a ‘new’ pregnancy (See Appendix 7). 

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Any SAE occurring in association with the pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK 
10.15.6.2. Pharmacokinetics 
Refer to Section 8.6 in the protocol. 
All pregnant participants who elect to remain in the study will have additional PK 
sampling obtained. Blood samples for evaluation of plasma concentrations of 
cabotegravir and rilpivirine will be collected prior to each LA injection throughout the 
pregnancy. A final PK sample for cabotegravir and rilpivirine concentrations will 
obtained at the first postpartum LA visit. All PK samples will be trough levels and will be 
collected prior to the scheduled LA injection. The pre-dose trough PK sample is to be 
collected within 15 minutes prior to the LA dose, on the day of the study visit.  
Please refer to the laboratory manual SPM for PK sample collection, processing, and 
shipping instructions. The actual date and time of each PK sample collection will be 
recorded in the eCRF. 
 
10.15.7. 
References 
Antiretroviral Pregnancy Registry (APR) Steering Committee. Antiretroviral Pregnancy 
Registry International Interim Report for 1 January 1989 through 31 January 2013. 
Wilmington, NC: Registry Coordinating Center; 2013. Available from URL: 
www.APRegistry.com. 
Edurant Prescribing Information, February 2018 
UNAIDS (2011) Reference Group on Estimates, Modelling and Projections. Working 
Paper on Mother-to-Child HIV Transmission Rates for use in Spectrum, 6 June 2011. 
Available online at http://www.epidem.org/Publications/MTCTratesworkingpaper.pdf. 
World Health Organization (WHO) (2010). Antiretroviral drugs for treating pregnant 
women and preventing HIV infection in infants: Recommendations for a public health 
approach.  Available online at: 
http://whqlibdoc.who.int/publications/2010/9789241599818_eng.pdf, accessed 6 Feb 
2013. 
World Health Organization (WHO) (2012). Antiretroviral Treatment as Prevention 
(TasP) of HIV and TB:  2012 Update.  June 2012, Available online at: 
http://www.who.int/hiv/pub/mtct/programmatic_update_tasp/en/index.html 
World Health Organization (WHO) (2013). Consolidated Guidelines on the Use of 
Antiretroviral Drugs for Treating and Preventing HIV Infection. 30 June 2013.  Available 
online at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html 
Zash R, Holmes L, Diseko M, Jacobson D, Mayondi G. Update on neural tube defects 
with antiretroviral exposure in the Tsepamo study, Botswana. JAIDS 2020 

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10.16. 
Appendix 16: Device Deficiencies: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting in Medical Device Studies 
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155, European Medical Device Regulation (MDR) 2017/745 for clinical device 
research, and the US Food and Drug Administration (FDA) combination product 
reporting rule, 21 CFR 4, Subpart B. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements for medical devices. 
The detection and documentation procedures described in this protocol apply to all 
medical devices used in the study (see Section 6.9 for the list of medical devices). 
10.16.1. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer. 
10.16.2. 
Recording and Follow-Up of Device Deficiencies 
Device Deficiency Recording 
• 
When a device deficiency occurs, with or without an associated AE/SAE, it is the 
investigator’s responsibility to review all applicable documentation (e.g., hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant device deficiency information on the 
appropriate form. If applicable, any associated AE or SAE will be documented in 
the participant’s medical records, in accordance with the investigator’s standard 
clinical practice. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. 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 the sponsor. 
• 
The investigator will attempt to fully describe the device deficiency and provide 
details on any treatment provided.  
• 
For device deficiencies, it is very important that the investigator describe any 
corrective or remedial actions taken to prevent the deficiency’s recurrence. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent the recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 

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2 1 3 1 9 9  
 
2 2 8  
 
Assess me nt of I nte nsit y of ass oci ate d A E/ S A Es  
•  If a n A E or S A E is ass ociate d wit h a de vice defici e nc y, t he i n vesti gat or will ma ke 
a n assess me nt of i nte nsit y f or eac h A E or S A E as o utli ne d i n S ecti o n 8. 5  
F oll o w -u p  of de vice deficie nc y  
•  T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d u ct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q uest e d b y t he 
s p o ns or t o el uci date t he n at ure of t he d e vice d efici e nc y a n d a n y ass ociat e d A E or 
S A E as f ull y as p ossi ble  
•  Ne w or u p d ate d i nf or mati o n re gar di n g t he de vice deficie nc y will be rec or de d i n t he 
ori gi nall y c o m plete d m e dical de vice d eficie nc y re p ort f or m.  
•  If t here is a n ass ociat e d S A E wit h t he de vice d efici e nc y, t he i n vesti gat or will 
s u b mit a n y u p date d S A E data t o G S K wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n.  
1 0. 1 6. 3.  
R e p orti n g of M e di c al D e vi c e D efi ci e n ci e s f or p arti ci p a nt s  
•  
Re p orti n g t o G S K  
•  
N O T E: T here are a d diti o nal re p orti n g o bli gati o ns f or me dical d e vice defici e ncies 
t hat are p ote ntiall y rel ate d t o S A Es t hat m ust f ulfil t he le gal res p o nsi bilit y t o n otif y 
a p pr o priate re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n safet y 
i nf or mati o n relati n g t o me dical de vices bei n g use d i n cli nical st u dies.  
•  Me dical de vice defici e ncies t hat are n ot r elate d t o a n A E or S A E s h o ul d be 
re p orte d via e mail t o
, usi n g t he me dical de vice 
deficie nc y re p ort f or m.  
•  If t he me dic al de vice d eficie nc y is rel ate d t o a n o n -seri o us A E a n d n ot li n ke d t o a n 
S A E, please se n d t he me dical de vice d eficie nc y re p ort f or m via e m ail t o
 o nl y. T he e C R F f or t he s u bject s h o ul d als o be u p d ate d 
wit h A E i nf or mati o n, as o utli ne d i n S ecti o n 8. 5  
•  If t he de vic e i nci de nt is li n ke d t o a n S A E, please e mail t he me dical de vice 
deficie nc y re p ort f or m, wit hi n 2 4 h o urs, t o b ot h
 ( or fa x + 4 4( 0) 2 0 8 7 5 4 7 8 2 2) a n d
. 
T he S A E f or m s h o ul d al s o be re p ort e d, as o utli ne d i n Secti o n 8 . 5. T he e C R F f or 
t he s u bject s h o ul d als o be u p date d wit h t he S A E i nf or mati o n.  
•  G S K will re vie w all de vi ce defi cie ncies a n d deter mi ne a n d d oc u me nt i n writi n g 
w het her t he y c o ul d ha ve le d t o a n S A E. T hese de vice defici e ncies will be re p orte d 
t o t he re g ulat or y a ut h orities a n d I R Bs/I E Cs as re q uire d b y nati o nal re g ul ati o ns.  
•  C o ntacts f or Me dical D e vice Defi cie nc y re p orti n g ca n be f o u n d i n t he m e dical 
de vice deficie nc y re p ort f or m.  
P P D
P P D
P P D
P P D

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C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
2 2 9  
 
1 0. 1 6. 4.  
R e p orti n g of M e di c al D e vi c e D efi ci e n ci e s f or A s s o ci at e d P er s o n  
 
 
•  
Re p orti n g t o G S K  
If a n Ass oci ate d Pers o n  (i.e. a healt hcare pr ofessi o nal) e x perie nces a de vice deficie nc y, 
t he me dical de vice defi cie nc y i nf or mati o n a n d a n y ass o ciate A E/ S A E i nf or mati o n will 
be re p ort e d t o G S K. T he ass ociate d pers o n will be pr o vi de d wit h t he safet y re p orti n g 
i nf or mati o n a n d a ut horizati o n t o c o ntact p h ysi cia n letter.  
If f oll o w u p i nf or mati o n is re q uire d, a ut h orizati o n t o c o ntact p h ysi cia n ( or ot her 
lice nse d me dial pr actiti o ner) m ust be si g ne d t o o btai n c o nse nt.  
•  Me dical de vice defici e ncies t hat are n ot r elate d t o a n A E or S A E s h o ul d be 
re p orte d via e mail t o
, usi n g t he me dical de vice 
deficie nc y re p ort f or m.  
•  If t he me dic al de vice d efi cie nc y is rel ate d t o a n o n-seri o us A E a n d n ot li n ke d t o a n 
S A E, please se n d t he me dical de vice d eficie nc y re p ort f or m wit h d etails of t he 
ass ociate d A E via e mail t o
 o nl y.  
•  If t he de vic e i nci de nt is li n ke d t o a n S A E, please e mail t he me dical de vice 
deficie nc y re p ort f or m, wit hi n 2 4 h o urs, t o b ot h  
 ( or fa x + 4 4( 0) 2 0 8 7 5 4 7 82 2) a n d  
. 
T he ass ociate d S A E f or m s h o ul d als o be re p orte d t o
 ( or fa x + 4 4( 0) 2 0 8 7 5 4 7 8 2 2). 
•  G S K will re vie w all de vi ce defi cie ncies a n d deter mi ne a n d d oc u me nt i n writi n g 
w het her t he y c o ul d ha ve le d t o a n S A E. T hese de vice defici e ncies will be re p orte d 
t o t he re g ulat or y a ut h orities a n d I R Bs/I E Cs as re q uire d b y nati o nal re g ul ati o ns. 
•  C o ntacts f or Me dical D e vice Defi cie nc y re p orti n g ca n be f o u n d i n t he m e dical 
de vice deficie nc y re p ort f or m.  
P P D
P P D
P P D
P P D
P P D

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10.17. 
Appendix 17: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 01- 02-DEC-2020 
Overall Rationale for the Amendment 01:  
Changes were made to correct discrepancies in the document and to update the statistical 
section based on Ethics Committee requirement. 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 2.3.1 Oral CAB and 
CAB LA 
(GSK1265744/GSK1265744 
LA)  
Section 4.3 Treatment 
Groups and Duration 
Updated HAART therapy initiation 
during LTFU from ‘within 4 weeks’ to 
‘within 8 weeks (+/-7 days) after the 
last Q2M injection’ 
Correction 
Section 1.3 Schedule of 
Activities (SoA) 
PSP SoA  
• Added footnote regarding 
AE/SAE assessment for M 2, 
M 6 and M 10 visits  
• Updated footnote regarding 
CAB LA + RPV LA IM 
treatment to clarify where 
possible IM Dose 1 to be 
dosed within 2 hours of taking 
the last oral regimen dose 
• Updated footnote related to 
recording of visit length 
• RPR updated as ‘Syphilis 
serology + reflex RPR’ 
SSP SoA  
• Checkpoint for Provider Toolkit 
deleted for ‘arm- e Only’  
Clarification 
Section 2.3.1 Oral CAB and 
CAB LA 
(GSK1265744/GSK1265744 
LA) 
Deleted duplicate text under ‘ISRs’ 
 
Clarification added under mitigation 
strategy for development of resistance 
Correction 
 
Clarification 
Section 1.1 Synopsis 
Section 4.3 Treatment 
Groups and Duration 
Deleted text ‘a single repeat viral load 
to determine eligibility may be allowed 
ONLY after consultation with the 
medical monitor”.  
Correction 
 
  
Section 5.1 Inclusion 
Criteria 
Deleted text ‘single repeat allowed’ 
from plasma HIV-1 RNA criteria 
Correction 
 
Section 6.4 Study 
Intervention Compliance 
Updated text to reflect, the date and 
time of each dose administered in the 
clinic will be recorded in the 
participant’s source records and the 
eCRF. 
Clarification 
Section 6.5 Dose 
Modification 
Section 6.6 Concomitant 
Therapy 
Interchanged Section 6.5 and Section 
6.6  
For better flow and 
presentation 

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Section 6.5.3 IM Dosing 
Added text under nursing visit that ‘in 
cases of nursing visits, where feasible, 
all assessments should also be 
performed as per SoA’  
Clarification  
Section 7.1.5 Restart 
Section 10.3 Appendix 3: 
Liver Safety: Required 
Actions, Follow-up 
Assessments and Study 
Intervention Restart 
Guidelines 
Deleted study intervention rechallenge 
after stopping treatment for liver criteria 
Ethics Committee 
requirement 
Section 8.4.1 Clinical 
Evaluations 
Deleted lipid assessment which is not 
performed in this study 
Correction  
Section 8.4.4 Clinical Safety 
Laboratory Assessments 
Removed RPR assessment at 
Baseline  
Updated urinalysis to be done at 
screening and withdrawal/LTFU 
Updated PT/ PTT/ INR to be done at 
withdrawal/LTFU 
Updated footnote regarding glucose 
assessment which can be done in a 
non-fasting or fasted state 
Correction  
Section 8.6 
Pharmacokinetics 
Added text regarding PK sample to be 
collected at plasma HIV 1 RNA SVF 
re-test 
Clarification 
Section 9.1 Statistical 
Hypotheses 
Added hypotheses testing on the 
quantitative aspects of the study, 
considering enhanced implementation 
strategy is superior than the standard 
implementation   
Ethics Committee 
requirement 
Section 9.2 Sample Size 
Determination 
Added ‘Power to Show Superiority in 
mean SSP AIM/IAM/FIM scores’ 
Ethics Committee 
requirement 
Section 9.4.1 Primary 
Endpoint(s) Statistical 
Analysis Methods 
Section 9.4.2 Secondary 
Endpoint(s) Statistical 
Analysis Methods 
Updated SSP and PSP Statistical 
Analysis Methods with details of 
AIM/IAM/FIM scores comparison 
between the two implementation arms 
Ethics Committee 
requirement  
 
Section 10.1.7 Data Quality 
Assurance 
 
Added text ‘Detailed information about 
study data collection and management 
process including systems used can be 
found in the study Data Management 
Plan.’ 
Clarification 
Section 10.5.2 Definition of 
Serious Adverse Events 
 
Updated SAE definition  
SAE definition was 
truncated and replaced 
with complete definition 

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Section 10.6.5 Specific 
Toxicities/ Adverse Event 
Management 
 
Deleted ‘Section 10.6.5.3 
Hypertriglyceridemia/ 
Hypercholesterolemia’ and ‘Section 
10.6.5.9 Proteinuria’ 
Correction as lipid 
assessments are not 
performed in this study 
and urinalysis is not 
performed while on 
study treatment  
Section 10.8 Appendix 8: 
Country-specific 
requirements 
Added country specific requirement for 
Germany 
 
Ethics Committee 
requirement 
Section 10.9 Appendix 9: 
Abbreviations and 
Trademarks 
Updated table for abbreviations and 
trademarks 
Correction 
Section 10.10 Appendix 10: 
Patient Study Participant 
Questionnaires 
Updated measurement timing of PSP 
questionnaires as per original SoA 
Correction 
Section 10.14 Appendix 14: 
COVID-19 Pandemic and 
Clinical Trial Continuity 
Deleted text related to “Memo to 
Investigators” issued on March 18th, 
2020 which served as a record of 
approved emergency actions being 
taken within prior on-going clinical trial 
to manage issues related to COVID-19 
and not applicable to this new study. 
Correction 
Section 11 References 
Deleted reference Mugwanya, 2018 
Updated reference Wensing, 2019 
Correction 
 

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2 3 6  
 
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C CI