Conditions: HIV Infections
Keywords: Cabotegravir Rilpivirine Long-acting injectables Patient study participants Staff study participants
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 437
Healthy volunteers: no

Brief summary:
The overall objective of the CAB LA + RPV LA clinical development program is to develop a highly effective, well-tolerated, two-drug, LA injectable regimen which has the potential to offer improved treatment convenience, compliance and improved quality of life for people living with HIV compared to current standard of care. This interventional study will examine different implementation strategies in different clinic settings across European countries to identify strategies which best meet the needs in each local context and involve both participants receiving study treatment CAB LA + RPV LA (patient study participants \[PSP\]) as well as the healthcare providers at the investigator site level (staff study participants \[SSP\]). SSPs consists of 2 groups: standard and enhanced arm.

Detailed description:

Arms:
arm 1: HIV-infected participants will receive CAB LA + RPV LA regimen for a month of oral lead in (OLI) at Day 1 followed by CAB LA + RPV LA injections at Months 1 and 2 and every 2 months (Q2M) thereafter. arm 2: Staff study participants will be randomized to receive standard implementation support (Arm-S; through visit(s) with the medication lead in their country, education on the medication, and patient and staff education/support materials) or through enhanced implementation support (Arm-E; through the addition of continuous quality improvement during the study).

Interventions: intervention 1: CAB OLI intervention 2: CAB LA intervention 3: RPV OLI intervention 4: RPV LA intervention 5: Continuous Quality Improvement (CQI) calls
Intervention descriptions: intervention 1: CAB will be available as 30 milligrams (mg) tablet. It will be administered as one tablet once daily with food from Day 1 to Month 1. intervention 2: CAB LA 600 mg will be administered as intramuscular (IM) injection. intervention 3: RPV will be available as 25 mg tablet. It will be administered as one tablet once daily with food from Day 1 to Month 1. intervention 4: RPV LA 900 mg will be administered as IM injection. intervention 5: CQI will be attended by the enhanced arm (Arm-E). The CQI calls will be conducted to identify problems/challenges, generate plans to address the challenges, and identify how to measure the change that results from the plan.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan Amendment 1
Study ID:  213199
Official Title of Study: 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
NCTID: NCT04399551
Date of Document: 12 December 2022


 
C O N FI D E N TI A L  
 
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
 
2 1 3 1 9 9  
 
1  
 
Di visi o n  
: W orl d wi de  De vel o p me nt  
I nf or m ati o n T y pe 
: Re p orti n g a n d A nal ysis Pla n  ( R A P) 
Title  
: Re p orti n g a n d A n al ysis Pl a n f or A P h ase III b, o pe n -
l a bel, h y bri d t y pe III tri al e v al u ati n g i m ple me nt ati o n 
str ate gies f or l o n g-acti n g c a b ote gr a vir pl us l o n g -acti n g 
ril pi viri ne e ver y t w o m o nt hs i n HI V -1 i nfecte d, 
vir ol o gic all y s u p presse d a d ults i n select E ur o pe a n 
he alt hc are setti n gs.  
C o m p o u n d N u m ber  : G S K 1 2 6 5 7 4 4  
Cli nic al St u d y 
I de ntifier 
: 2 1 3 1 9 9  
Effecti ve D ate  
: 3 0 N o v 2 0 2 2  
 
Descri pti o n:  
•  
T he p ur p ose of t his R A P is t o descri be t he pla n ne d a nal ys es a n d o ut p ut t o b e 
i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 2 1 3 1 9 9 , s pecificall y f or cli nical 
effic ac y a n d s afet y d ata. A n y i m ple me ntati o n scie nce/ healt h o utc o me a nal ysis 
n o n -cli nical data will be detaile d i n t he E vi dera S A P.  
•  
T his R A P will be pr o vi de d t o t he st u d y tea m me m bers t o c o n ve y t he c o nte nt of 
pertai ni n g  t o cli nical data  f or t he i nteri m, M o nt h 1 2, a n d E n d of St u d y ( E O S) 
a nal ys es . 
R A P A ut h or(s):  
A ut h or  
D ate  
 
1 0 -N O V -2 0 2 2  
Pri nci pal Statisticia n ( G S K Cli nical Statistics)  
C o -A ut h or  
 
 
Electr o nic ( N O V  -
2 0 2 2 ) 
Pri nci pal Pr o gra m mer  (G S K Cli nical Pr o gra m mi n g ) 
 
C o p yri g ht  2 0 2 2  t he Gla x o S mit h Kli ne gr o u p of c o m pa nies. All ri g hts r eser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d . 
 
 
P P D
P P D


 
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2 1 3 1 9 9  
 
2  
 
R A P Te a m R e vie ws : 
R A P Te a m R e vie w C o nfir m ati o ns  
( Met h o d: E-m ail)  
Re vie wer  
D ate  
 
Cli nical Scie nce Lea d ( Vii V Healt hcare)  
1 6 -N O V -2 0 2 2  
 
1 8 - N O V  -2 0 2 2  
 I n n o v ati o n a n d & I m ple me nt ati o n Scie nce ( Vii V 
I n n o v ati o n & I m ple m e ntati o n Scie nce) 
 
S E R M Ma na ger  (P har m a Safet y S E R M ) 
1 8 - N O V  -2 0 2 2  
 
 ( Vii V Healt hcare ) 
1 1 - N O V  -2 0 2 2  
 
Data Ma na ge me nt Q ualit y Lea d (G S K Data Ma n a ge m e nt)  
1 8 - N O V -2 0 2 2  
 
1 6 - N O V  -2 0 2 2  
 Gl o b al I m pl e me ntati o n Researc h ( Vii V I n n o v ati o n & 
I m ple me nt ati o n Scie nce) 
 
Cli nical St u d y  Ma n a ger  (Gl o bal Cli nical Scie nces & Deli ver y, 
G S K ) 
1 8 - N O V  -2 0 2 2  
 
, Researc h & D e vel o p me nt ( Cli nical 
De vel o p me nt  Lea d, Vii V P h ysicia ns)  
1 8 - N O V  -2 0 2 2  
 
Cli nical De vel o p me nt Ma na ger, Vir ol o g y ( Vii V Healt hcare ) 
1 6 - N O V  -2 0 2 2  
 
Cli nic al St atistics a n d Cli nic al Pr o gr a m mi n g Li ne A p pr o v als : 
Cli nic al St atistics & Cli nic al Pr o gr a m mi n g Li ne A p pr o v als  
( Met h o d: P h ar m a T M F e Si g n at ure) 
A p pr o ver  
D ate  
 
Electr o nic ( N O V  -
2 0 2 2 ) 
, Statistics ( G S K Cli nical Statistics) 
 
Electr o nic ( N O V  -
2 0 2 2 ) 
 Pr o gra m mi n g (G S K  Cli nical Pr o gra m mi n g)  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
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3  
 
T A B L E O F C O N T E N T S  
P A G E  
1.  
I N T R O D U C TI O N ...................................................................................................... 6  
1. 1.  
R A P A m e n d m e nt s  ........................................................................................ 6  
2.  
S U M M A R Y O F K E Y P R O T O C O L I N F O R M A TI O N  .................................................. 7  
2. 1.  
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  ............................ 7  
2. 1. 1.  
C h a n g e s t o Pr ot o c ol D efi n e d  A n al y si s Pl a n  ................................... 8  
2. 2.  
St u d y O bj e cti v e( s) a n d E sti m a n d( s) / E n d p oi nt( s)  ......................................... 8  
2. 3.  
St u d y D e si g n  .............................................................................................. 1 1  
2. 4.  
St ati sti c al H y p ot h e s e s / St ati sti c al A n al y s e s  ............................................... 1 3  
2. 4. 1.  
S a m pl e Si z e D et er mi n ati o n  ......................................................... 1 3  
3.  
P L A N N E D A N A L Y S E S  .......................................................................................... 1 8  
3. 1.  
I nt eri m A n al y s e s ......................................................................................... 1 8  
3. 2.  
F i n al A n al y s e s ............................................................................................ 1 8  
4.  
A N A L Y SI S P O P U L A TI O N S  ................................................................................... 1 9  
4. 1.  
Pr ot o c ol D e vi ati o n s  ..................................................................................... 1 9  
5.  
C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S A N D D A T A  H A N D LI N G 
C O N V E N TI O N S  ..................................................................................................... 2 0  
5. 1.  
St u d y Tr e at m e nt & S u b -gr o u p Di s pl a y D e s cri pt or s  ..................................... 2 0  
5. 2.  
B a s eli n e D efi niti o n s  .................................................................................... 2 0  
5. 3.  
M ulti c e ntr e St u di e s  ..................................................................................... 2 0  
5. 4.  
E x a mi n ati o n of C o v ari at e s, Ot h er Str at a a n d S u b gr o u p s  ............................ 2 0  
5. 4. 1.  
C o v ari at e s a n d Ot h er Str at a  ........................................................ 2 0  
5. 4. 2.  
E x a mi n ati o n of S u b gr o u p s  ........................................................... 2 0  
5. 5.  
Ot h er C o n si d er ati o n s f or D at a A n al y s e s a n d D at a H a n dli n g 
C o n v e nti o n s  ................................................................................................ 2 1  
6.  
S T U D Y P O P U L A TI O N A N A L Y S E S  ....................................................................... 2 2  
6. 1.  
O v er vi e w of Pl a n n e d St u d y P o p ul ati o n A n al y s e s  ........................................ 2 2  
7.  
E F FI C A C Y A N A L Y S E S  .......................................................................................... 2 3  
7. 1.  
S e c o n d ar y Effi c a c y A n al y s e s  ...................................................................... 2 3  
7. 1. 1.  
E n d p oi nt / V ari a bl e s  ..................................................................... 2 3  
7. 1. 2.  
P o p ul ati o n of I nt er e st  ................................................................... 2 3  
7. 1. 3.  
Str at e g y f or I nt er c urr e nt ( P o st -R a n d o mi z ati o n) E v e nt s  ................ 2 3  
7. 1. 4.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 2 4  
8.  
S A F E T Y A N A L Y S E S  ............................................................................................. 2 5  
8. 1.  
S af et y E n d p oi nt s  ......................................................................................... 2 5  
8. 2.  
A d v er s e E v e nt s A n al y s e s  ........................................................................... 2 5  
 
 
8. 3.  
A d v er s e E v e nt s of S p e ci al I nt er e st A n al y s e s  .............................................. 2 6  
8. 4.  
Cli ni c al L a b or at or y A n al y s e s  ....................................................................... 2 6  
8. 5.  
Ot h er S af et y A n al y s e s  ................................................................................ 2 6  
9.  
P H A R M A C O KI N E TI C A N A L Y S E S  ......................................................................... 2 7  
9. 1.  
E n d p oi nt / V ari a bl e s  .................................................................................... 2 7  
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9.1.1. 
Drug Concentration Measures ..................................................... 27 
10. VIROLOGY ............................................................................................................ 28 
10.1. 
Genotypic and Phenotypic Data .................................................................. 28 
11. OTHER ANALYSES ............................................................................................... 29 
11.1. 
Endpoint / Variables .................................................................................... 29 
11.1.1. 
Study Visit length ......................................................................... 29 
11.1.2. 
Pregnancy ................................................................................... 29 
12. REFERENCES ....................................................................................................... 30 
13. APPENDICES ........................................................................................................ 31 
13.1. 
Appendix 1: Schedule of Activities .............................................................. 31 
13.1.1. 
Protocol Defined Schedule of Events: Schedule of 
Activities for Patient Study Participants ........................................ 31 
13.2. 
Appendix 2: Assessment Windows ............................................................. 37 
13.2.1. 
Definitions of Assessment Windows for Analyses ........................ 37 
13.2.2. 
Assessment Windows for PK Concentration Data ........................ 41 
13.2.3. 
Assessment Windows for Pregnancy Data .................................. 41 
13.3. 
Appendix 3: Study Phases .......................................................................... 42 
13.3.1. 
Study Phases .............................................................................. 42 
13.3.2. 
Treatment State ........................................................................... 45 
13.3.3. 
Oral Lead-in Period ...................................................................... 45 
13.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 47 
13.4.1. 
Reporting Process ....................................................................... 47 
13.4.2. 
Reporting Standards .................................................................... 47 
13.4.3. 
Reporting Standards for Pharmacokinetic Data ........................... 48 
13.5. 
Appendix 5: Derived and Transformed Data ............................................... 49 
13.5.1. 
General ........................................................................................ 49 
13.5.2. 
Study Population .......................................................................... 50 
13.5.3. 
Efficacy ........................................................................................ 52 
13.5.4. 
Safety .......................................................................................... 52 
13.5.5. 
Virology ....................................................................................... 55 
13.5.6. 
Other Assessments ..................................................................... 56 
13.6. 
Appendix 6: Reporting Standards for Missing Data ..................................... 57 
13.6.1. 
Premature Withdrawals ................................................................ 57 
13.6.2. 
Handling of Missing Data ............................................................. 57 
13.7. 
Appendix 7: Values of Potential Clinical Importance ................................... 60 
13.7.1. 
Hepatobiliary Abnormality Criteria ................................................ 60 
13.8. 
Appendix 8: Snapshot Algorithm Details ..................................................... 61 
13.9. 
Appendix 9: Identification of Adverse Events of Special Interest ................. 65 
13.9.1. 
Hepatic Safety Profile .................................................................. 65 
13.9.2. 
Hyperglycaemia ........................................................................... 69 
13.9.3. 
Hypersensitivity Reactions ........................................................... 71 
13.9.4. 
Rash including severe cutaneous adverse reactions ................... 72 
13.9.5. 
Prolongation of the Corrected QT Interval of the ECG in 
Supra Therapeutic Doses ............................................................ 74 
13.9.6. 
Suicidal Ideation/Behaviour ......................................................... 75 
13.9.7. 
Depression .................................................................................. 77 
13.9.8. 
Bipolar Disorder ........................................................................... 78 
13.9.9. 
Psychosis .................................................................................... 78 


 
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5  
 
1 3. 9. 1 0.  M o o d Di s or d er s  ........................................................................... 8 2  
1 3. 9 . 1 1. A n xi et y  ......................................................................................... 8 3  
1 3. 9. 1 2.  Sl e e p Di s or d er s  ........................................................................... 8 8  
 
1 3. 9. 1 4.  S ei z ur e s  ...................................................................................... 9 1  
1 3. 9. 1 5.  W ei g ht G ai n  ................................................................................. 9 6  
1 3. 9. 1 6.  R h a b d o m y ol y si s  .......................................................................... 9 7  
1 3. 9. 1 7.  P a n cr e atiti s  .................................................................................. 9 7  
1 3. 9. 1 8.  I m p a ct o n Cr e ati ni n e .................................................................... 9 9  
1 3. 9. 1 9.  S af et y D uri n g Pr e g n a n c y  ........................................................... 1 0 1  
1 3. 1 0.  A p p e n di x 1 0: I d e ntifi c ati o n of C O VI D -1 9 A d v er s e E v e nt s  ......................... 1 0 2  
1 3. 1 1.  A p p e n di x 1 1: A b br e vi ati o n s & Tr a d e M ar k s  .............................................. 1 0 4  
1 3. 1 1. 1.  A b br e vi ati o n s  ............................................................................. 1 0 4  
1 3. 1 1. 2.  Tr a d e m ar k s  ............................................................................... 1 0 5  
1 3. 1 2.  A p p e n di x 1 2: Li st of D at a Di s pl a y s ............................................................ 1 0 6  
1 3. 1 2. 1.  D at a Di s pl a y N u m b eri n g  ............................................................ 1 0 6  
1 3. 1 2. 2.  M o c k E x a m pl e S h ell R ef er e n ci n g  .............................................. 1 0 6  
1 3. 1 2. 3.  D eli v er a bl e s  ............................................................................... 1 0 6  
1 3. 1 2. 4.  St u d y P o p ul ati o n T a bl e s  ............................................................ 1 0 8  
1 3. 1 2. 5.  Effi c a c y T a bl e s  .......................................................................... 1 1 2  
1 3. 1 2. 6.  Effi c a c y Fi g ur e s  ......................................................................... 1 1 4  
1 3. 1 2. 7.  S af et y T a bl e s  ............................................................................. 1 1 6  
1 3. 1 2. 8.  S af et y Fi g ur e s  ........................................................................... 1 2 6  
1 3. 1 2. 9.  Ot h er T a bl e s  .............................................................................. 1 2 7  
1 3. 1 2. 1 0.  I C H Li sti n g s ............................................................................... 1 2 8  
1 3. 1 2. 1 1.  N o n -I C H Li sti n g s ........................................................................ 1 3 1  
1 3. 1 3.  A p p e n di x 1 3: E x a m pl e M o c k S h ell s f or D at a Di s pl a y s  .............................. 1 3 5  
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 213199. This RAP is based on the 
original protocol (Dated 06-MAY-2020) of study GSK1265744/213199 (GSK Document 
Number 2019N420690_01) and its protocol amendments 01 (Dated 02-DEC-2020, GSK 
Document Number 2019N420690_02) and 02 (Dated 24-MAY-2021, GSK Document 
No. TMF-13794092). 
GlaxoSmithKline 
Document Number 
Date 
Version 
TMF-11899418 
12-MAR-2021 
Original 
TMF-15213711 
30 Nov 2022 
Amendment No. 1 
The reasons for this amendment were to: plan specific outputs related to participant 
pregnancy in line with protocol amendment 02; add clarity on the Covid PD impact on 
exposure formula; Adjust on treatment definition to add 63 days post injection instead 
of 35; Additional categories added to summarize oral exposure to Oral Bridging (Covid 
and Non-Covid related); if SOC ART started immediately after missed injection, then 
injection would not be count as missed. Clarity added around entry into LTFU and 
transition to commercial product. List of displays for EOS updated to account for 
pregnancy and RAPIDO Data Viewer.  
1.1. 
RAP Amendments 
Revision chronology:  
RAP Section 
Amendment Details 
Reporting and Analysis Plan (RAP) CARISEL_213199_Final [12-MAR-2021] 
Reporting and Analysis Plan (RAP) CARISEL_213199_Amendment_1 [30 Nov 2022] 
Inclusion of additional pregnancy based output 
• 
Protocol amendment 02 allows pregnant 
participants to continue on study. Listings 
have been added to address pregnancy 
specific events.  
Data Handling 
• 
Pregnancy data accommodations have been 
added. 
• 
Exposure formulas were adjusted to account 
for Q8W dosing, protocol deviation impact, 
transition to commercial product, and various 
scenarios related to Oral Bridging or missed 
injections. 
Data Displays 
• 
Display status for EOS was updated to 
consider use of the RAPIDO Data Viewer. The 
following displays were added for pregnancy 
summarization: Listings 49-57 


 
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7 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
Cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) is an  HIV-1 
treatment regimen administered as two individual intramuscular injections monthly or 
every two months (following an optional oral lead-in [OLI] period). The overall objective 
of the CAB LA + RPV LA clinical development program was 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. 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
A change to the originally planned statistical analysis specified in the 213199 protocol 
[Dated: 06MAY2020] consists of dropping the ITT-E population and introducing the 
Enrolled population. This is being done as the ITT-E carries the same definition as the 
Safety population so both populations are not needed. Efficacy is also a secondary 
endpoint so it would add unnecessary programming work to include an identical 


 
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8 
 
population. The Safety population will serve as the primary population for both safety 
and efficacy analyses. The Enrolled population is being added in order to adhere to 
EudraCT standards. 
2.1.1. 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Rationale 
• 
An ITT-E population is listed to 
be used in statistical analysis.  
• 
This population is being 
dropped and the Safety 
population will be used for 
efficacy analysis. An 
Enrolled population is also 
being added. 
• 
The ITT-E and Safety 
populations carry the 
same definition so only 
one is needed for 
analysis. The Enrolled 
population is added to 
adhere to EudraCT 
standards.  
 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Endpoints/Estimands 
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 and 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) 


 
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9 
 
Objectives 
Endpoints/Estimands 
 
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. 
 
To evaluate Patient Study 
Participants experience for 
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 


 
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1 0  
 
O bjecti ves  
E n d p oi nts / Esti m a n ds 
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 nce 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) at q ua ntitati vel y ass esse d via prefere n ce 
q uesti o n naire at D ose 7  
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2.3. 
Study Design 
Study 213199 (Cabotegravir And Rilpivirine Implementation Study in European 
Locations -CARISEL) is a cluster randomized, two-arm, open-label, hybrid 
effectiveness-implementation study designed to evaluate two implementation strategy 
conditions (Enhanced [Arm-e] vs Standard [Arm-s]) in various clinical settings across 
five European countries. 
This study is an evaluation of implementation strategies on the degree of acceptability, 
appropriateness, feasibility, fidelity, and sustainability of clinic practices to deliver the 
CAB LA + RPV LA regimen. The study will use an implementation science approach to 
understand the barriers and facilitators for both patients and providers, including best 
practices for delivering CAB LA + RPV LA within an interventional clinical trial where 
the CAB LA + RPV LA regimen is delivered to HIV-1-infected, virologically-suppressed 
adult patients. 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 
result, the primary focus of this study is implementation.  The secondary focus is on the 
clinical effectiveness. 
All patients who fulfill eligibility requirements will receive the study treatment of CAB 
LA + RPV LA and will begin oral therapy with CAB 30 mg + RPV 25 mg once daily for 
approximately one month to determine individual safety and tolerability prior to 
receiving CAB LA + RPV LA for an additional 11 months. Total patient study 
participant duration in the study is approximately 13 months including screening.  
Patient participants in CARISEL who successfully complete the study (Dose 7), without 
meeting study-defined withdrawal criteria, will be given the option to continue to receive 
CAB LA + RPV LA, administered Q2M in the Extension Phase until the study treatment 
is either locally approved and commercially available (including through local 
public/government health sectors), the participant no longer derives clinical benefit, the 
participant meets a protocol-defined reason for discontinuation or until development of 
either CAB LA + RPV LA Q2M is terminated. Alternatively, participants can choose to 
complete study participation and enter the 52-week LTFU Phase of the study.  
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 will enter a 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. Cluster randomization will 
be used to randomize sites in each country to either arm-e or arm-s. 


 
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Overview of Study Design and Key Features 
• 
N=450 patients; Open-label in respect to treatment; patients selected to CAB LA+RPV LA Interview 
or CAB LA + RPV LA Non-Interview based on stratification factors of gender, age, and race. 
• 
18 sites randomized to each of the implementation strategy arms, ARM-E or ARM-S 
Design 
Features 
• 
The proposed study is a cluster-randomized, implementation-effectiveness 
hybrid type III study to identify and evaluate strategies for successful 
implementation of the cabotegravir + rilpivirine long-acting injectable regimen in 
Europe. 
• 
The CARISEL study comprises of screening phase (up to 35 days prior to 
enrolment), Maintenance Phase from Day 1 to Month 12, including Oral Lead-
in, long term follow-up (LTFU) phase, and extension phase. During screening 
phase all clinical and laboratory assessments of eligibility must be performed 
and reviewed. Participants may be re-screened once 
Dosing 
• 
Intervention Phase” Open-label in respect to treatment;  
• 
Site Randomization: 
Intervention Phase: Site Randomization 1:1 to ARM-E: ARM-S 
Time & 
Events 
• 
Refer to Appendix 1: Schedule of Activities 
Treatment 
Assignment 
• 
CAB LA+RPV LA (N=450) 
Interim 
Analysis 
• 
Interim analyses will be conducted at two timepoints: 1) when 50% of subjects 
have received their 3rd injection and 2) when 100% of subjects have received 
their 3rd injection. 
• 
The primary analysis will be conducted at Month 12 
 
 
 


 
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2.4. 
Statistical Hypotheses / Statistical Analyses 
The hypotheses on the quantitative aspects of this study is that enhanced implementation 
strategy is superior than the standard implementation strategy in terms of mean staff 
study participant (SSP) AIM/IAM/FIM scores. i.e., 
• 
H0: µ(enhanced) = µ(standard) vs. H1: µ(enhanced) > µ(standard) 
Further analysis details for this hypothesis will be covered in the Evidera SAP. 
2.4.1. 
Sample Size Determination 
The study size is based on practical considerations in terms of feasibility of enrolling an 
adequate number of sites on each implementation strategy balanced with the desire to 
have interventions tested across several types of investigative sites; as well as enrolling 
an adequate number of patient study participants in each site.  
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. 
2.4.1.1. 
Power to Show Superiority in mean SSP AIM/IAM/FIM scores 
Table A shows preliminary AIM/IAM/FIM data from the ongoing U.S. implementation 
study CUSTOMIZE (209493). 
Table A 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 


 
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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 in line with our primary hypothesis 
are shown in Table B.   
Table B 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% 
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 B, 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 A (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. 
2.4.1.2. 
Sample Size for Provider Population 
An overall average number of 9 sites, per arm (18 sites), 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. 
 
 


 
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Table C 
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 
 
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 D 
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 
 


 
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Figure A 
Sensitivity Analysis for Sample Size versus Half-Width (Precision)- 
Two-Sided 95% Confidence Interval (for Sites and Providers) 
2.4.1.3. 
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. 
Table E 
Sensitivity Analysis for Sample Size versus Half-Width (Precision)- 
Two-Sided 95% Confidence Interval (for Patients) 
Sample Size 
Actual Distance from Mean 
Difference to Limits (Precision) 
SD=0.5 
SD=1.0 
100 
0.099 
0.198 
125 
0.089 
0.177 
150 
0.081 
0.161 
175 
0.075 
0.149 
200 
0.070 
0.139 
225 
0.066 
0.131 
250 
0.062 
0.125 
 


 
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Fi g ur e B  
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 Diff 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 t he 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 
prese nt  c h alle n ges t hat w ere n ot o bser ve d i n a cli nical trial setti n g. T h eref ore,  i n a d diti o n 
t o t he pri mar y a nal yses w hic h f oc uses o n st u d y staff partici p a 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 ’ 
satisfacti o n sc ore res ults, t o all o w a n i nf or mal c o m paris o n bet wee n t h e t w o 
i m ple me ntati o n strate gies.    
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3. 
PLANNED ANALYSES 
This RAP describes standard analyses that will be applied to descriptively summarize 
clinical adverse events, laboratory evaluations, virologic parameters and other clinical 
safety and efficacy outcomes.  
Details pertaining to reporting of survey/interview data and health 
outcomes/effectiveness analyses will be described in a separate analysis plan provided by 
Evidera or other CRO partner under GSK’s oversight. 
At least three analyses will be conducted to evaluate primary and secondary objectives of 
the protocol; an interim analysis after 50% of subjects have received their 3rd injection, 
and interim analysis after 100% of subjects have received their 3rd injection, and finally 
the primary analysis at Month 12. Further data cuts and analyses may be conducted as 
necessary, in order to support for internal use and publications. 
A final end-of-study (EOS) analysis will be conducted when all subjects have completed 
the study. 
3.1. 
Interim Analyses 
As mentioned previously, interim analyses will be performed when 50% and 100% of 
subjects have received their 3rd injection. No formal criteria for stopping or amending the 
study based on the interim analysis are envisioned. Further interim analyses may be 
planned for publication data.  
3.2. 
Final Analyses 
The planned Month 12 primary analysis will be performed after the completion of the 
following sequential steps: 
• All participants have completed Month 12 of the study as defined in the protocol, 
including any required re-tests. 
• All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data 
Management. 


 
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4. 
ANALYSIS POPULATIONS 
This RAP defines patient study participants in detail. Analysis populations that pertain to 
implementation science deliverables are documented in the Evidera SAP. 
Population 
Definition / Criteria 
Analyses Evaluated 
All Subjects 
Screened 
Population 
• 
All participants who were screened for eligibility and 
inclusion in the study 
• 
Patient Study 
Population 
Enrolled 
Population 
• 
All patient study participants who passed screening 
and entered the study.  
• 
Patient Study 
Population 
Safety 
• 
All enrolled participants who received at least one 
dose of CAB + RPV Oral or CAB LA + RPV LA. 
• 
Patient Study 
Population, 
Safety, Efficacy, 
Virology, Other 
Assessments 
Long Term 
Follow-up 
Population 
• 
All subjects receiving at least one dose of CAB LA 
and/or RPV LA who have discontinued CAB LA +RPV 
LA regimen and have at least one Long Term Follow-
up phase clinic visit 
• 
Efficacy, Safety 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [25NOV2020 v2.0]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
Protocol deviations related to the implementation process, and not the clinical conduct of 
the study will be reported separately. The identification and categorization of PDs as 
important may be different for implementation PDs vs those associated with the clinical 
conduct of the study.


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
Data Displays for Reporting  
Description 
Order in TLF  
Analysis 
CAB Oral +RPV Oral 
1 
OLI Safety 
CAB LA +RPV LA 
(includes both QM and Q2M dosing) 
1 
Study Population, Efficacy, Safety 
 
5.2. 
Baseline Definitions 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3. 
Multicentre Studies 
In this multicentre, European-based study, enrolment and demographics will be presented 
by investigator site. 
Exploratory analyses will be considered only if applicable. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
Category 
Details 
Covariates 
Implementation strategy, Site, Country, Gender, Age Group, Race, CD4 Count 
 
5.4.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be combined. 


 
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Subgroup 
Categories  
Implementation Strategy 
• 
Standard 
• 
Enhanced 
Site 
18 European sites 
Country 
As collected 
Gender 
• 
Male  
• 
Female 
Age 
• 
≥50 
• 
<50 
Race  
• 
White  
• 
African Heritage 
• 
Asian 
• 
Other 
CD4 Count 
• 
<350 
• 
≥350 
 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
13.1 
Appendix 1: Schedule of Activities 
13.2 
Appendix 2: Assessment Windows 
13.3 
Appendix 3: Study Phases 
13.4 
Appendix 4: Data Display Standards & Handling Conventions 
13.5 
Appendix 5: Derived and Transformed Data 
13.6 
Appendix 6: Reporting Standards for Missing Data 
13.7 
Appendix 7: Values of Potential Clinical Importance 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays. 
Enrollment and demographics will be displayed by Implementation strategy, site, 
country, and overall. 
For the two interim analyses based on subjects’ 3rd injection data, study population tables 
and listings will be produced by GSK. Details of these Interim Analysis deliverables can 
be found in Appendix 12: List of Data Displays. 


 
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7. 
EFFICACY ANALYSES 
Implementation Science/Health Outcomes endpoints will form the basis for the overall 
primary analysis of the study, and details of implementation science/health outcomes 
analyses are documented in a separate Evidera SAP. Clinical efficacy endpoints are 
evaluated as secondary objectives for this study. 
Efficacy analyses will be performed at Month 12 and EOS. There will be no efficacy 
reported at the interim analyses.  
7.1. 
Secondary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
• Proportion of participants with Plasma HIV-RNA < 50 copies/mL and plasma HIV-1 
RNA ≥ 50 copies/mL as per Food and Drug Administration (FDA) Snapshot 
algorithm at Month 12 (Safety Population). See Appendix 8 for Snapshot Algorithm 
details. 
• Participants with protocol-defined confirmed virologic failure (CVF) over time 
(Safety population) 
• Incidence of treatment-emergent genotypic and phenotypic resistance to CAB and 
RPV in patient study participants with CVF (Safety population) 
7.1.2. 
Population of Interest  
The primary efficacy analyses will be based on the Safety population, unless otherwise 
specified. HIV-1 RNA summaries will also be reported for the Long-Term Follow-up 
Population.  
7.1.3. 
Strategy for Intercurrent (Post-Randomization) Events 
Participants with last available HIV-1 RNA measurement less than 50 copies/mL while 
the participant is on treatment within the analysis visit window of interest are classified as 
HIV-1 RNA < 50 c/mL. Participants without evaluable HIV-RNA data for the visit of 
interest or who change treatment not permitted per protocol before the analysis window 
are considered non-responders.  
Participants with last available HIV-1 RNA measurement greater or equal to 50 
copies/mL while the participant is on treatment within the analysis visit window of 
interest are classified as HIV-1 RNA ≥ 50 c/mL. Participants without evaluable HIV-
RNA data for the visit of interest and who discontinue treatment for reasons not related to 
adverse event while having HIV-1 RNA ≥50 copies/mL at time of discontinuation or who 
change study treatment not permitted per protocol before the analysis window are also 
classified as having HIV-RNA ≥50 copies/mL.  
Missing viral load values for reasons related to COVID-19 issues (e.g. participant is 
unable to have viral load assessed due to barriers in attending the clinic during the 
pandemic or COVID-19 related adverse events leading to treatment discontinuation) will 


 
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be considered as random missingness and classified the same as all other missingness for 
the primary efficacy Snapshot analysis. A sensitivity analysis using a modified Snapshot 
which includes subcategories for Covid-19 related and Non-Covid-19 related missingness 
will also be performed to display the impact of Covid-19 intercurrent events on the study. 
See Appendix 8 for Modified Snapshot Algorithm details. 
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.1.4.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
Proportion of participants with plasma HIV-1 RNA < 50 c/mL at Month 12 
using the FDA Snapshot algorithm (Safety population) 
• 
Proportion of participants with plasma HIV-1 RNA ≥50 c/mL at Month 12 
using the FDA Snapshot algorithm (Safety population) 
• 
Proportion of participants with protocol-defined confirmed virologic failure 
(CVF) over time (Safety population) 
• Incidence of treatment-emergent genotypic and phenotypic resistance to CAB 
and RPV in patient study participants with CVF (Safety population) 
Results Presentation 
• 
The proportion of participants with HIV-1 RNA <50 c/mL, HIV-1 RNA ≥ 
50c/mL, and with recorded CVF at each planned visit with corresponding 95% 
confidence intervals calculated using the Clopper-Pearson exact method. 
• 
Proportion of subjects with incidence of treatment-emergent genotypic and 
phenotypic resistance to CAB and RPV in patient study participants with CVF 
at each visit with corresponding 95% confidence intervals calculated using the 
Clopper-Pearson exact method. 
• 
Descriptive statistics for the nominal values and change from baseline values in 
CD4+ cell counts and the CD4/CD8 ratio. 
Subgroup Analyses 
• Summary of study outcomes will be repeated for subgroups of interest as 
specified in Section 5.4.2: Implementation strategy, Participant sex, age group 
(<50 vs ≥50), race (White, African Heritage, Asian, Other), and CD4 count 
(<350, ≥350). 
• The proportion of participants in each Snapshot study outcome category and 
sub-category will be summarized in which default sub-categories have been 
expanded to present Covid-19 vs. Non-Covid-19 related impact (as described in 
Appendix 8). 


 
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8.  
S A F E T Y A N A L Y S E S  
T he safet y a nal yses will be base d o n t he Safet y a n d L o n g T er m  F oll o w -u p ( L T F U) 
p o p ulati o ns , u nless ot her wise s pecifie d. 
 
F or t he i nteri m a n al ys es, a d here n ce t o d osi n g will be re p ort e d f or t he Safet y p o p ulati o n. 
F or t he M o nt h 1 2 pri mar y a n al ysis, o ut p uts will be prese nt e d f or t he  Safet y p o p ulati o n i n 
t he I nt er ve nti o n P hase u nless ot her wise s pecifie d. F or t he E O S a n al ysis, o ut p uts will be 
prese nte d f or t he Safet y p o p ulati o n i n t he I nter ve nti o n  a n d E xte nsi o n  p hases as well as 
f or t he L T F U p o p ulati o n  i n t he L T F U p has e.  
 
F or t he M o nt h 1 2 a n al ysis, a set of se parate o ut p uts will als o be prese nte d f or t he oral 
lea d-i n peri o d, i ncl udi n g a s u m mar y of a d v erse e v e nts, S A Es, A Es lea di n g t o wit h dra wal, 
p ost -baseli ne e mer ge nt c he mistr y/ hae mat ol o g y a b n or malit ies, a n d s u bjects wit h 
he pat o biliar y a b n or m alit y criteria.  
 
8. 1.  
S af et y E n d p oi nt s  
Sec o n dar y  a n d tertiar y s afet y e n d p oi nts f or t his st u d y i ncl u de:  
•  
Perce nta ge of i njecti o ns occ urri n g wit hi n tar get wi n d o w fr o m t he tar get d ate.  
•  
I n ci de nce a n d se v erit y of A Es a n d S A Es o ver ti m e  
r ti me  
8. 2.  
A d v er s e E v e nt s A n al y s e s  
A d verse e ve nts a n al ys es  i ncl u di n g t he a n al ysis of a d verse e ve nts ( A Es), Seri o us ( S A Es), 
Dr u g -relate d A Es, A Es l ea di n g t o wit h dra wal, A Es b y ma xi m u m se verit y, C O VI D -1 9 
A Es , a n d ot her si g nifica nt A Es will be base d o n G S K C ore D ata S ta n dar ds. T he details of 
t he pla n ne d dis pla ys are pr o vi de d i n A p pe n di x 1 2 : List of Data Dis pla ys. 
C CI
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2 6  
 
8. 3.  
A d v er s e E v e nt s of S p e ci al I nt er e st  A n al y s e s  
A c o m pre he nsi v e list of Me d D R A ter ms base d o n cli nical re vie w will be use d t o i de ntif y 
A d verse E v e nts of S peci al I nt erest ( A E SI).  C ha n ges t o t he Me d D R A dicti o nar y ma y 
occ ur bet w ee n t he st art of t he st u d y a n d t he ti me of re p orti n g a n d/ or e mer gi n g dat a fr o m 
o n -g oi n g st u dies ma y hi g hli g ht a d diti o nal  a d verse e ve nts of s peci al i nterest, t heref ore t he 
list of ter ms t o be use d f or eac h e ve nt of i nterest a n d t he s pecific e ve nts of i nterest will be 
base d o n t he safet y re vi e w tea m ( S R T) a gree me nts i n place at t he ti me of re p orti n g.  T h e 
details of t he c urre nt pla n ne d gr o u pi n g, i ncl u di n g Sta n dar dize d Me d D R A Q uer y ( S M Q) 
val ues (as a p plica ble), a n d pla n ne d dis pla ys are pr o vi de d i n A p pe n di x 9 : A E SI 
i de ntificati o n a n d A p pe n di x 1 2 : List of Data Dis pla ys. 
8. 4.  
Cl i ni c al L a b or at or y A n al y s e s 
La b orat or y e val uati o ns i ncl u di n g t he a nal yses of C he mistr y la b orat or y tests  a n d 
He mat ol o g y l a b orat or y t ests will be base d o n G S K C ore Data Sta n d ar ds. T he details of 
t he pla n ne d dis pla ys are i n A p pe n di x  1 2 : List of Data Dis pla ys.  
8. 5.  
Ot h er S af et y A n al y s e s  
T he a nal yses of i njecti o ns i n t he tar get wi n d o w as well as n o n -la b orat or y safet y t est 
res ults i ncl u di n g vital si g ns will be base d o n G S K C ore Data Sta n dar ds, u nless ot her wise 
s pecifie d. T he d etails of t he pla n ne d dis pla ys are prese nte d i n A p pe n di x 1 2 : List of Data 
Dis pla ys.
C CI


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Endpoint / Variables 
9.1.1. 
Drug Concentration Measures 
Available concentration-time data for CAB and RPV will be presented in listings as 
specified in Appendix 12: List of Data Displays and will be based on GSK Data 
Standards and statistical principles 


 
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10. 
VIROLOGY 
10.1. 
Genotypic and Phenotypic Data 
Available genotypic and phenotypic data at all collection timepoints will be presented by 
subject (separately for CVF and Non-CVF subjects), as specified in Appendix 12: List of 
Data Displays.


 
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11. 
OTHER ANALYSES 
11.1. 
Endpoint / Variables 
11.1.1. 
Study Visit length 
Study Visit Length will be reported for all analyses including interim analyses, Month 12, 
and EOS. Details of the planned displays for study visit length data are provided in 
Appendix 12 List of Data Displays and will be based on GSK Data Standard and 
statistical principle.  
11.1.2. 
Pregnancy 
Protocol amendment 02 allows for pregnant participants to remain on study and continue 
the use of study drug. Should any participants become pregnant while on study drug, 
pregnancy specific listings will be produced. Listings will include any adverse events, 
clinical lab results including HIV-1 RNA and plasma CAB & RPV concentrations, 
exposure to study drug during pregnancy, and pregnancy details including duration and 
outcomes reported by the participants including birth outcomes. Details of the planned 
displays are provided in Appendix 12 


 
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12. 
REFERENCES 
GSK document number 2019N420690_01. 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.  
GSK document number 2019N420690_02. 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.  
Wensing AM, et al. 2019 update of the drug resistance mutations in HIV-1. Topics in 
antiviral medicine. 2019;27:111-121.  
 


 
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13. 
APPENDICES 
13.1. 
Appendix 1: Schedule of Activities 
The protocol also lists a schedule of activities for staff study participants (not listed here) 
13.1.1. 
Protocol Defined Schedule of Events: Schedule of Activities for Patient Study Participants 
Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm    
 
 
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 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
Current medical conditions   
X 
 
 
 
 
 
 
 
 
 
 
Center for Disease Control and 
Prevention (CDC) HIV-1 
Classification 
X 
 
 
 
 
 
 
 
 
 
 


 
C O N FI D E N TI A L  
 
 
 
 
2 1 3 1 9 9  
 
3 2  
 
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              
                  
 
 
 
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) 
S y p hilis ser ol o g y + refle x 
R a pi d Pl as m a Re a gi n ( R P R)  
X  
 
 
 
 
 
 
 
 
 
 
S y m pt o m Directe d P h ysic al 
E x a m a n d M e dic al 
Assess me nt c  
 
X  
X  
 
X  
 
X  
 
X  
X  
X  
HI V -ass oci ate d C o n diti o ns, 
A E a n d seri o us a d verse e v e nt 
( S A E) Assess me nts d , C o n 
M e ds  
X  
X  
X  
 
X  
 
X  
 
X  
X  
X  
Vit al Si g ns  
( bl o o d press ure [ B P], he art 
r ate [ H R]) e 
X  
X  
X  
 
X  
 
X  
 
X  
X  
 
Wei g ht, Hei g ht & b o d y m ass 
i n de x ( B MI)f  
X  
X  
X  
 
X  
 
X  
 
X  
X  
 
Cli nic al C he mistr y, 
He m at ol o g y a n d ot her Tests o 
X  
X  
X  
X  
X  
 
X  
 
X  
X  
X  
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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm    
 
 
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) 
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 
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 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testing  
Urine (U) or Serumg  
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
Notification of Interviewt 
 
X 
 
 
 
 
 
 
 
 
 


 
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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm    
 
 
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) 
Oral CAB + RPV Medication 
Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
CAB LA + RPV LA IM 
Treatment Administrationi 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Participant Visit Reminder 
Contact 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Participant Contact Detail 
Confirmation 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient Toolkits 
 
X 
X 
X 
X 
X 
 
 
Record Visit Lengthj 
 
 
X 
X 
 
X 
X 
 
 
 
 
Contraception Counselingu 
 
 
 
 
 
 
 
 
 
X 
X 
HAART dispensationv 
 
 
 
 
 
 
 
 
 
X 
X 
Patient Questionnairesk 
 
 
X 
 
X 
 
 
 
X 
 
 
Selected Patient Interviewsl 
 
X 
 
 
 
 
 
 
X 
 
 


 
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Procedure 
Screeninga 
up to 35d 
Intervention Period (Month) 
 Withdrawalm    
 
 
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) 
HIV and patient satisfaction 
(HIVTSQs) 
 
Xr 
X 
 
X 
 
 
 
X 
 
 
HIVTSQc 
 
 
 
 
 
 
 
 
X 
 
 
Preference Question 
 
 
 
 
 
 
 
 
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. See protocol 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 protocol Section 8.5.1 . 
e) Measure vital signs after about 5 minutes of rest in a semi-supine position. 
f) 
Height is 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 Protocol 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 


 
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reaction. Bring RPV LA to approximately room temperature prior to injecting. Time and location of injection (right or left) as well as needle length used will 
be collected in the eCRF. IM dosing is expected to occur on the same date of the month as determined by IM Dose 1 visit date, this is the Target Date; 
where possible, this first injection should be performed within 2 hours of taking the last oral regimen dose.  For Dose 2, a dosing window of +0 / -7 
days from the target visit date is stipulated. A (+ or -) 7-day window from the target date visit is stipulated for IM dosing beginning at Dose 3. All 
decisions regarding dose interruption/ resumption must be discussed with the Medical Monitor in advance. 
j) 
Length of study visit from arrival until departure from clinic will be evaluated. Participant’s time of arrival, actual start time of the appointment, and 
actual end time of the appointment will be collected in the eCRF. 
k) Questionnaires should be completed before receiving the injections.  
l) 
Interviews should be conducted before the PSP receives Dose 1 and within 4 weeks of receiving Dose 7. Interviews may be done in person, virtually, or 
by phone. A minimum of 6 patients per site will be selected for interviews.   
m) Withdrawal Visit - Conduct ~4 weeks after the last dose of investigational product (IP) if not entering Long-Term Follow Up and only if the participant 
has ongoing AEs or lab abnormalities at the last on-study visit. May be conducted by telephone.  
n) Participants receiving one or more injections with CAB LA and/or RPV LA will be assessed with clinic visits at months 3, 6, 9 and 12 during the Long-
Term Follow-Up phase. The start of the 52-week follow-up period begins the day of the last CAB LA and/or RPV LA dose. 
o) See protocol Section 8.4.4 for list of tests  
p) Whole blood/PBMC collection samples may be used for virologic analyses. PBMCs will be collected at baseline Day1 and at Withdrawal. 
q) Hepatitis B (HBsAg), Anti-HBc, Anti-HBsAg, Hepatitis C (anti-HCVAb). A (+) anti-HCVAb will be followed by a confirmatory nucleic acid test for 
HCV RNA. HBV DNA will only be performed for participants with a (+) anti-HBc and (-) HBsAg and (-) anti-HBs (past and/or current evidence). 
r) Administer HIVTSQs in Day 1 before OLI initiation.  
s) 
At a minimum the study toolkit will be offered at the time pointed noted in the protocol Table 6.  However, the toolkit items are intended to be used 
throughout the study.     
t) 
Notification of interviews may occur between Day 1 or during the 7 days after Day 1. 
u) Women of childbearing potential should continue to receive counselling on the need to use adequate contraception for the entirety of the Long-Term 
Follow-Up period. 
v) Investigators must discuss choice of HAART regimen and timing of initiation with the Medical Monitor before initiating. 


 
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13.2. 
Appendix 2: Assessment Windows 
13.2.1. 
Definitions of Assessment Windows for Analyses 
Laboratory data, vital signs, adverse events, and genotypic/phenotypic data will be 
assigned to assessment windows according to actual dates rather than the nominal visit 
labels as recorded on the eCRF or in the laboratory database. 
 
Prior to visit slotting, assessments are first assigned to a study phase (Screening, 
Intervention Phase, Extension, or Long Term Follow Up) as defined in Appendix 3. 
 
According to the protocol, the nominal target study visit date will be based on the first 
injection, the Month 1 date. For instance, if Month 1 occurred on July 7th, all subsequent 
visits are expected to occur on the 7th of each month such that subsequent visits will be 
August 7th, September 7th, October 7th, etc. Since there are not >28 days in every month 
of the year, if the Month 1 injection occurred on the 29th, 30th, or 31st of the month, then 
the target study visit date for the remainder of the visits will be the 28th of the month.   
The nominal target study visit day is derived as 
• M1 Target Day = Date of Actual M1 Injection Visit Date – Date of First Oral lead-in 
Dose + 1, if subject receives M1 injection; else M1 Target Day = 30. 
• Mx Target Day = Mx Nominal Target Study Visit Date – Date of First Oral lead-in 
Dose + 1, for x=2,3, … 
Assessment windows will be derived based on the midpoint between two consecutive 
planned target study visit dates. For the Snapshot efficacy data, the same approach will be 
used, except for Month 12, which will use a +/- 6-week window around the projected 
target study visit date at Month 12. 
For parameters which are not scheduled to be assessed at visits, the all-inclusive 
assessment windows will still be used; however, data summaries will only report 
scheduled visits. Assessments at unscheduled visits will be included in summaries of 
worst-case values across visit (e.g. during the intervention phase) and in data listings, as 
well any algorithms that make use of additional data (e.g., Snapshot). 
For participants transitioning to commercial product at EOS, the safety follow-up visit 
date will be the last date referenced and serve as the ending timepoint for the final visit 
window.  
 


 
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Table 1 
Assessment Windows for Screening, Intervention and Extension 
Phase Data (Excluding HIV-1 RNA) 
Target 
(Study 
Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
Day of 
earliest 
record 
Assessment Study Day 1 
Screening 
For subjects discontinuing prior to receiving first injection: 
30 
Assessment Study Day = 2 
Study Day of Last CAB/RPV 
Oral Dose+1 
Month 1 
 
Assessment Study Day >  
(Study Day of Last CAB/RPV Oral Lead-in Dose +1) 
Follow-up 
For subjects receiving first injection: 
Day of First 
Injection 
Study Day = 2 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
Month 1 
M2  
Target Day 
M1 target day + floor [(M2 target day 
– M1 target day)/2] + 1 
M2 target day + floor [(M4 
target day – M2 target day)/2] 
Month 2 
M4  
Target Day 
M2 target day + floor [(M4 target day 
– M2 target day)/2] + 1 
M4 target day + floor [(M6 
target day – M4 target day)/2] 
Month 4 
M6  
Target Day 
M4 target day + floor [(M6 target day 
– M4 target day)/2] + 1 
M6 target day + floor [(M8 
target day – M6 target day)/2] 
Month 6 
M8  
Target Day 
M6 target day + floor [(M8 target day 
– M6 target day)/2] + 1 
M8 target day + floor [(M12 
target day – M8 target day)/2] 
Month 8 
M10  
Target Day 
M8 target day + floor [(M10 target 
day – M8 target day)/2] + 1 
M10 target day + floor [(M12 
target day – M10 target 
day)/2]  
Month 10 
M12  
Target Day 
M10 target day + floor [(M12 target 
day – M10 target day)/2] + 1 
M12 target day + floor [(M14 
target day – M12 target 
day)/2]  
Month 12 
Mx  
Target Day 
M(x-2) target day - floor [(Mx target 
day – M(x-2) target day)/2] + 1 
Mx target day + floor 
[(M(x+2) target day – Mx 
target day)/2] 
Month x 
For x = 
14, 16, 
etc. 
For subjects who permanently discontinue study treatment: 
 
Assessment Study Day > 
 Min (LTFU ART Start Date, Max (Study Day of Last Dose of Oral 
Study Treatment (CAB+RPV or SOC Bridging) + 1, Study Day of 
Last CAB + RPV Injection + 63)) 
Follow-up 
 


 
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Table 2 
Assessment Windows for Screening and Intervention Phase HIV-1 
RNA Data 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
Day of earliest 
record 
Assessment Study Day 1 
Screening 
 
For subjects discontinuing prior to receiving first injection: 
28 
Assessment Study Day = 2 
Study Day of Last Oral Lead-
in Dose +1 
Month 1 
 
Assessment Study Day > 
 (Study Day of Last CAB/RPV Oral Lead-in Dose +1) 
Follow-up 
 
For subjects receiving first injection: 
Date of First 
Injection 
Study Day = 2 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
Month 1 
M2 Target Day 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
+1 
M2 target day + floor [(M4 
target day – M2 target day)/2] 
Month 2 
M4 Target Day 
M2 target day + floor [(M4 
target day – M2 target day)/2] + 
1 
M4 target day + floor [(M6 
target day – M4 target day)/2] 
Month 4 
M6 Target Day 
M4 target day + floor [(M6 
target day – M4 target day + 1 
M6 target day + floor [(M8 
target day – M6 target day)/2] 
Month 6 
M8 Target Day 
M6 target day + floor [(M8 
target day – M6 target day)/2] + 
1 
M8 target day + floor [(M10 
target day – M8 target day)/2] 
Month 8 
M10 Target 
Day 
M8 target day + floor [(M10 
target day – M8 target day)/2] + 
1 
M12 target day – 43 
Month 10 
M12 Target 
Day 
M12 target day - 42 
M12 target day + 42 
Month 12 
M14 Target 
Day 
Assessment Study Day > M12 target day + 42 
Month 14 
For subjects who permanently discontinue study treatment during the Intervention Phase: 
 
Assessment Study Day > 
Min (LTFU ART Start Date, Max (Study Day of Last Dose of Oral 
Study Treatment (CAB+RPV or SOC Bridging) +1, Study Day of 
Last CAB + RPV Injection + 63)) 
Follow-up 
 


 
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Table 3 
Assessment Windows for Extension Phase HIV-1 RNA Data 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
M14 Target 
Day 
Study Day of Nominal Week 14 
Visit 
M14 target day - floor [(M16 
target day – M14 target day)/2]  
Month 14 
M16 Target 
Day 
M14 target day - floor [(M16 
target day – M14 target day)/2] 
+ 1 
M16 target day + floor [(M18 
target day – M16 target day)/2] 
Month 16 
Mx Target Day 
M(x-2) target day - floor [(Mx 
target day – M(x-2) target 
day)/2] + 1 
Mx target day + floor [(M(x+2) 
target day – Mx target day)/2] 
Month x 
For x =18, 
20 etc. 
 
For subjects who permanently discontinue study treatment during the Extension Phase: 
 
Assessment Study Day > 
Min (LTFU ART Start Date, Max (Study Day of Last Dose of Oral 
Study Treatment (CAB+RPV or SOC Bridging) +1, Study Day of 
Last CAB + RPV Injection + 63)) 
Follow-up 
 
Table 4 
Assessment Windows for Study Visit Length Data (Intervention and 
Extension Phase) 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Study Day of Actual M1 
Injection 
Study Day of Actual M1 Injection 
Month 1 
Study Day of Actual M2 
Injection 
Study Day of Actual M2 Injection 
Month 2 
Study Day of Actual M6 
Injection 
Study Day of Actual M6 Injection 
Month 6 
Study Day of Actual M8 
Injection 
Study Day of Actual M8 Injection 
Month 8 
Study Day of Actual Mx 
Injection 
Study Day of Actual Mx Injection 
Month x 
For x=17, 20, 
etc. 
 
If none of the above, then 
 Analysis Timepoint = Other 
 
 


 
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Table 5 
Assessment Windows for Summaries of Long-Term Follow-up 
Phase Data from Subjects who Received at Least One Injection of 
CAB+RPV and Permanently Discontinued from the Study 
Day of Assessment 
Assessment Window 
Target LTFU Study Day of 
Window 
1 ≤ LTFU Study Day ≤ 135 
LTFU Month 3 
90 
136≤ LTFU Study Day ≤ 225 
LTFU Month 6 
180 
226 ≤ LTFU Study Day ≤ 315 
LTFU Month 9 
270 
316 ≤ LTFU Study Day ≤ 405 
LTFU Month 12 
360 
(30*m-44) ≤ LTFU Study Day ≤ 
(30*m+45) 
LTFU Month m  
M = 15, 18, 21 
30*m 
• 
LTFU Study Day is defined in 13.5.1 
13.2.2. 
Assessment Windows for PK Concentration Data 
PK data will be presented in data listings according to planned nominal visits (i.e. as 
collected in the eCRF), without additional assignment to assessment windows. 
13.2.3. 
Assessment Windows for Pregnancy Data 
Pregnancy visits will be assigned in accordance with the derivations listed in Table 1 to 
Table 5 as appropriate for the relevant data. Post-partum visit data will be labelled based 
on the nominal timepoint 


 
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13.3. 
Appendix 3: Study Phases 
13.3.1. 
Study Phases 
Participants are considered to have entered the Extension phase if they have a Month 14 
visit. They are considered to enter the LTFU period if they have a post-treatment, non-
bridging ART start date or LTFU visit entered in the CRF, including LTFU withdrawal.  
Participants are considered to have completed the Intervention Phase upon successful 
completion of the Month 12 visit without discontinuing from study treatment. Extension 
Phase completion is defined as successful transition to commercial product whenever it 
becomes available by attending a Safety Follow-up visit and not discontinuing treatment.  
Table 6 
Participant Phase Entry and Conclusion Windows 
Phase 
Qualifying Entry 
Timepoint 
Qualifying Conclusion Timepoint 
Intervention 
Phase 
First CAB + RPV dose date 
Month 14 visit date; or Safety Follow-up visit 
date (if transitioned to commercial product); 
or LTFU ART start date (if discontinued from 
treatment after receiving at least one dose of 
CAB/RPV LA) 
Extension Phase 
Month 14 visit date 
Safety Follow-up visit date (if transitioned to 
commercial product); or LTFU ART start date 
(if discontinued from treatment after receiving 
at least one dose of CAB/RPV LA) 
LTFU Phase 
LTFU ART start date or 
LTFU Visit date existence 
LTFU Month 12 visit date 
AEs will be assigned to study phases as defined in Table 7. Laboratory data (efficacy, 
safety, and virology), HIV associated Conditions, health outcomes assessments, and vital 
signs will be assigned to study phases as defined in Table 8. 
Assessments/events are assigned to study phases sequentially, starting from the top of 
each table. 
Table 7 
Study Phases for AEs 
Study Phase 
Definition 
Screen  
Date < Intervention Phase Treatment Start Date 
 
Intervention Phase 
For subjects continuing into the Extension Phase: 
Intervention Phase Treatment Start Date ≤ Date < Date of Nominal Month 14 Visit 
 
For subjects not continuing into the Extension Phase: 
Intervention Phase Treatment Start Date ≤ Date < LTFU ART Start Date[a] 
 


 
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Study Phase 
Definition 
For subjects transitioning to commercial product without discontinuing or 
entering Extension: 
Intervention Phase Treatment Start Date ≤ Date ≤ Safety Follow-up visit date 
 
For AEs leading to treatment withdrawal with start date equal to the LTFU ART 
Start Date, Intervention Phase instead of Long-term Follow-up Phase will be 
assigned. 
Extension Phase 
For subjects transitioning to commercial product: 
Date of Nominal Month 14 Injection ≤ Date ≤ Safety Follow-up visit date 
 
For subjects not transitioning to commercial product: 
Date of Nominal Month 14 Injection ≤ Date < LTFU ART Start Date [a] 
 
For AEs leading to treatment withdrawal with start date equal to the LTFU ART 
Start Date, Extension Phase instead of Long-Term Follow-up Phase will be 
assigned. 
Long Term Follow-
Up 
For subjects who receive at least one CAB/RPV injection and permanently 
discontinue study treatment: 
AE Start Date  LTFU ART Start Date 
AEs with completely missing start date: 
• 
If AE end date is ≤ Intervention Phase Treatment Start Date, then assign to Screening Phase; 
• 
Else if AE end date is completely missing or Intervention Phase Treatment Start Date < AE end 
date ≤ Date of Nominal Month 14 Injection, then assign to Intervention Phase; 
• 
Else if AE end date > Date of Nominal Month 14 Injection, then assign to Extension Phase. 
• 
Date=AE Start Date  
• 
[a] If participants have missing LFTU ART start date, only the lower bound will be considered in the derivation. 
Table 8 
Study Phases for Laboratory, Vital Signs, HIV-1 Associated 
Conditions, and Protocol Deviation Data 
Study Phase 
Definition 
Screen 
Date ≤ Study Treatment Start Date 
Intervention Phase 
For subjects continuing into the Extension Phase: 
Intervention Phase Treatment Start Date < Date < Date of Nominal Month 14 Visit 
 
For subjects not continuing into the Extension Phase: 
Intervention Phase Treatment Start Date < Date ≤ LTFU ART Start Date [a]  
 
For subjects transitioning to commercial product without discontinuing or 
entering Extension: 
Intervention Phase Treatment Start Date < Date ≤ Safety Follow-up visit date 
Extension Phase 
For subjects continuing into Extension Phase: 
Date of Nominal Month 14 Visit ≤ Date ≤ LTFU ART Start Date [a] or Safety Follow-
up visit date 
Long Term Follow-
Up 
For subjects who receive at least one CAB/RPV injection and permanently 
discontinue study treatment: 
Assessment Date > LTFU ART Start Date 
• 
Date = start or assessment date 
• 
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Study phase of discontinuation will be determined according to Table 9. 
Table 9 
Study Phases for Study Conclusion/IP Discontinuation 
Study Phase 
Definition 
Intervention Phase 
Discontinuation Date is not missing, and no assessments collected at any 
extension phase nominal visits (i.e. Month 14, Month 16, Month 18 etc.). 
Extension Phase 
Discontinuation Date is not missing, and assessments collected at any extension 
phase nominal visits (i.e. Month 14, Month 16, Month 18 etc.). 
• 
Discontinuation Date = date of failure to complete study/date of IP discontinuation 
Medication use will be classified as prior and concomitant with study treatment according 
to Table 10, noting that a medication can be assigned as “taken” during more than one 
study phase. 
Table 10 
Study Phases for Non-ART Medications/ART Medications 
 
Definition 
Prior  
Medication Taken < Intervention Treatment Start Date 
Concomitant during 
Intervention Phase 
For subjects continuing into Extension Phase: 
Intervention Treatment Start Date[a] ≤ Medication Taken < Date of Nominal 
Month 14 Visit  
 
For subjects not continuing into Extension Phase[b]: 
Intervention Treatment Start Date[a] ≤ Medication Taken < LTFU ART Start Date 
 
For subjects transitioning to commercial product without discontinuing or 
entering Extension: 
Intervention Phase Treatment Start Date ≤ Medication Taken ≤ Safety Follow-up 
visit date 
Concomitant during 
Extension Phase 
For subjects transitioning to commercial product: 
Date of Nominal Month 14 Injection ≤ Medication Taken ≤ Safety Follow-up visit 
date 
 
For subjects not transitioning to commercial product: 
Date of Nominal Month 14 Injection ≤ Medication Taken < LTFU ART Start Date 
Received during 
Long-term Follow-up 
For subjects who received at least one CAB and/or RPV injection and have 
started LTFU ART: 
Medication Taken ≥ LTFU ART Start Date 
NOTES:  
• 
Please refer to Appendix 6: Reporting Standards for Missing Data for handling of missing and partial 
dates for medications. Use the rules in this table if medication date is completely missing. 
a. 
The ART medication stopped on start date of Intervention treatment will be considered a prior medication 
and will not be considered concomitant during the Intervention phase. If the stop date of ART medication 
is completely missing and this medication is recorded in eCRF as prior, it will be considered a prior 
medication and will not be considered concomitant during the intervention phase. 
b. 
If subjects have missing LFTU ART start date, only the lower bound will be considered in the derivation. 
 
 
 


 
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13.3.2. 
Treatment State 
Within each study phase (based on assignment of study phase described in Section 
13.3.1), only those events/assessments which occur within the ranges shown in Table 11 
will be considered ‘on-treatment’ for the given phase.  No treatment states will be 
assigned to medications. 
For adverse events, partial AE start date will use imputation as described in 13.6.2.1. 
Table 11 
Treatment State within Study Phases 
Study Phase 
State 
Definition 
Screen 
Pre-Treatment 
All assessments/events within phase 
Intervention/Extension 
On-treatment 
Date ≤ max (Date of Last CAB LA +RPV LA IM Dose 
+ 63, Date of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1) 
Post-Treatment 
Date > max (Date of Last CAB LA +RPV LA IM Dose 
+ 63, Date of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1) 
Long Term Follow-Up 
Post-Treatment 
All assessments/events within phase 
NOTES:  
• 
Date = Assessment/Start Date 
a. 
Treatment State is determined after data has been assigned to the study phases as defined in Section 13.3.1. 
b. 
Last injection and/or last dose of oral study treatment (CAB+RPV or SOC bridging) are only applied to 
participants who permanently discontinued the study treatment. The assessments for participants who did not 
permanently discontinue the study treatment will be considered ‘On-treatment’. For participants continuing into 
extension phase, all data assigned to intervention phase per Section 13.3.1 will be considered ‘On-treatment’. 
 
13.3.3. 
Oral Lead-in Period 
Certain displays will be produced for data collected or events occurring during the oral-
lead-in period as defined in Table 12 and Table 13. 
Table 12 
Oral Lead-in Period for AEs 
Study Period 
Date Range 
Oral Lead-in 
For participants receiving at least one Injection: 
Intervention Treatment Start Date ≤ Date [a] < Date of First IM Injection  
 
For participants withdrawing prior to first Injection: 
Date  Intervention Treatment Start Date 
Note that the oral lead-in period is only applicable to the participants who received at 
least one dose of study treatment during the oral lead-in period in the study. Oral 
lead-in period is within the intervention phase. 
[a] AEs with completely missing start date which have been assigned to the Intervention Phase based on Table 7 
will not be assigned to the Oral Lead-in Period. 
NOTES: 
• 
Date = AE Start date 
 


 
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Table 13 
Oral Lead-in Period for Laboratory Data 
Period 
Date Range 
Oral Lead-in 
For participants receiving at least one Injection: 
Intervention Treatment Start Date < Date ≤ Date of First IM Injection  
 
For participants withdrawing prior to first Injection: 
Date > Intervention Treatment Start Date 
 
Note that the oral lead-in period is only applicable to the participants 
who received at least one dose of study treatment during the oral lead-in 
period in the study. Oral lead-in period is within the intervention phase. 
NOTES: 
• 
Date = Date of assessment 


 
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13.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
13.4.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
us1salx00259 
HARP Compound 
  \ARPROD\GSK1265744\mid213199\interim_01 
  \ARPROD\GSK1265744\mid213199\interim_02 
  \ARPROD\GSK1265744\mid213199\primary_01 
Analysis Datasets  
• 
Analysis datasets will be created for the interim analyses according to SI data standards. 
• 
Analysis datasets will be created for the Month 12 reporting effort according to CDISC standards 
(SDTM IG Version 3.2 & ADaM IG Version 1.1).  
Generation of RTF Files 
• 
RTF files will be generated for all reporting efforts described in the RAP. 
13.4.2. 
Reporting Standards 
General 
• 
The current GSK Statistical Display Standards in the GSK Standards Library (IDSL) will be applied 
for reporting, unless otherwise stated (Library Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
Formats 
• 
GSK Statistical Display Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the GSK Standard Statistical Display 
Principles but may be adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to GSK 
Standard Statistical Display Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
 
 


 
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Unscheduled Visits 
• Unscheduled visits will be assigned to an analysis visit using the all-inclusive windows 
defined in Section 13.2. 
• However, data summaries will only report visits that are planned assessment time points for 
each parameter (according to the Schedule of Activities in Section 13.1.1). 
• 
Evaluable assessments at unscheduled visits will be used when categorizing values across 
visits, such as ‘maximum grade during the intervention phase’ or ‘at any time post-
baseline’, and for any algorithm that has specific rules for which observation to use (e.g. 
snapshot algorithm or CVF identification). 
Descriptive Summary Statistics 
Continuous Data 
Refer to GSK Standard Statistical Display Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to GSK Standard Statistical Display Principals 7.01 to 7.13. 
13.4.3. 
Reporting Standards for Pharmacokinetic Data 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to the GSK Standard PK Display Standard. 
Refer to the GSK Standard Statistical Display Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  


 
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13.5. 
Appendix 5: Derived and Transformed Data 
13.5.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
If there are two values within a time window (as per Section 13.2.1) the value closest to the target 
day for that window will be used. If values are the same distance from the target, then the mean 
(geometric mean for HIV-1 RNA, arithmetic mean for all other measurement) will be taken. 
• 
Assessments not chosen for use in summary statistics by this algorithm will still appear in the 
associated listings.  
• 
All applicable valid assessments, irrespective of proximity to the target study day, will be used when 
categorizing values across visits, such as ‘maximum grade during the intervention phase’ or ‘at any 
time post-baseline’, and for any algorithm that has specific rules for which observation to use (e.g. 
snapshot algorithm, LOCF or CVF identification). 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Treatment Start Date 
• 
Intervention Phase Treatment Start Date = Earliest date of CAB + RPV oral lead-in entered in the IP 
exposure eCRF form 
Nominal Month 14 Visit Date 
• 
For participants who received Month 14 injection, the nominal Month 14 visit date is defined by the 
Month 14 injection date. 
• 
Otherwise, nominal Month 14 visit date is defined by the date of latest Month 14 assessment. 
• 
For participants who continued into Extension Phase but missed the Month 14 visit, the nominal 
Month 14 visit date is defined by the last contact date prior to the date of the first nominal extension 
phase visit (i.e. Month 16, Month 18, etc.). 
Study Day 
• 
The Study Day of an event (e.g., lab assessment, vital sign, ECG, start date of AE or HIV associated 
condition) will be derived as the number of days between the date of the event and the Intervention 
Phase treatment start date as follows:  
o If date of event ≥ start date of study treatment, then 
▪ 
Study Day = Date of Event - Intervention Phase Treatment Start Date +1 
o If date of event < start date of study treatment, then 
▪ 
Study Day = Date of Event - Intervention Phase Treatment Start Date 
• 
Note that the start date of intervention phase study treatment is on Study Day 1 and the day before 
this is Study Day -1; i.e., there is no Study Day 0. 
 
 


 
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Long Term Follow-up Study Day 
• 
Participants are considered to have entered LTFU if they have a post-treatment, non-bridging ART 
medication start date or a LTFU visit entered in the CRF. 
• 
The Long-Term Follow Up (LTFU) Study Day of an event (e.g., lab assessment, start date of AE or 
HIV associated condition) will be derived as the number of days between the date of the event and 
the end of IP treatment [i.e. min(LTFU ART Start Date, max(Last IM Injection Date, Last Oral 
Bridging End Date)] as follows: 
o If the date of event falls in Long-term Follow up phase, then 
▪ 
LTFU Study Day = Date of event - min(LTFU ART Start Date, max(Last IM 
Injection Date, Last Oral Bridging End Date)) + 1 
Study Treatment 
• 
Refers to CAB+RPV oral lead-in, CAB + RPV oral bridging, SOC bridging, CAB LA + RPV LA 
Change from Baseline 
• Post-Dose Visit Value – Baseline 
o Unless otherwise specified, the baseline definitions specified in Section 5.2 will 
be used for derivations for endpoints / parameters. 
 
13.5.2. 
Study Population 
Demographics 
Age 
• 
Age, in whole years, will be calculated with respect to the subject’s Screening visit. 
• 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows: 
• 
Any subject with a missing date and month will have this imputed as ‘30th June’. 
• 
Birth date will be presented in listings as ‘YYYY’. 
• 
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, 
the age of the subject will not be calculated and will remain missing. 
Body Mass Index 
• 
Calculated as Weight (kg)/Height (m)² 
Hepatitis Status 
• 
Hepatitis C status will be determined using antibody and/or hepatitis C virus (HCV) RNA 
assessments performed during screening or during the conduct of the study.  
• 
If both antibody and virus RNA assessments are available, then the latter will take precedence and 
positive/negative status will be based on whether HCV RNA is detectable (i.e., ≥ limit of 
quantification) or not. 
• 
A participant will be considered positive for hepatitis B virus (HBV) if they have a positive surface 
antigen or detectable HBV DNA result. “HBV DNA DETECTED” in the lab comment takes 
precedence over HBV DNA test result for positive hepatitis B status; for example, if a participant has 
HBV DNA test result below level of detection and the lab comment shows that HBV DNA detected, 
this participant will be considered positive for hepatitis B. If HBV DNA result is available, it will be 
used to qualify hepatitis B status as positive or negative (positive if ≥ limit of quantification); 
otherwise Hepatitis B status will be determined using the surface antigen result. 
• 
Hepatitis status at entry will be based on the assessments prior to/on the start of the study treatment. 
Adherence to CAB/RPV Injection Schedule 
• 
Timeliness of Injections relative to Date of Projected Dosing Visits are assessed by using "actual 
injection visit date - projected visit date from first injection". The injections of interest in adherence 


 
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Demographics 
analysis are those after first injection at Month 1. (. Each injection visit is counted only once. 
Individual CAB and RPV injections administered at the same visit are not counted twice. "Extra" 
unscheduled injections are excluded from all derivations. For example, if during a scheduled visit a 
participant receives 1 ml of injection instead of 2 ml due to a dosing error, but this participant returns 
one week later for the remaining 1 ml injection, then the additional visit is excluded. If a participant 
receives an extra injection at an unscheduled visit by mistake, this visit will also be excluded. 
• 
The categories of Timeliness of Injections relative to Date of Projected Dosing Visits are listed below: 
• 
< -14 days 
• 
-14 to   - 8 days 
• 
-7   to   1 
• 
0 
• 
1 to 7 days  
• 
8 to 14 days 
• 
>14 days 
• 
Missed Injection without Oral Bridging (COVID-19 related) 
• 
Missed Injection without Oral Bridging (Non COVID-19 related) 
• 
Missed Injection with Oral Bridging (COVID-19 related) 
• 
Missed Injection with Oral Bridging (non COVID-19 related) 
• 
Missed Injection with subsequent SOC ART Initiation 
• 
The following categories surrounding out of window (OOW) visits will also be calculated separately 
for participants at each visit. 
• Oral Bridging without a Missed Injection 
• OOW Injection with Oral Bridging (non-Covid-19 related) 
• OOW Injection with Oral Bridging (Covid-19 related) 
• OOW Injection without Oral Bridging (Covid-19 related) 
• 
Injection visits are expected bi-monthly after an initial Month 1 Q4W injection from Month 2 until the 
nominal month of a participant’s last injection visit during the phase(s) of interest.  For example: 
• 
If a participant discontinues study treatment with last injection visit occurring at nominal visit 
Month 6, then injection visits are expected at Month 1, Month 2, Month 4, and Month 6. 
• 
Expected injection visits will include all treatment visits (not LTFU) where an assessment was 
recorded regardless of whether the injection took place, including visits where treatment was 
discontinued. 
• Missed injections with subsequent LTFU SOC ART Initiation are not counted in ‘Missed 
Injection without Oral Bridging’ categories. Missed injections will be slotted to this category if 
LTFU SOC ART is initiated within 30 days of the missed injection. 
• Out of Window injections are determined based on criteria listed in protocol Section 4.3.3. 
• Covid-19 relatedness is determined as follows: 
• 
As labelled in concomitant medication or exposure as Oral Bridging due to Covid-19 
• 
As indicated by Covid-19 protocol deviations that occur on the impacted visit date 
 


 
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13.5.3. 
Efficacy 
Efficacy 
Snapshot 
• 
The Snapshot algorithm is intended to be primarily a virologic assessment of the endpoint, and as 
such follows a “virology first” hierarchy. 
• 
‘HIV-1 RNA < 50 c/mL’ or ‘HIV-1 RNA ≥ 50 c/mL’ within an analysis window (see Table 2 and Table 
3) is typically determined by the last available HIV-1 RNA measurement in that window while the 
participant is On-treatment in the Intervention Phase (as assigned based on Section 13.3). 
• 
When no HIV-1 RNA data is available within a window, a participant cannot be assigned to the 
category of ‘HIV-1 RNA < 50 c/mL’.  Depending on the reason for lack of data, the participant will 
be classified as ‘HIV-1 RNA ≥ 50 c/mL’ or reported as ‘No Virologic Data at Week X’; in the latter 
case, the algorithm further classifies the nature of the missing data. Typically, a participant withdrawn 
(i) due to AE or, (ii) for another reason yet was suppressed at the time, will be counted as ‘No 
Virologic Data at Week X’.  Should a participant withdraw for reasons other than AE and was not 
suppressed at the time, they will be categorized as ‘HIV-1 RNA ≥ 50 c/mL’. 
• 
Full details of the algorithm, including the handling of special cases, are included in Appendix 8: 
Snapshot Algorithm Details. 
Plasma HIV-1 RNA 
• 
HIV-1 RNA results may be provided as censored values, such as <40 or >9,999,999 c/mL. For the 
purposes of summary statistics, such values will be replaced by the next value beyond the limit of 
detection, e.g., 39 or 10,000,000 c/mL, respectively, for the given examples. Data listings will show 
the censored values as provided. 
Confirmed Virologic Failure (CVF) 
• 
For the purposes of clinical management in this study, CVF is defined as:  
o Rebound as indicated by two consecutive plasma HIV-1 RNA levels  200 c/mL. 
• 
The CVF definition is provided in the protocol Section 7.1.7 
• 
Only plasma HIV-1 RNA values determined by the central laboratory will be used to assess virologic 
failure.  
CDC Classification for HIV-1 Infection (2014) 
• CDC HIV-1 Classification at Baseline is collected in eCRF and no derivation with be 
performed programmatically for analysis purposes. Please refer to study protocol for detail 
description of CDC HIV-1 Classification. 
 
13.5.4. 
Safety 
Adverse Events 
DAIDS Grading 
• 
Clinical adverse events will be graded based on the Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March 2017, as specified in the protocol 
Appendix 10.2. 
• If a grade value is expected per DAIDS but is missing in the eCRF, then the missing grade 
will be given an ordinal grade value of -1 for determining the maximum grade within and 
across preferred terms.  For example: 


 
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Adverse Events 
• if a participant has two separate instances of the same preferred term, one with grade 2 
and one with missing grade, then the maximum grade for the preferred term will be set 
to grade 2. 
• if a participant reports two different AE preferred terms overall, one with grade 1 and 
one with missing grade (where a DAIDS grade is expected), then the maximum grade 
across preferred terms (i.e. in the ANY EVENT row) will be set to grade 1. 
• If a participant reports only one AE overall and this has a missing grade (where a DAIDS 
grade is expected), then this will be presented under a grade = missing category  
Days since First Dose (Days) 
• 
AE Start Date – Intervention Phase Treatment Start Date + 1 
Days since Last Dose (Days) 
• 
AE Start Date – Date of Last Dose of Study Treatment (Oral CAB+RPV, SOC bridging, CAB/RPV IM 
Injection) prior to/on the Start Date of AE + 1 
Days since Phase Start 
• 
For AEs in Intervention/Extension Phase: 
o AE Start Date - Intervention Treatment Start Date + 1 
• 
For AEs in Long-term Follow-up Phase: 
o AE Start Date – LTFU ART Start Date 
Duration (Days) 
• 
AE Resolution Date – AE Start Date + 1 
Drug-related 
• 
If relationship is marked ‘YES’ on Inform/eCRF 
• 
Injection site reactions will be considered as drug-related if the relationship to study drug value is 
missing in the eCRF. 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the number of significant digits in the observed values will be used to determine how 
much to add or subtract in order to impute the corresponding numeric value. If a character value 
starting with “<=x”, then the numeric value will be x. 
o Example 1: 2 Significant Digits = ‘< x ‘becomes x – 0.01 
o Example 2: 1 Significant Digit = ‘> x’ or ‘>=x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1 
Lab Toxicities – DAIDS Grading  
• 
Toxicities will be based on the Division of AIDS (DAIDS) grading system, Version 2.1, March 2017, 
as specified in the protocol of Appendix 10.2  
• 
Toxicity grades provided by the central laboratory do not distinguish between abnormally high or low 
criteria, when both are relevant for a particular parameter.    
 
 
 


 
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Other Safety Endpoints 
Extent of Exposure 
• 
Exposure to CAB+RPV (oral lead-in or oral bridging) and CAB LA+RPV LA will be calculated from 
the IP eCRF pages. 
For Intervention Phase: 
• 
Exposure to CAB+RPV Oral Lead-in = IP (oral lead-in) stop date - IP (oral lead-in) start date +1 
• 
Exposure to CAB LA + RPV LA = Number of IP injection visits received during the Intervention 
Phase (up to but not including injections administered at Month 14) 
• 
Exposure to SOC oral bridging: Duration of the SOC ART medication taken as oral bridging during 
the Intervention Phase. If the SOC oral bridging is taken in different periods during the Intervention 
Phase, the duration will be calculated by the sum of non-overlapped periods.  
• 
Exposure to CAB+RPV Oral Bridging (COVID-19 Related): Duration of the CAB+RPV taken as 
oral bridging for reasons related to COVID-19 during the Intervention Phase. If COVID-19 related 
CAB+RPV oral bridging is taken in different periods during the Intervention Phase, the duration will 
be calculated by the sum of the non-overlapped periods.  
• 
Exposure to CAB+RPV Oral Bridging (Non COVID-19 Related): Duration of the CAB+RPV taken 
as oral bridging for reasons not related to COVID-19 during the Intervention Phase. If non COVID-19 
related CAB+RPV oral bridging is taken in different periods during the Intervention Phase, the 
duration will be calculated by the sum of the non-overlapped periods.  
• 
Overall Exposure to Study Treatment: min [Date of Latest Intervention Phase Visit up to and 
including Month 12, max (Date of Last Injection + 63, Date of Last Dose of Oral CAB+RPV, Date of 
Last Dose of SOC Oral Bridging)] – min (Start Date for Oral lead-in CAB+RPV, Date of First 
CAB/RPV Injection) + 1 
• 
Overall Exposure to CAB + RPV = Overall Exposure to Study Treatment – Exposure to SOC Oral 
Bridging 
For Intervention + Extension Phase: 
• 
Exposure to CAB LA + RPV LA = Number of IP injection visits received during Intervention Phase 
and Extension Phase 
• 
Exposure to SOC or CAB+RPV Oral Bridging during the Intervention and Extension Phase will be 
calculated similarly to that during the Intervention Phase except that the exposure includes both 
Intervention and Extension Phase.  
• 
Overall Exposure to Study Treatment: min [LTFU ART start date, Commercial product Safety 
Follow-up Visit date, max (Date of Last Injection + 63, Date of Last Dose of Oral CAB+RPV, Date of 
Last Dose of SOC Oral Bridging)] – min (Start Date for Oral lead-in CAB+RPV, Date of First Study 
Injection) + 1 
• 
Overall Exposure to IP = Overall Exposure to Study Treatment – Exposure to SOC Oral Bridging 
• 
Duration of dosing in participant years will be calculated as the sum of participant duration of dosing 
in days (across all participants)/365.25 
 
 
 


 
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13.5.5. 
Virology 
Genotype  
Amino Acid Changes 
• 
A mutation is considered present whenever the encoded amino acid residue differs from the amino 
acid that would have been encoded by the wild-type (e.g., HXB2, NL43) comparator gene; e.g., 
Q148K.  
• 
If the encoded amino acid is seen as a mixture of wild-type and mutant amino acid, e.g., Q148Q/K, 
the mutated amino acid is considered present at the codon of interest.  
• 
If the encoded amino acid is seen as a mixture of two or more amino acids, which may or may not 
include wild type, e.g., Q184K/H or Q184K/H/Q, etc., for the purposes of calculating the number of 
mutated amino acids, only one mutation is considered to be present at the codon of interest. 
 
Representation of Amino Acid Changes  
Mutations 
Amino Acid Change 
T69S 
Single mutation from amino acid 'T' (vendor reference) to 'S' (sample) at codon '69 
Q148H/K/R 
Mixture of amino acid mutations ‘H’, ‘K’ and ‘R’ (sample) from amino acid ‘Q 
(vendor reference) at codon ‘148’ 
_69_1T 
First insertion of amino acid 'T' (sample) at codon '69' 
_69_2S 
Second insertion of amino acid 'S' (sample) at codon '69' 
_69_3S/A 
Third insertion of a mixture of amino acids 'S' and 'A' (sample) at codon '69' 
L74L/- 
Mixture of amino acid 'L' (sample) and a deletion at codon '74' 
V75- 
Single deletion of amino acid (sample) at codon '75' 
Resistance Associated mutations 
Known INI mutations associated with the development of resistance to Integrase Strand Transfer 
Inhibitors: 
Amino Acids in 
HIV Integrase for 
Analysis 
H51Y, T66A/I/K, L68V/I, L74I/M, E92Q/V/G, Q95K, T97A, G118R, F121Y, 
E138A/D/K/T, G140A/C/R/S, Y143C/H/R/K/S/G/A, P145S, Q146P, S147G, 
Q148H/K/R/N, V151/IL/A, S153F/Y, N155H/S/T, E157Q, G163R/K, G193E, 
S230R, R263K 
• 
Draft listing; may be modified in case of additional substantive data availability. 
• 
Based on the IAS-USA list of mutations associated with resistance to Bictegravir, Cabotegravir, 
Dolutegravir, Elvitegravir, or Raltegravir (IAS-USA 2019 resistance mutations update volume 27 issue 3, 
2019): T66A/I/K, L74M, E92Q/G, T97A, G118R, F121Y, E138A/K/T, G140A/C/R/S, Y143C/H/R, S147G, 
Q148H/K/R, S153F/Y, N155H, R263K) and observed mutations during in vitro passage of DTG or seen in a 
previous DTG study in INI-experienced subjects (study ING112574): H51Y, L74I, L68V/I, E92V, Q95K, 
E138D, Y143K/S/G/A, P145S, Q146P, V151I/L/A, N155S/T, E157Q, G163R/K, G193E, S230R.  
• 
Major USA-IAS mutations associated with resistance to INSTI are bolded. 
 
• 
Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as defined by the International 
Antiviral Society-USA (IAS-USA). The most up to date IAS-USA guidelines available at the time of 
DBF will be used in the analysis [Wensing, 2019]. 
Class 
Mutations 
NRTIs 
M41L, A62V, K65R/E/N, D67N, 69 insert, K70E/R, L74V, V75I, F77L, Y115F, F116Y, 
Q151M, M184V/I, L210W, T215Y/F, K219Q/E 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138/A/G/K/Q/R, V179L, 
Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I/L 


 
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Genotype  
PIs 
D30N, V32I, M46I/L, I47A/V, G48V, I50V/L, I54V/M/L, Q58E, T74P, L76V, 
V82A/T/F/L/S, N83D, I84V, N88S, L90M 
• 
Draft listing; may be modified in case of additional substantive data availability. 
 
13.5.6. Other Assessments 
Study Visit Length 
• 
Lead Time = Actual Start Time of Appointment – Arrival Time 
• 
Process Time = Actual End Time of Appointment – Actual Start Time of Appointment 
• 
Total Time = Actual End Time of Appointment – Arrival Time 


 
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13.6. 
Appendix 6: Reporting Standards for Missing Data 
13.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Withdrawn participants were not replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be slotted according to Appendix 2: Assessment Windows 
(excluding PK data) 
 
13.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 
13.6.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.  
• 
Where necessary, display macros may impute dates as temporary variables for 
sorting data in listings only. In addition, partial dates may be imputed for ‘slotting’ 
data to study phases or for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., 
time since diagnosis). In addition, imputed dates are not used for deriving the last 
contact date in overall survival analysis dataset. 
Adverse 
Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• 
Partial dates for AEs recorded in the CRF will be imputed using the following 
conventions: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month. 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of study 
treatment start date, then 


 
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Element 
Reporting Detail 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date, then set start 
date= 1st of month. 
▪ 
Else set start date = study treatment start date. 
• 
Else  
o 
For Non-ISR AEs: set start date = 1st of month 
o 
For ISR AEs: if oral bridging taken during the 
month and year, set start date = min(last day of 
the month, day of AE stop date if available, day 
of study treatment discontinuation if occurring 
during the month and year); else set start date = 
1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start date, 
then 
▪ 
If stop date contains a full date and stop date is 
earlier than study treatment start date, then set start 
date = January 1. 
▪ 
Else set start date = study treatment start date. 
o 
Else set start date = January 1. 
Missing stop day  
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied.  
Non-ART 
Medications 
(including 
Oral 
Bridging 
CAB + RPV) 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month. 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of study 
treatment start date, then 
▪ 
If stop date contains a full date and stop date is earlier 
than study treatment start date, then set start date= 1st 
of month. 
▪ 
Else set start date = study treatment start date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start date, 
then 
▪ 
If stop date contains a full date and stop date is earlier 
than study treatment start date, then set start date = 
January 1. 
▪ 
Else set start date = study treatment start date.       
• 
Else set start date = January 1. 


 
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Element 
Reporting Detail 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year)  
Missing end day and 
month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
 
• 
The recorded partial date will be displayed in listings. 
ART 
Medications 
• 
Partial dates recorded in the eCRF will be imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month. 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. If 
medications recorded in the PRIOR ART form of the eCRF, then the earlier date 
of the imputed and the day prior to the maintenance phase treatment start date 
will be used, i.e. min (imputed stop date, Intervention phase treatment start date 
- 1). 
• 
For medications with completely missing start date, they will be considered started 
prior to the Intervention phase treatment start date. 
• 
For medications with completely missing stop date, they will be considered ongoing 
unless recorded in the PRIOR ART form of the eCRF. 
• 
For ART booster medications, the start and stop dates are not recorded in the 
database (i.e. missing), the dates will be imputed to be the same as the dates of their 
parent medications.  
• 
The recorded partial or missing date will be displayed in listings. 
 
13.6.2.2. 
Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
Snapshot 
• 
 In the Snapshot dataset, subjects without HIV – 1 RNA data in the 
assessment window for the visit of interest (due to missing data or 
discontinuation of IP prior to the visit window) do not belong to ‘HIV-1< 
50 c/mL (or 200 c/mL) The nature of this missing data will be further 
classified in Snapshot summaries as either ‘HIV-1 RNA≥50’ or ‘No 
Virologic Data at Week X’; 
• 
See Appendix 8: Snapshot Algorithm Details 
• Note: The primary snapshot analysis will not impute any missing 
data due to Covid-19 and will consider Covid-19 related missing 
data in accordance with all other missing data. 


 
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13.7. 
Appendix 7: Values of Potential Clinical Importance 
Values of clinical importance will be summarized for hepatobiliary abnormalities. 
Abnormal laboratory value grades will be assigned as specified by protocol Section 10.2. 
Liver chemistry stopping criteria can be found in the protocol Section 10.3.1. 
13.7.1. 
Hepatobiliary Abnormality Criteria 
Element 
Reporting Detail 
General 
• 
To include ALT, ALP, Bilirubin, & INR parameters 
ALT >=3xULN and BIL >=2xULN 
• 
If direct bilirubin is available (on the same date as Total 
Bilirubin), then direct bilirubin as a portion of total bilirubin 
must be >=35% when total bilirubin is >=2xULN, in order 
to satisfy the criteria. 
• 
Bilirubin value is on or up to 28 days after ALT value. 
ALT >=3xULN and INR >1.5 
• 
INR value is on or up to 28 days after ALT value. 
ALT >=3xULN and BIL >=2xULN and 
ALP 2 (<1%) <2xULN 
• 
If direct bilirubin is available (on the same date as Total 
Bilirubin), then direct bilirubin as a portion of total bilirubin 
must be >=35% when total bilirubin is >=2xULN, in order 
to satisfy the criteria. 
• 
Bilirubin value is on or up to 28 days after ALT value. 
• 
The ALP value must occur on or up to 28 days after the 
ALT value. 
Hepatocellular injury 
• 
Hepatocellular injury is defined as ((ALT/ALT 
ULN)/(ALP/ALP ULN)) >=5 and ALT >=3xULN. ALT and 
ALP values must occur on the same day. 
Hepatocellular injury and BIL >=2xULN 
• 
Hepatocellular injury is defined as ((ALT/ALT 
ULN)/(ALP/ALP ULN)) >=5 and ALT >=3xULN. ALT and 
ALP values must occur on the same day. 
• 
If direct bilirubin is available (on the same date as Total 
Bilirubin), then direct bilirubin as a portion of total bilirubin 
must be >=35% when total bilirubin is >=2xULN, in order 
to satisfy the criteria. 
• 
Bilirubin value is on or up to 28 days after ALT value. 
BIL >=2xULN 
• 
If direct bilirubin is available (on the same date as Total 
Bilirubin), then direct bilirubin as a portion of total bilirubin 
must be >=35% when total bilirubin is >=2xULN, in order 
to satisfy the criteria. 
AST >3xULN and ALP <2xULN and BIL 
>=2xULN 
• 
ALP and BIL values must occur on or up to 28 days after 
AST value. 
• 
If direct bilirubin is available (on the same date as Total 
Bilirubin), then direct bilirubin as a portion of total bilirubin 
must be >=35% when total bilirubin is >=2xULN, in order 
to satisfy the criteria. 
ALT>=X ULN and AST>=X ULN 
• 
AST and ALT values must occur on the same day 
 


 
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13.8. 
Appendix 8: Snapshot Algorithm Details 
Detailed Algorithm Steps 
• 
Consider an analysis visit window for Month X as defined in Table 2.  
• 
The HIV-1 RNA threshold of 50 will be analysed in this study  
• 
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. The snapshot algorithm is 
modified to allow for the presentation of full scope of COVID-19 relatedness. The analysis 
window for ‘Month 12’ and HIV-1 RNA threshold of ’50 c/mL’ are used for the purpose of 
illustration. A participant’s Snapshot response and reason at Month 12 are categorized as 
below. 
 
o 
HIV-1 RNA < 50 c/mL 
o 
HIV-1 RNA ≥ 50 c/mL 
   Data in window not below 50 
  Non-COVID-19 related  
Discontinued for lack of efficacy 
Discontinued for other reason while not below 50 
  COVID-19 related 
Discontinued for lack of efficacy 
Discontinued for other reason while not below 50 
 
o 
No Virologic Data at Month 12 Window 
  Non-COVID-19 related 
Discontinued study due to AE or death 
Discontinued study for other reasons 
On study but missing data in window 
              COVID-19 related 
Discontinued study due to AE or death  
Discontinued study for other reasons 
On study but missing data in window 
            Change in background therapy* 
 
* Note: Use of CAB + RPV oral bridging and SOC oral bridging medication, where the latter 
is due to unavailability of CAB/RPV IM injections or oral CAB+RPV during the pandemic, will 
not be considered a “Change in background therapy” in the Snapshot algorithm.  All other 
permanent changes in ART are not permitted in this protocol. 
• 
The steps in determining response and reasons are indicated in the table below, in the 
order stated. 
 
• 
Background therapy is not given to participants while on study. The “change in background 
therapy” in detailed steps below refers to the “change in ART” in this study. 
 
Detailed steps 
• 
Please note that the following scenarios will NOT be penalized in the Snapshot algorithm Oral bridging 
(CAB+RPV or SOC, where SOC oral bridging medication is permitted during COVID-19 pandemic due to 
the unavailability of the CAB/RPV IM injections and oral CAB+RPV)  


 
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Detailed Algorithm Steps 
Condition (‘Month 12’ indicates Month 12 window) 
Response  
Reasons 
1. If non-permitted change in background therapy prior 
to Month 12   
HIV-1 RNA ≥ 50 
Change in 
background therapy 
2. If non-permitted change in background therapy during 
Month 12 
 
 
• Last on-treatment VL during Month 12 prior to/on 
the date of change ≥ 50 c/mL 
HIV-1 RNA ≥ 50 
Data in window not 
below 50 
• Last on-treatment VL during Month 12 prior to/on 
the date of change < 50 c/mL 
HIV-1 RNA < 50 
 
• No VL during Month 12 prior to/on the date of 
change  
HIV-1 RNA ≥ 50 
Change in 
background therapy  
3. If none of the above conditions met 
 
 
3.1. On-treatment VL available during Month 12 
 
 
• 
Last on-treatment VL during Month 12 ≥ 50 
c/mL 
HIV-1 RNA ≥ 50 
Data in window not 
below 50 
• 
Last on-treatment VL during Month 12 < 50 
c/mL 
HIV-1 RNA < 50 
 
3.2. No on-treatment VL during Month 12 
 
 
3.2.1. If participants are still on study, i.e. a 
participant has not permanently 
discontinued the study treatment yet, or if a 
participant permanently discontinued the 
study treatment and the upper bound of 
analysis snapshot window is prior to the 
following date:  
• 
Min[max(Date of last injection + 35, 
Date of Last  Dose of Oral Study 
Treatment (CAB+RPV, SOC Bridging) + 
1), LTFU ART Start Date] 
 
 
3.2.1.1. If no on-treatment VL during Month 
12 is not due to COVID-19 
No virologic 
data at Month 
12 Window 
On study but missing 
data in window (Non-
COVID-19 related) 
3.2.1.2. If no on-treatment VL during Month 
12 is due to COVID-19 
No virologic 
data at Month 
12 Window 
On study but missing 
data in window 
(COVID-19 related) 
3.2.2. If participants withdraw before/during 
Month 12 due to 
 
 
3.2.2.1. Non-COVID-19 related safety 
reasons (e.g. AE/death, liver 
chemistry stopping criteria, renal 
toxicity withdrawal criteria, QTc 
withdrawal criteria etc., as recorded 
in eCRF Conclusion form) 
No virologic 
data at Month 
12 Window 
Disc due to AE/death 
(Non-COVID-19 
related) 


 
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Detailed Algorithm Steps 
3.2.2.2. COVID-19 related safety reasons 
(e.g. AE/death, liver chemistry 
stopping criteria, renal toxicity 
withdrawal criteria, QTc withdrawal 
criteria etc., as recorded in eCRF 
Conclusion form) 
No virologic 
data at Month 
12 Window 
Disc due to AE/death 
(COVID-19 related) 
3.2.2.3.  Non-safety and Non-COVID-19 
related reasons (e.g. Lack of 
efficacy, protocol deviation, withdrew 
consent, loss to follow-up, study 
closed/terminated, investigator 
discretion etc., as recorded in eCRF 
Treatment Discontinuation Form) 
 
 
o Last on-treatment VL <50 c/mL 
OR no on-treatment VL 
available during study   
No virologic 
Data at Month 
12 Window 
Disc for other 
reasons (Non-
COVID-19 related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy 
HIV-1 RNA ≥ 50 
Disc. for lack of 
efficacy (Non-
COVID-19 related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to all 
other non-safety related 
reasons 
HIV-1 RNA ≥ 50 
Disc. for other 
reason while not 
below 50 (Non-
COVID-19 related) 
3.2.2.4. Non-safety and COVID-19 related 
reasons (e.g. protocol deviation, 
withdrew consent, loss to follow-up, 
study closed/terminated, investigator 
discretion etc., as recorded in eCRF 
Conclusion Form) 
 
 
o Last on-treatment VL <50 c/mL 
OR no on-treatment VL 
available during study   
No virologic 
Data at Month 
12 Window 
Disc for other 
reasons (COVID-19 
related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy 
HIV-1 RNA ≥ 50 
Disc. for lack of 
efficacy (COVID-19 
related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to all 
other non-safety related 
reasons 
HIV-1 RNA ≥ 50 
Disc. for other 
reason while not 
below 50 (COVID-19 
related) 
a. 
Excluding permitted change in background therapy where change or decision to change is made prior to/on the 
first on-treatment viral result  
Examples from FDA guidance 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window: 
• 
HIV-1 RNA = 580 c/mL at Day 336, HIV-1 RNA below 50 c/mL on Day 350. This should be categorized 
as HIV-1 RNA below 50 c/mL. 
No Data in Window 


 
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Detailed Algorithm Steps 
Discontinued study due to Adverse Event or Death: 
• 
Any patient who discontinues because of an AE or death before the window should be classified as 
Discontinued due to AE or Death (as appropriate), regardless of the HIV-1 RNA result, even if the HIV-1 
RNA is below 50 c/mL at the time of discontinuation.  
• 
However, if a patient has an HIV-1 RNA value in the time window and also discontinues in the time 
window, the viral load data should be used to classify the patient’s response. This is the Virology First 
hierarchy: 
a. 
HIV-1 RNA below 50 c/mL at Day 336 and discontinues because of AE or even dies on Day 
360 — this person is categorized as having HIV-1 RNA below 50 c/mL.  
b. 
HIV-1 RNA is 552 c/mL on Day 336 and the patient discontinues on Day 360, the patient is 
categorized as having HIV-1 RNA ≥ 50 c/mL. 
Discontinued for Other Reasons: 
• 
Only patients who have achieved virologic suppression can be counted as Discontinued for Other 
Reasons. 
• 
If a patient discontinues the study before the time window because of lack of efficacy, then the patient 
should be included in the HIV-1 RNA ≥ 50 row and not in the Discontinued for Other Reasons row. 
• 
If a patient discontinues because participant withdrew consent and his or her HIV-1 RNA result at the time 
of discontinuation was equal to or above 50 c/mL, then he or she should be categorized as HIV-1 RNA ≥ 
50 and NOT as Discontinued for Other Reasons.  
• 
If a patient discontinued because of Lost to Follow-Up and the last HIV-1 RNA result was 49 c/mL, then 
the patient can be categorized as Discontinued for Other Reasons. 
• 
If patients changed background treatment — not permitted by protocol— they should be considered an 
efficacy failure and captured in the HIV-1 RNA ≥ 50 c/mL row. 
On study but missing data in window: 
• 
If there are no data during Days 294 to 377, but there is an HIV-1 RNA below 50 c/mL on Day 380, this 
patient should be considered On Study but Missing Data in Window. 
• 
If there are no data during Days 294 to 377, but there is an HIV-1 RNA equal to or above 50 c/mL on Day 
280, this patient also should be classified as On Study but Missing Data in Window. 


 
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13.9. 
Appendix 9: Identification of Adverse Events of Special 
Interest 
SMQ and PT codes based on MedDRA dictionary version 23.1 for the Month 12 
analysis. 
13.9.1. 
Hepatic Safety Profile  
Medical concept of hepatic failure and hepatitis. Sub- SMQs (1) 'Hepatic failure, fibrosis 
and cirrhosis and other liver damage-related conditions' and (2) 'Hepatitis, non-
infectious', both of parent SMQ 'Hepatic Disorders (SMQ code 20000005)'; only narrow 
terms selected from sub-SMQs. Some preferred terms, e.g. PT 'hepatitis fulminant' are 
duplicated. 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acquired hepatocerebral degeneration 
10080860 
Acute hepatic failure 
10000804 
Acute on chronic liver failure 
10077305 
Acute yellow liver atrophy 
10070815 
Ascites 
10003445 
Asterixis 
10003547 
Bacterascites 
10068547 
Biliary cirrhosis 
10004659 
Biliary fibrosis 
10004664 
Cardiohepatic syndrome 
10082480 
Cholestatic liver injury 
10067969 
Chronic hepatic failure 
10057573 
Coma hepatic 
10010075 
Cryptogenic cirrhosis 
10063075 
Diabetic hepatopathy 
10071265 
Drug-induced liver injury 
10072268 


 
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SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Duodenal varices 
10051010 
Gallbladder varices 
10072319 
Gastric variceal injection 
10076237 
Gastric variceal ligation 
10076238 
Gastric varices 
10051012 
Gastric varices haemorrhage 
10057572 
Gastrooesophageal variceal haemorrhage prophylaxis 
10066597 
Flood Syndrome 
10084797 
Hepatectomy 
10061997 
Hepatic atrophy 
10019637 
Hepatic calcification 
10065274 
Hepatic cirrhosis 
10019641 
Hepatic encephalopathy 
10019660 
Hepatic encephalopathy prophylaxis 
10066599 
Hepatic failure 
10019663 
Hepatic fibrosis 
10019668 
Hepatic hydrothorax 
10067365 
Hepatic infiltration eosinophilic 
10064668 
Hepatic lesion 
10061998 
Hepatic necrosis 
10019692 
Hepatic steato-fibrosis 
10077215 
Hepatic steatosis 
10019708 
Hepatitis fulminant 
10019772 
Hepatobiliary disease 
10062000 
Hepatocellular foamy cell syndrome 
10053244 
Hepatocellular injury 
10019837 
Hepatopulmonary syndrome 
10052274 
Hepatorenal failure 
10019845 


 
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SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Hepatorenal syndrome 
10019846 
Hepatotoxicity 
10019851 
Immune-mediated cholangitis 
10083406 
Immune-mediated hepatic disorder 
10083521 
Intestinal varices 
10071502 
Intestinal varices haemorrhage 
10078058 
Liver dialysis 
10076640 
Liver disorder 
10024670 
Liver injury 
10067125 
Liver operation 
10062040 
Liver transplant 
10024714 
Lupoid hepatic cirrhosis 
10025129 
Minimal hepatic encephalopathy 
10076204 
Mixed liver injury 
10066758 
Nodular regenerative hyperplasia 
10051081 
Nonalcoholic fatty liver disease 
10082249 
Non-alcoholic steatohepatitis 
10053219 
Non-cirrhotic portal hypertension 
10077259 
Oedema due to hepatic disease 
10049631 
Oesophageal varices haemorrhage 
10030210 
Peripancreatic varices 
10073215 
Portal fibrosis 
10074726 
Portal hypertension 
10036200 
Portal hypertensive colopathy 
10079446 
Portal hypertensive enteropathy 
10068923 
Portal hypertensive gastropathy 
10050897 
Portal vein cavernous transformation 
10073979 
Portal vein dilatation 
10073209 


 
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SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Portopulmonary hypertension 
10067281 
Primary biliary cholangitis 
10080429 
Regenerative siderotic hepatic nodule 
10080679 
Renal and liver transplant 
10052279 
Retrograde portal vein flow 
10067338 
Reye's syndrome 
10039012 
Reynold's syndrome 
10070953 
Splenic varices 
10067823 
Splenic varices haemorrhage 
10068662 
Steatohepatitis 
10076331 
Subacute hepatic failure 
10056956 
Sugiura procedure 
10083010 
Varices oesophageal 
10056091 
Varicose veins of abdominal wall 
10072284 
White nipple sign 
10078438 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatitis, non-infectious’ 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acute graft versus host disease in liver 
10066263 
Allergic hepatitis 
10071198 
Alloimmune hepatitis 
10080576 
Autoimmune hepatitis 
10003827 
Chronic graft versus host disease in liver 
10072160 
Chronic hepatitis 
10008909 
Graft versus host disease in liver 
10064676 
Hepatitis 
10019717 
Hepatitis acute 
10019727 
Hepatitis cholestatic 
10019754 


 
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SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Hepatitis chronic active 
10019755 
Hepatitis chronic persistent 
10019759 
Hepatitis fulminant 
10019772 
Hepatitis toxic 
10019795 
Immune-mediated hepatitis 
10078962 
Ischaemic hepatitis 
10023025 
Lupus hepatitis 
10067737 
Non-alcoholic steatohepatitis 
10053219 
Radiation hepatitis 
10051015 
Steatohepatitis 
10076331 
13.9.2. 
Hyperglycaemia 
Medical concept of Hyperglycaemia/new onset diabetes mellitus - SMQs (1) 
'Hyperglycaemia/new onset diabetes mellitus (SMQ) Narrow SMQ code 20000041. 
SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related  
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acquired lipoatrophic diabetes 
10073667 
Blood 1,5-anhydroglucitol decreased 
10065367 
Blood glucose increased 
10005557 
Diabetes complicating pregnancy 
10012596 
Diabetes mellitus 
10012601 
Diabetes mellitus inadequate control 
10012607 
Diabetes with hyperosmolarity 
10012631 
Diabetic arteritis 
10077357 
Diabetic coma 
10012650 
Diabetic coronary microangiopathy 
10080788 
Diabetic hepatopathy 
10071265 


 
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SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Diabetic hyperglycaemic coma 
10012668 
Diabetic hyperosmolar coma 
10012669 
Diabetic ketoacidosis 
10012671 
Diabetic ketoacidotic hyperglycaemic coma 
10012672 
Diabetic ketosis 
10012673 
Diabetic metabolic decompensation 
10074309 
Diabetic wound 
10081558 
Euglycaemic diabetic ketoacidosis 
10080061 
Fructosamine increased 
10017395 
Fulminant type 1 diabetes mellitus 
10072628 
Gestational diabetes 
10018209 
Glucose tolerance impaired 
10018429 
Glucose tolerance impaired in pregnancy 
10018430 
Glucose urine present 
10018478 
Glycated albumin increased 
10082836 
Glycosuria 
10018473 
Glycosuria during pregnancy 
10018475 
Glycosylated haemoglobin abnormal 
10018481 
Glycosylated haemoglobin increased 
10018484 
Hyperglycaemia 
10020635 
Hyperglycaemic hyperosmolar nonketotic syndrome 
10063554 
Hyperglycaemic seizure 
10071394 
Hyperglycaemic unconsciousness 
10071286 
Impaired fasting glucose 
10056997 
Insulin resistance 
10022489 
Insulin resistant diabetes 
10022491 
Insulin-requiring type 2 diabetes mellitus 
10053247 
Ketoacidosis 
10023379 


 
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SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Ketonuria 
10023388 
Ketosis 
10023391 
Ketosis-prone diabetes mellitus 
10023392 
Latent autoimmune diabetes in adults 
10066389 
Monogenic diabetes 
10075980 
Neonatal diabetes mellitus 
10028933 
New onset diabetes after transplantation 
10082630 
Pancreatogenous diabetes 
10033660 
Steroid diabetes 
10081755 
Type 1 diabetes mellitus 
10067584 
Type 2 diabetes mellitus 
10067585 
Type 3 diabetes mellitus 
10072659 
Urine ketone body present 
10057597 
13.9.3. 
Hypersensitivity Reactions  
Notes: Medical concept of hypersensitivity reactions/DRESS. Only narrow terms selected 
from Category A of SMQ 'Drug reaction with eosinophilia and systemic symptoms 
syndrome'. Algorithmic approach for this SMQ not used due to complexity in applying 
and poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms) and a pre-requisite for any combination in 
algorithmic search. Overlap of some preferred terms with SMQ 'Severe Cutaneous 
Adverse Reactions'. Plus additional preferred terms selected from HGLT 'Allergic 
conditions' under SOC 'Immune system disorders'. 
SMQ: Drug reaction with eosinophilia and systemic symptoms syndrome 
SMQ Code: 20000225 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Drug reaction with eosinophilia and systemic symptoms 
10073508 
Pseudolymphoma 
10037127 
Additional preferred terms selected from HLGT 'Allergic conditions' 
under SOC 'Immune system disorders'; HLGT code 10001708 
Preferred Term 
PT Code 


 
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SMQ: Drug reaction with eosinophilia and systemic symptoms syndrome 
SMQ Code: 20000225 
Category: A 
Scope: Narrow 
 
Drug hypersensitivity 
10013700 
Hypersensitivity 
10020751 
Type IV Hypersensitivity reaction 
10053613 
Eosinophillia 
10014950 
Eye swelling 
10015967 
Eyelid oedema 
10015993 
Lip swelling 
10024570 
Angioedema 
10002424 
Circumoral oedema 
10052250 
Face oedema 
10016029 
Idiopathic angioedema 
10073257 
Lip oedema 
10024558 
Mouth swelling 
10075203 
Oedema mouth 
10030110 
Periorbital oedema 
10034545 
Swelling face 
10042682 
Periorbital swelling 
10056647 
Swelling of eyelid 
10042690 
Granulomatous T-cell pseudolymphoma 
10084214 
13.9.4. 
Rash including severe cutaneous adverse reactions 
Medical concept of rash including severe cutaneous adverse reactions. Only narrow terms 
from SMQ 'Severe cutaneous adverse reactions' selected. Plus several additional 
preferred terms selected from HLTs 'Rashes, eruptions and exanthems NEC', 'Pruritus 
NEC', 'Pustular conditions', 'Dermatitis ascribed to specific agent' all under SOC 'Skin 
and subcutaneous tissue disorders'. 


 
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SMQ: Severe Cutaneous Adverse Reactions 
SMQ Code: 20000020 
Category: A 
Scope: Narrow 
 
SMQ 
PT Code 
Acute generalised exanthematous pustulosis 
10048799 
Bullous haemorrhagic dermatosis 
10083809 
Cutaneous vasculitis 
10011686 
Dermatitis bullous 
10012441 
Dermatitis exfoliative 
10012455 
Dermatitis exfoliative generalised 
10012456 
Drug reaction with eosinophilia and systemic symptoms 
10073508 
Epidermal necrosis 
10059284 
Erythema multiforme 
10015218 
Erythrodermic atopic dermatitis 
10082985 
Exfoliative rash 
10064579 
Oculomucocutaneous syndrome 
10030081 
SJS-TEN overlap 
10083164 
Skin necrosis 
10040893 
Stevens-Johnson syndrome 
10042033 
Target skin lesion 
10081998 
Toxic epidermal necrolysis 
10044223 
Toxic skin eruption 
10057970 
Addition selected preferred terms from HLTs 'Rashes, eruptions and 
exanthems NEC', HLT Code 1005266; 'Pruritus NEC', HLT Code 
10049293, 'Pustular conditions', HLT Code 10037573; 'Dermatitis 
ascribed to specific agent', HLT Code 10012437. 
 
Preferred Term 
PT Code 
Eyelid rash 
10074620 
Genital rash 
10018175 
Mucocutaneous rash 
10056671 


 
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SMQ: Severe Cutaneous Adverse Reactions 
SMQ Code: 20000020 
Category: A 
Scope: Narrow 
 
Nodular rash 
10075807 
Perineal rash 
10075364 
Rash 
10037844 
Rash erythematous 
10037855 
Rash generalised 
10037858 
Rash macular 
10037867 
Rash maculo-papular 
10037868 
Rash maculovesicular 
10050004 
Rash morbilliform 
10037870 
Rash papular 
10037876 
Rash rubelliform 
10057984 
Rash scarlatiniform 
10037890 
Rash vesicular 
10037898 
Rash pruritic 
10037884 
Rash follicular 
10037857 
Rash pustular 
10037888 
Drug eruption 
10013687 
13.9.5. 
Prolongation of the Corrected QT Interval of the ECG in Supra 
Therapeutic Doses 
Medical concept of QT prolongation and complications. Only narrow terms from SMQ 
'Torsade de pointes/QT prolongation' selected plus one additional PT under HLT 'ECG 
investigations'. 
SMQ: Torsade de pointes/QT prolongation 
SMQ Code: 20000001 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Electrocardiogram QT interval abnormal 
10063748 


 
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SMQ: Torsade de pointes/QT prolongation 
SMQ Code: 20000001 
Category: A 
Scope: Narrow 
 
Electrocardiogram QT prolonged 
10014387 
Long QT syndrome 
10024803 
Long QT syndrome congenital 
10057926 
Torsade de pointes 
10044066 
Ventricular tachycardia 
10047302 
Additional selected preferred terms from HLT 'ECG investigations', HLT 
Code 10053104. 
Preferred Term 
PT Code 
Electrocardiogram repolarisation abnormality 
10052464 
13.9.6. 
Suicidal Ideation/Behaviour  
Medical concept of suicidal ideation and behaviour. Sub-SMQ 'Suicide/self-injury' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury (SMQ Code 20000035)'. 
Only narrow terms from the sub-SMQ selected. 
SMQ: 'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Suicide/self-injury' 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Assisted suicide 
10079105 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Poisoning deliberate 
10036000 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 


 
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SMQ: 'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Suicide/self-injury' 
Category: A 
Scope: Narrow 
 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 
Suspected suicide 
10082458 
Suspected suicide attempt 
10081704 


 
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13.9.7. 
Depression  
Medical concept of Depression. Sub-SMQ 'Depression (excl suicide and self-injury)' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury'. Only narrow terms 
from the sub-SMQ selected. 
SMQ: ‘'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Depression (excl suicide and self-injury)'  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Activation syndrome 
10066817 
Adjustment disorder with depressed mood 
10001297 
Adjustment disorder with mixed anxiety and depressed mood 
10001299 
Agitated depression 
10001496 
Anhedonia 
10002511 
Antidepressant therapy 
10054976 
Childhood depression 
10068631 
Decreased interest 
10011971 
Depressed mood 
10012374 
Depression 
10012378 
Depression rating scale score increased 
10084390 
Discouragement 
10084257 
Depression postoperative 
10012390 
Depressive symptom 
10054089 
Dysphoria 
10013954 
Electroconvulsive therapy 
10014404 
Feeling guilty 
10049708 
Feeling of despair 
10016344 
Feelings of worthlessness 
10016374 
Helplessness 
10077169 


 
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SMQ: ‘'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Depression (excl suicide and self-injury)'  
Category: A 
Scope: Narrow 
 
Major depression 
10057840 
Menopausal depression 
10067371 
Mixed anxiety and depressive disorder 
10080836 
Perinatal depression 
10078366 
Persistent depressive disorder 
10077804 
Post stroke depression 
10070606 
Postictal depression 
10071324 
13.9.8. 
Bipolar Disorder 
Medical concept of bipolar disorder. All preferred terms from HLGT ‘Manic and Bipolar 
mood disorders and disturbances’ under SOC “Psychiatric disorders”; HLGT Code 
10026753. 
Preferred Term 
PT Code 
Bipolar I disorder 
10004939 
Bipolar II disorder 
10004940 
Bipolar disorder 
10057667 
Cyclothymic disorder 
10011724 
Hypomania 
10021030 
Mania 
10026749 
Manic symptom 
10084119 
13.9.9. 
Psychosis 
Medical concept of psychosis. Only narrow terms from SMQ 'Psychosis and psychotic 
disorders' selected. 
 
 


 
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SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Acute psychosis 
10001022 
Alcoholic psychosis 
10001632 
Alice in wonderland syndrome 
10001666 
Brief psychotic disorder with marked stressors 
10048549 
Brief psychotic disorder without marked stressors 
10056395 
Brief psychotic disorder, with postpartum onset 
10006362 
Charles Bonnet syndrome 
10063354 
Childhood psychosis 
10061040 
Clang associations 
10009232 
Cotard's syndrome 
10059591 
Delusion 
10012239 
Delusion of grandeur 
10012241 
Delusion of parasitosis 
10012242 
Delusion of reference 
10012244 
Delusion of replacement 
10012245 
Delusion of theft 
10084030 
Delusional disorder, erotomanic type 
10012249 
Delusional disorder, grandiose type 
10012250 
Delusional disorder, jealous type 
10012251 
Delusional disorder, mixed type 
10012252 
Delusional disorder, persecutory type 
10053195 
Delusional disorder, somatic type 
10012254 
Delusional disorder, unspecified type 
10012255 
Delusional perception 
10012258 
Dementia of the Alzheimer's type, with delusions 
10012295 


 
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SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Depressive delusion 
10063033 
Derailment 
10012411 
Epileptic psychosis 
10059232 
Erotomanic delusion 
10015134 
Flight of ideas 
10016777 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, synaesthetic 
10062824 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Hysterical psychosis 
10062645 
Ideas of reference 
10021212 
Illusion 
10021403 
Jealous delusion 
10023164 
Loose associations 
10024825 
Mixed delusion 
10076429 
Neologism 
10028916 
Neuroleptic-induced deficit syndrome 
10075295 
Paranoia 
10033864 
Paranoid personality disorder 
10033869 
Parkinson's disease psychosis 
10074835 


 
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SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Paroxysmal perceptual alteration 
10063117 
Persecutory delusion 
10034702 
Postictal psychosis 
10070669 
Post-injection delirium sedation syndrome 
10072851 
Posturing 
10036437 
Psychosis postoperative 
10065617 
Psychotic behaviour 
10037249 
Psychotic disorder 
10061920 
Psychotic disorder due to a general medical condition 
10061921 
Reactive psychosis 
10053632 
Rebound psychosis 
10074833 
Schizoaffective disorder 
10039621 
Schizoaffective disorder bipolar type 
10068889 
Schizoaffective disorder depressive type 
10068890 
Schizophrenia 
10039626 
Schizophreniform disorder 
10039647 
Schizotypal personality disorder 
10039651 
Senile psychosis 
10039987 
Shared psychotic disorder 
10040535 
Somatic delusion 
10041317 
Somatic hallucination 
10062684 
Substance-induced psychotic disorder 
10072388 
Tangentiality 
10043114 
Thought blocking 
10043495 
Thought broadcasting 
10052214 
Thought insertion 
10043496 


 
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SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Thought withdrawal 
10043497 
Transient psychosis 
10056326 
Waxy flexibility 
10047853 
13.9.10. 
Mood Disorders 
Medical concept of mood disorders. All preferred terms from HLGT 'Mood disorders and 
disturbances NEC', under SOC 'Psychiatric disorders'; HLGT Code 10027946. 
Preferred Term 
PT Code 
Affect lability 
10054196 
Affective ambivalence 
10077173 
Affective disorder 
10001443 
Alexithymia 
10077719 
Anger 
10002368 
Apathy 
10002942 
Blunted affect 
10005885 
Boredom 
10048909 
Constricted affect 
10010778 
Crying 
10011469 
Diencephalic syndrome of infancy 
10012774 
Discouragement 
10084257 
Dysphoria 
10013954 
Emotional disorder 
10014551 
Emotional distress 
10049119 
Emotional poverty 
10014557 
Euphoric mood 
10015535 
Flat affect 
10016759 


 
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Preferred Term 
PT Code 
Frustration tolerance decreased 
10077753 
Inappropriate affect 
10021588 
Irritability 
10022998 
Laziness 
10051602 
Lethargy 
10024264 
Listless 
10024642 
Moaning 
10027783 
Mood altered 
10027940 
Mood disorder due to a general medical condition 
10027944 
Mood swings 
10027951 
Morose 
10027977 
Neuroleptic-induced deficit syndrome 
10075295 
Premenstrual dysphoric disorder 
10051537 
Premenstrual syndrome 
10036618 
Screaming 
10039740 
Seasonal affective disorder 
10039775 
Steroid withdrawal syndrome 
10042028 
Substance-induced mood disorder 
10072387 
13.9.11. 
Anxiety 
Notes: Medical concept of anxiety disorders. All preferred terms from HLGT “Anxiety 
disorders and symptoms”, under SOC “Psychiatric disorders”; HLGT Code 10002861. 
Preferred Terms 
PT Code 
Acrophobia 
10000605 
Activation syndrome 
10066817 
Acute stress disorder 
10001084 
Aerophobia 
10080300 
Agitation 
10001497 


 
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Preferred Terms 
PT Code 
Agitation postoperative 
10049989 
Agoraphobia 
10001502 
Akathisia 
10001540 
Algophobia 
10078056 
Animal phobia 
10002518 
Anniversary reaction 
10074066 
Anticipatory anxiety 
10002758 
Anxiety 
10002855 
Anxiety disorder 
10057666 
Anxiety disorder due to a general medical condition 
10002859 
Arachnophobia 
10051408 
Astraphobia 
10078372 
Autophobia 
10071070 
Body dysmorphic disorder 
10052793 
Burnout syndrome 
10065369 
Catastrophic reaction 
10082329 
Cibophobia 
10082413 
Claustrophobia 
10009244 
Compulsions 
10010219 
Compulsive cheek biting 
10076510 
Compulsive handwashing 
10071263 
Compulsive hoarding 
10068007 
Compulsive lip biting 
10066241 
Compulsive shopping 
10067948 
Cryophobia 
10082662 
Dermatillomania 
10065701 
Dysmorphophobia 
10049096 
Emetophobia 
10070637 


 
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Preferred Terms 
PT Code 
Fear 
10016275 
Fear of animals 
10016276 
Fear of closed spaces 
10016277 
Fear of crowded places 
10050365 
Fear of death 
10066392 
Fear of disease 
10016278 
Fear of eating 
10050366 
Fear of falling 
10048744 
Fear of injection 
10073753 
Fear of open spaces 
10016279 
Fear of pregnancy 
10067035 
Fear of surgery 
10084519 
Fear of weight gain 
10016280 
Fear-related avoidance of activities 
10080136 
Generalised anxiety disorder 
10018075 
Glossophobia 
10080077 
Haemophobia 
10073458 
Haphephobia 
10067580 
Herpetophobia 
10081809 
Hydrophobia 
10053317 
Hyperarousal 
10080831 
Immunisation anxiety related reaction 
10075205 
Kinesiophobia 
10078430 
Limited symptom panic attack 
10024511 
Mysophobia 
10078769 
Nail picking 
10066779 
Nervousness 
10029216 
Neurosis 
10029333 


 
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Preferred Terms 
PT Code 
Noctiphobia 
10057946 
Nocturnal fear 
10057948 
Nosocomephobia 
10083993 
Nosophobia 
10063546 
Obsessive need for symmetry 
10077179 
Obsessive rumination 
10056264 
Obsessive thoughts 
10029897 
Obsessive-compulsive disorder 
10029898 
Obsessive-compulsive symptom 
10077894 
Ochlophobia 
10050095 
Osmophobia 
10060765 
Paediatric autoimmune neuropsychiatric disorders associated with 
streptococcal infection 
10072147 
Panic attack 
10033664 
Panic disorder 
10033666 
Panic reaction 
10033670 
Paruresis 
10069024 
Performance fear 
10034432 
Phagophobia 
10050096 
Pharmacophobia 
10069423 
Phobia 
10034912 
Phobia of driving 
10056676 
Phobia of exams 
10034913 
Phobic avoidance 
10034918 
Phonophobia 
10054956 
Photaugiaphobia 
10064420 
Postpartum anxiety 
10082233 
Postpartum neurosis 
10036419 


 
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Preferred Terms 
PT Code 
Postpartum stress disorder 
10056394 
Post-traumatic stress disorder 
10036316 
Procedural anxiety 
10075204 
Pseudoangina 
10056610 
Selective mutism 
10039917 
Separation anxiety disorder 
10040045 
Sitophobia 
10080170 
Social anxiety disorder 
10041242 
Social fear 
10041247 
Stress 
10042209 
Tension 
10043268 
Terminal agitation 
10077416 
Thanatophobia 
10064723 
Thermophobia 
10075147 
Trichotemnomania 
10072752 
Trichotillomania 
10044629 


 
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13.9.12. 
Sleep Disorders 
Medical concept of sleep disorders. All preferred terms from (1) HLGT 'Sleep Disorders 
and Disturbances', 'Psychiatric disorders' SOC plus (2) HLGT 'Sleep disturbances (incl 
subtypes)', 'Nervous system' SOC. Numerous duplicated preferred terms e.g. middle 
insomnia. 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Abnormal dreams 
10000125 
Abnormal sleep-related event 
10061613 
Advanced sleep phase 
10001423 
Behavioural induced insufficient sleep syndrome 
10081938 
Behavioural insomnia of childhood 
10072072 
Breathing-related sleep disorder 
10006344 
Cataplexy 
10007737 
Circadian rhythm sleep disorder 
10009191 
Confusional arousal 
10067494 
Delayed sleep phase 
10012209 
Dyssomnia 
10061827 
Exploding head syndrome 
10080684 
Hypersomnia 
10020765 
Hypersomnia related to another mental condition 
10020767 
Hypersomnia-bulimia syndrome 
10053712 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Hyposomnia 
10067530 
Initial insomnia 
10022035 
Insomnia 
10022437 
Insomnia related to another mental condition 
10022443 
Irregular sleep phase 
10022995 
Irregular sleep wake rhythm disorder 
10080301 


 
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HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Loss of dreaming 
10065085 
Middle insomnia 
10027590 
Narcolepsy 
10028713 
Nightmare 
10029412 
Non-24-hour sleep-wake disorder 
10078086 
Parasomnia 
10061910 
Paradoxical insomnia 
10083337 
Periodic limb movement disorder 
10064600 
Pickwickian syndrome 
10035004 
Poor quality sleep 
10062519 
Rapid eye movement sleep behaviour disorder 
10077299 
Rapid eye movements sleep abnormal 
10037841 
Shift work disorder 
10078088 
Sleep apnoea syndrome 
10040979 
Sleep attacks 
10040981 
Sleep disorder 
10040984 
Sleep disorder due to a general medical condition 
10063910 
Sleep disorder due to general medical condition, hypersomnia type 
10040985 
Sleep disorder due to general medical condition, insomnia type 
10040986 
Sleep disorder due to general medical condition, mixed type 
10040987 
Sleep disorder due to general medical condition, parasomnia type 
10040988 
Sleep inertia 
10067493 
Sleep paralysis 
10041002 
Sleep sex 
10067492 
Sleep talking 
10041009 
Sleep terror 
10041010 
Sleep-related eating disorder 
10067315 
Somnambulism 
10041347 


 
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HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Somnolence 
10041349 
Somnolence neonatal 
10041350 
Sopor 
10058709 
Stupor 
10042264 
Terminal insomnia 
10068932 
Upper airway resistance syndrome 
10063968 
HLGT Sleep disturbances (incl subtypes), HLGT code 10040998 
 
Abnormal dreams 
10000125 
Abnormal sleep-related event 
10061613 
Advanced sleep phase 
10001423 
Behavioural induced insufficient sleep syndrome 
10081938 
Behavioural insomnia of childhood 
10072072 
Breathing-related sleep disorder 
10006344 
Cataplexy 
10007737 
Central-alveolar hypoventilation 
10007982 
Circadian rhythm sleep disorder 
10009191 
Confusional arousal 
10067494 
Delayed sleep phase 
10012209 
Dyssomnia 
10061827 
Fatal familial insomnia 
10072077 
Hypersomnia 
10020765 
Hyposomnia 
10067530 
Initial insomnia 
10022035 
Insomnia 
10022437 
Irregular sleep phase 
10022995 
Irregular sleep wake rhythm disorder 
10080301 
Loss of dreaming 
10065085 
Microsleep 
10076954 


 
C O N FI D E N TI A L  
 
 
 
 
2 1 3 1 9 9  
 
9 1  
 
H L G T Slee p Dis or ders a n d Dist u r ba nces, H L G T C o de 1 0 0 4 0 9 9 1 
 
Mi d dle i ns o m nia  
1 0 0 2 7 5 9 0  
Narc ole ps y  
1 0 0 2 8 7 1 3  
N o n -2 4 -h o ur sle e p -w a ke dis or der  
1 0 0 7 8 0 8 6  
Peri o dic li m b m o ve me nt dis or der  
1 0 0 6 4 6 0 0  
Pic k wic kia n s y n dr o me  
1 0 0 3 5 0 0 4  
P o or q ualit y slee p  
1 0 0 6 2 5 1 9  
Ra pi d e ye m o ve me nt slee p be ha vi o ur dis or d er  
1 0 0 7 7 2 9 9  
Ra pi d e ye m o ve me nts slee p a b n or m al  
1 0 0 3 7 8 4 1  
S hift w or k dis or der  
1 0 0 7 8 0 8 8  
Slee p a p n oea s y n dr o me  
1 0 0 4 0 9 7 9  
Slee p deficit  
1 0 0 8 0 8 8 1  
Slee p i nertia  
1 0 0 6 7 4 9 3  
Slee p paral ysis  
1 0 0 4 1 0 0 2  
Slee p se x  
1 0 0 6 7 4 9 2  
Slee p tal ki n g  
1 0 0 4 1 0 0 9  
Slee p terr or  
1 0 0 4 1 0 1 0  
Slee p -relat e d eati n g dis or der 
1 0 0 6 7 3 1 5  
S o m na m b ulis m  
1 0 0 4 1 3 4 7  
S u d de n o nset of slee p  
1 0 0 5 0 0 1 4  
Ter mi nal i ns o m nia  
1 0 0 6 8 9 3 2  
U p per air wa y resista nce s y n dr o me  
1 0 0 6 3 9 6 8  
1 3. 9. 1 4.  
S ei z ur e s  
Me dical c o nce pt of seiz ures. O nl y narr o w ter ms fr o m S M Q ' C o n v ulsi o ns' s electe d pl us 
selecte d P Ts of p ossi ble seiz ure e ve nts fr o m H L T ' Dist ur ba n ces i n c o ns ci o us ness N E C' 
u n der S O C ' N er v o us s yst e ms dis or ders' a n d H L T ' C o nf usi o n a n d dis orie ntati o n' u n der 
S O C ' Ps yc hiatric dis or ders' . 
C CI


 
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SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
1p36 deletion syndrome 
10082398 
2-Hydroxyglutaric aciduria 
10078971 
Acquired epileptic aphasia 
10052075 
Acute encephalitis with refractory, repetitive partial seizures 
10076948 
Alcoholic seizure 
10056347 
Alpers disease 
10083857 
Aspartate-glutamate-transporter deficiency 
10079140 
Atonic seizures 
10003628 
Atypical benign partial epilepsy 
10056699 
Automatism epileptic 
10003831 
Autonomic seizure 
10049612 
Baltic myoclonic epilepsy 
10054895 
Benign familial neonatal convulsions 
10067866 
Benign rolandic epilepsy 
10070530 
Biotinidase deficiency 
10071434 
CEC syndrome 
10083749 
CDKL5 deficiency disorder 
10083005 
Change in seizure presentation 
10075606 
Clonic convulsion 
10053398 
Congenital bilateral perisylvian syndrome 
10082716 
Convulsion in childhood 
10052391 
Convulsions local 
10010920 
Convulsive threshold lowered 
10010927 
CSWS syndrome 
10078827 
Deja vu 
10012177 


 
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SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Double cortex syndrome 
10073490 
Dreamy state 
10013634 
Drug withdrawal convulsions 
10013752 
Early infantile epileptic encephalopathy with burst-suppression 
10071545 
Eclampsia 
10014129 
Epilepsy 
10015037 
Epilepsy surgery 
10079824 
Epilepsy with myoclonic-atonic seizures 
10081179 
Epileptic aura 
10015049 
Epileptic psychosis 
10059232 
Faciobrachial dystonic seizure 
10084187 
Febrile convulsion 
10016284 
Febrile infection-related epilepsy syndrome 
10079438 
Focal dyscognitive seizures 
10079424 
Frontal lobe epilepsy 
10049424 
Gelastic seizure 
10082918 
Generalised onset non-motor seizure 
10083376 
Generalised tonic-clonic seizure 
10018100 
Glucose transporter type 1 deficiency syndrome 
10078727 
GM2 gangliosidosis 
10083933 
Grey matter heterotopia 
10082084 
Hemimegalencephaly 
10078100 
Hyperglycaemic seizure 
10071394 
Hypocalcaemic seizure 
10072456 
Hypoglycaemic seizure 
10048803 
Hyponatraemic seizure 
10073183 


 
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SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Idiopathic generalised epilepsy 
10071081 
Infantile spasms 
10021750 
Jeavons syndrome 
10084303 
Juvenile myoclonic epilepsy 
10071082 
Lafora's myoclonic epilepsy 
10054030 
Lennox-Gastaut syndrome 
10048816 
Migraine-triggered seizure 
10076676 
Molybdenum cofactor deficiency 
10069687 
Multiple subpial transection 
10079825 
Myoclonic epilepsy 
10054859 
Myoclonic epilepsy and ragged-red fibres 
10069825 
Neonatal epileptic seizure 
10082068 
Neonatal seizure 
10082067 
Partial seizures 
10061334 
Partial seizures with secondary generalisation 
10056209 
Petit mal epilepsy 
10034759 
Polymicrogyria 
10073489 
Post stroke epilepsy 
10076982 
Post stroke seizure 
10076981 
Postictal headache 
10052470 
Postictal paralysis 
10052469 
Postictal psychosis 
10070669 
Postictal state 
10048727 
Post-traumatic epilepsy 
10036312 
Schizencephaly 
10073487 
Seizure 
10039906 


 
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SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Seizure anoxic 
10039907 
Seizure cluster 
10071350 
Seizure like phenomena 
10071048 
Severe myoclonic epilepsy of infancy 
10073677 
Simple partial seizures 
10040703 
Status epilepticus 
10041962 
Sudden unexplained death in epilepsy 
10063894 
Temporal lobe epilepsy 
10043209 
Tonic clonic movements 
10051171 
Tonic convulsion 
10043994 
Tonic posturing 
10075125 
Topectomy 
10073488 
Transient epileptic amnesia 
10081728 
Tuberous sclerosis complex 
10080584 
Uncinate fits 
10045476 
Additional selected preferred terms from HLT Disturbances in 
consciousness NEC, HLT code 10013509 and HLT Confusion and 
disorientation, HLT code 10010301. 
Preferred Term 
PT Code 
Confusional state 
10010305 
Loss of consciousness 
10024855 
Syncope 
10042772 
Sopor 
10058709 
Stupor 
10042264 
Altered state of consciousness 
10050093 
Depressed level of consciousness 
10012373 
Consciousness fluctuating 
10050093 


 
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13.9.15. 
Weight Gain 
Medical concept of weight gain. Selected PTs from HLT 'General nutritional disorders 
NEC', under SOC 'Metabolism and nutrition disorders', and HLT 'Physical examination 
procedures and organ system status', under SOC 'Investigations' and HLT 'General signs 
and symptoms NEC', under SOC 'General disorders and administration site conditions'. 
PTs (Select) from HLT General nutritional disorders NEC, HLT code 10018067 
Preferred Term 
PT Code 
Abdominal fat apron 
10077983 
Overweight 
10033307 
Abnormal weight gain 
10000188 
Central obesity 
10065941 
Obesity 
10029883 
Abdominal fat apron 
10077983 
Overweight 
10033307 
Abnormal weight gain 
10000188 
Central obesity 
10065941 
Obesity 
10029883 
PTs (Select) from HLT Physical examination procedures and organ system status, 
HLT Code 10071941 
Preferred Term 
PT Code 
Weight abnormal 
10056814 
Weight increased 
10047899 
Waist circumference increased 
10064863 
Body mass index abnormal 
10074506 
Body mass index increased 
10005897 
PTs (Select) from HLT General signs and symptoms NEC, HLT Code 10018072 
Preferred Term 
PT Code 
Fat tissue increased 
10016251 
Sarcopenic obesity 
10083992 


 
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13.9.16. 
Rhabdomyolysis 
Medical concept of rhabdomyolysis. Only narrow terms only for SMQ 
'Rhabdomyolysis/myopathy' plus 2 additional preferred terms selected from HGLT 
'muscle disorders' under SOC 'Musculoskeletal and connective tissue disorders'. 
SMQ: 'Rhabdomyolysis/myopathy' 
SMQ Code: 20000002 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Muscle necrosis 
10028320 
Myoglobin blood increased 
10028625 
Myoglobin blood present 
10059888 
Myoglobin urine present 
10028631 
Myoglobinaemia 
10058735 
Myoglobinuria 
10028629 
Myopathy 
10028641 
Myopathy toxic 
10028648 
Necrotising myositis 
10074769 
Rhabdomyolysis 
10039020 
Thyrotoxic myopathy 
10081524 
PTs (Select) from HGLT muscle disorders, HLGT Code 10028302 
Preferred Term 
PT Code 
Myalgia 
10028411 
Myositis 
10028653 
13.9.17. 
Pancreatitis  
Medical concept of acute pancreatitis. Only narrow terms of SMQ 'Acute pancreatitis' 
selected. Algorithmic approach for this SMQ not used due to complexity in applying and 
poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms). 
 
 


 
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SMQ: 'Acute pancreatitis'  
SMQ Code: 20000022  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Cullen's sign 
10059029 
Grey Turner's sign 
10075426 
Haemorrhagic necrotic pancreatitis 
10076058 
Hereditary pancreatitis 
10056976 
Immune-mediated pancreatitis 
10083072 
Ischaemic pancreatitis 
10066127 
Oedematous pancreatitis 
10052400 
Pancreatic abscess 
10048984 
Pancreatic cyst drainage 
10082531 
Pancreatic haemorrhage 
10033625 
Pancreatic necrosis 
10058096 
Pancreatic phlegmon 
10056975 
Pancreatic pseudoaneurysm 
10081762 
Pancreatic pseudocyst 
10033635 
Pancreatic pseudocyst drainage 
10033636 
Pancreatic pseudocyst haemorrhage 
10083813 
Pancreatic pseudocyst rupture 
10083811 
Pancreatitis 
10033645 
Pancreatitis acute 
10033647 
Pancreatitis haemorrhagic 
10033650 
Pancreatitis necrotising 
10033654 
Pancreatitis relapsing 
10033657 
Pancreatorenal syndrome 
10056277 
Subacute pancreatitis 
10084554 


 
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13.9.18. 
Impact on Creatinine 
Medical concept of worsening renal function/renal failure in the context of impact on 
creatinine. Only narrow terms from SMQ 'Acute renal failure' plus all PTs from HLT 
'Renal failure and impairment', under SOC 'Renal and urinary disorders'. Numerous 
duplicated preferred terms e.g. renal failure 
SMQ: ‘Acute renal failure’ 
SMQ Code: 20000003 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Acute kidney injury 
10069339 
Acute phosphate nephropathy 
10069688 
Anuria 
10002847 
Azotaemia 
10003885 
Continuous haemodiafiltration 
10066338 
Dialysis 
10061105 
Foetal renal impairment 
10078987 
Haemodialysis 
10018875 
Haemofiltration 
10053090 
Neonatal anuria 
10049778 
Nephropathy toxic 
10029155 
Oliguria 
10030302 
Peritoneal dialysis 
10034660 
Prerenal failure 
10072370 
Renal failure 
10038435 
Renal failure neonatal 
10038447 
Renal impairment 
10062237 
Renal impairment neonatal 
10049776 
Subacute kidney injury 
10081980 


 
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Renal Failure and Impairment HLT, HLT Code 10038443 
Preferred Term 
PT Code 
Acute Kidney injury 
10069339 
Anuria 
10002847 
Atypical haemolytic uraemic syndrome 
10079840 
Cardiorenal syndrome 
10068230 
Chronic kidney disease 
10064848 
Crush syndrome 
10050702 
Diabetic end stage renal disease 
10012660 
End stage renal disease 
10077512 
Foetal renal impairment 
10078987 
Haemolytic uraemic syndrome 
10018932 
Hepatorenal failure 
10019845 
Hepatorenal syndrome 
10019846 
Nail-patella syndrome 
10063431 
Neonatal anuria 
10049778 
Oliguria 
10030302 
Pancreatorenal syndrome 
10056277 
Postoperative renal failure 
10056675 
Postrenal failure 
10059345 
Prerenal failure 
10072370 
Propofol infusion syndrome 
10063181 
Renal failure 
10038435 
Renal failure neonatal 
10038447 
Renal impairment 
10062237 
Renal impairment neonatal 
10049776 
Renal injury 
10061481 
Scleroderma renal crisis 
10062553 
Traumatic anuria 
10044501 


 
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13.9.19. 
Safety During Pregnancy 
Use AE terms co-reported in pregnancy exposures to CAB.


 
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13.10. 
Appendix 10: Identification of COVID-19 Adverse Events 
COVID-19 adverse events are identified based on MedDRA coded values and/or AE 
referenced in the COVID-19 Coronavirus Infection assessment. The Lowest Level Terms 
(LLTs) and codes, Preferred Terms (PTs), High Level Terms (HLTs), High Level Group 
Terms (HLGTs), and System Organ Classes (SOCs), below are from MedDRA 23.0. In 
case there is a change to the version of MedDRA at time of reporting, the coded values 
based on the MedDRA version at the time of reporting will be used. The additional 
events may also be added based on the blinded review of AE data collected on study prior 
to the database freeze. 
SOC: Infections and infestations 
LLT 
code 
LLT 
PT 
HLT 
HLGT 
1008445
9 
Asymptomatic COVID-19 
Asymptomati
c COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008446
7 
Asymptomatic SARS-CoV-2 infection 
Asymptomati
c COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1005398
3 
Corona virus infection 
Coronavirus 
infection 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1005190
5 
Coronavirus infection 
Coronavirus 
infection 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008438
2 
Coronavirus disease 2019 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1007025
5 
Coronavirus test positive 
Coronavirus 
test positive 
Virus 
identificatio
n and 
serology 
Microbiology 
and serology 
investigation
s 
1008446
0 
COVID-19 treatment 
COVID-19 
treatment 
Antiinfectiv
e therapies 
Therapeutic 
procedures 
and 
supportive 
care NEC 
1008463
9 
SARS-CoV-2 sepsis 
SARS-CoV-2 
sepsis 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008427
1 
SARS-CoV-2 test positive 
SARS-CoV-2 
test positive 
Virus 
identificatio
n and 
serology 
Microbiology 
and serology 
investigation
s 


 
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LLT 
code 
LLT 
PT 
HLT 
HLGT 
1008464
0 
SARS CoV-2 viraemia 
SARS CoV-2 
viraemia 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008426
8 
COVID-19 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008440
1 
COVID-19 respiratory infection 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008427
0 
SARS-CoV-2 acute respiratory 
disease 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008427
2 
SARS-CoV-2 infection 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008438
1 
Coronavirus pneumonia 
COVID-19 
pneumonia 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008438
0 
COVID-19 pneumonia 
COVID-19 
pneumonia 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008438
3 
Novel COVID-19-infected pneumonia 
COVID-19 
pneumonia 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008445
1 
Suspected COVID-19 
Suspected 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008445
2 
Suspected SARS-CoV-2 infection 
Suspected 
COVID-19 
Coronaviru
s infections 
Viral 
infectious 
disorders 
1008446
1 
SARS-CoV-2 carrier 
SARS-CoV-2 
carrier 
Infectious 
disorders 
carrier 
Ancillary 
infectious 
topics 


 
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13.11. 
Appendix 11: Abbreviations & Trade Marks 
13.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library (GSK Standards Library) 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MMRM 
Mixed Model Repeated Measures 
PBMC 
Peripheral Blood Mononuclear Cells 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 


 
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Abbreviation 
Description 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
13.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
Cabotegravir 
 
Rilpivirine 
 
 
SAS 
 


 
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13.12. 
Appendix 12: List of Data Displays 
All data displays will use the term “subject” rather than “participant” in accordance with 
CDSIC and GSK Statistical Display Standards. 
Where applicable, all summary displays will present data across both the Intervention and 
Extension phases unless explicitly stated otherwise in the display title. 
At EOS, the RAPIDO Data Viewer will be produced to allow for the clinical team to 
review ADaM data directly related to adverse events, exposure, HIV-1 RNA, and labs. 
This will take the place of some, previously standard generic listings from these 
categories. Listings including results of pregnancy details will only be included if a 
pregnancy occurs.  
13.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.27 
 
Efficacy 
2.1 to 2.16 
2.1 to 2.4 
Safety 
3.1 to 3.75 
3.1 to 3.4 
Other 
4.1 to 4.4 
 
Section 
Listings 
ICH Listings 
1 to 24 
Other Listings 
25 to 57 
 
13.12.2. 
Mock Example Shell Referencing 
Nonstandard specifications will be referenced as indicated below (where a study specific 
mock shell is available) or the location of a similar display produced for a different study 
in the HARP reporting environment will be provided as reference.  If required example 
mock-up displays provided in Appendix 13: Example Mock Shells for Data Displays.   
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAF_Fn 
SAF_Tn 
SAF_Ln 
Other 
OTR_Tn 
OTR_Fn 
OTR_Ln 
 
13.12.3. 
Deliverables 
Delivery 
Description 
IA1 
Interim Analysis Statistical Analysis Complete at IA (Month 4) 
when 50% of subjects have received their 3rd injection. 
IA2 
Interim Analysis Statistical Analysis Complete at IA (Month 4) 
when 100% of subjects have received their 3rd injection. 


 
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Delivery 
Description 
HL 
Headline at Month 12 
M12 
Statistical Analysis Complete at Month 12 
EOS 
End of Study 
 


 
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13.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Disposition for the Subject Conclusion 
Record 
ICH E3, FDAAA, EudraCT 
HL, M12, 
EOS 
1.2. 
Safety 
SD1 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment 
ICH E3 
M12, EOS 
1.3. 
Safety 
DISP_T1 
Summary of Subject Disposition at Each Study Phase 
ICH E3 
Intervention/Extension phase: status 
and reason for withdrawal based on 
date and reason collected in the 
study treatment discontinuation form. 
Long term Follow-up: 
completion/withdrawal based on data 
collected in the Study Conclusion 
form. 
For the Intervention Phase, columns 
should report OLI results, LA results, 
& Total results; All other phases only 
list total results 
Under withdrawals, add subcategory 
for Covid-19 
M12, EOS 


 
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Study Population Tables 
No. 
Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.4. 
Safety 
DISP_T2 
Summary of Reason for Withdrawal at Each Study Phase 
FDAAA, EudraCT 
For Intervention Phase, columns 
should report OLI results, LA results, 
& Total results; All other phases only 
list total results 
See mockup for relevant Covid-19 
Subcategories 
IA2, HL, M12, 
EOS 
1.5. 
Safety 
ES11 
Summary of Outcome of Adverse Events Which Led to 
Study Withdrawal/Treatment Discontinuation at Each Study 
Phase 
EudraCT 
M12, EOS 
1.6. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Journal Requirements 
M12 
1.7. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
EudraCT/Clinical Operations 
IA1, HL, M12 
Protocol Deviation 
1.8. 
Enrolled 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
M12, EOS 
1.9. 
Enrolled 
DV1 
Summary of Important COVID-19 Related Protocol 
Deviations  
Update the label for the first row to 
be “ANY IMPORTANT COVID-19 
RELATED PROTOCOL 
DEVIATIONS” 
M12, EOS 
1.10. 
Enrolled 
DV1 
Summary of Important Non-COVID-19 Protocol Deviations  
Update the label for the first row to 
be “ANY IMPORTANT NON-COVID-
19 RELATED PROTOCOL 
DEVIATIONS” 
M12, EOS 
1.11. 
Enrolled 
DV1 
Summary of COVID-19 Protocol Deviations by Site 
Update the label for the first row to 
be “ANY COVID-19 RELATED 
PROTOCOL DEVIATIONS”. 
Summary for each site and ‘Total’ 
across sites. 
IA2, HL, M12, 
EOS 


 
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Study Population Tables 
No. 
Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.12. 
Enrolled 
DV1 
Summary of All Implementation Protocol Deviations by Site 
Update the label for the first row to 
be “ANY IMPLEMENTATION 
RELATED PROTOCOL 
DEVIATIONS” 
Summary for each site and ‘Total’ 
across sites. 
HL, M12, 
EOS 
Population Analysed 
1.13. 
Screened 
SP1 
Summary of Study Populations 
GSK Statistical Display Standard 
M12, EOS 
1.14. 
Enrolled 
SP2 
Summary of Exclusions from the Safety Population 
GSK Statistical Display Standard 
M12 
Demographic and Baseline Characteristics 
1.15. 
Safety 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
Include Baseline CD4+ Cell Count 
Results and CDC HIV-1 Infection 
Classification. 
IA1, HL, M12 
1.16. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
M12 
1.17. 
Safety 
DM6 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
M12 
Prior and Concomitant Medications 
1.18. 
Safety 
MH1 
Summary of Past Medical Conditions 
ICH E3 
M12 
1.19. 
Safety 
MH4 
Summary of Past Cardiac, Gastrointestinal, Metabolism and 
Nutrition, Psychiatric, Renal and Urinary, Nervous System 
Conditions, and Hepatobiliary Disorders 
ICH E3 
M12 
1.20. 
Safety 
MH1 
Summary of Current Medical Conditions 
ICH E3 
M12 
1.21. 
Safety 
MH4 
Summary of Current Cardiac, Gastrointestinal, Metabolism 
and Nutrition, Psychiatric, Renal and Urinary, Nervous 
System Conditions, and Hepatobiliary Disorders 
ICH E3 
M12 


 
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Study Population Tables 
No. 
Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.22. 
Safety 
CM9 
Summary of Concomitant Medications by Ingredient 
Combinations 
ICH E3 
See GSK Statistical Display 
Standard 
Multi-ingredient medications will be 
labelled according to the sum of their 
ingredients, i.e., Generic Term. 
M12, EOS 
1.23. 
Safety 
207966/primary_15/T1.30 Summary of Prior Antiretroviral Therapy Taken during 
Screening 
Remove the footnote. Follow 
definitions in Section 13.3.1 to 
determine the prior ART 
medications. 
M12 
1.24. 
Safety 
RF1 
Summary of HIV Risk Factors 
 
M12 
1.25. 
Safety 
201585/primary_02/T1.31 
Time Since First Antiretroviral Therapy Until 
Intervention Phase Start 
Add footnote “Note: Duration is 
calculated as the day prior to first 
dose of CAB+RPV – the first 
recorded date of prior ART usage 
+1.” 
M12 
1.26. 
Safety 
DM1 
Summary of Categorical Baseline BMI 
 
M12 
1.27. 
Safety 
DM1 
Summary of Baseline BMI Based on Day 1 Weight 
Values 
Repeat the descriptive BMI statistics 
from Table 1.15 and the categorical 
statistics from Table 1.26 using a 
newly calculated Baseline BMI 
based on Day 1 weight values 
instead of CRF reported BMI values. 
EOS 
 
 


 
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13.12.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
Snapshot 
2.1.  
Safety 
EFF_T1 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) –Snapshot Analysis 
 
HL, M12 
2.2.  
Safety 
EFF_T2 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) –Snapshot Analysis Considering 
Covid-19 Based Events 
With expanded COVID-19 
related/Non-related categories 
HL, M12 
2.3.  
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA ≥ 50 c/mL 
Over Time (Intervention Phase) –Snapshot Analysis 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
Expand to all visits, drop ‘n’ row, 
replace x (%) column data with x/n 
(%), drop ‘(Intervention Phase)’ and 
use Observed Case instead of 
Snapshot for EOS 
M12, EOS 
2.4.  
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA < 50 c/mL 
Over Time (Intervention Phase) –Snapshot Analysis 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
Expand to all visits, drop ‘n’ row, 
replace x (%) column data with x/n 
(%), drop ‘(Intervention Phase)’ and 
use Observed Case instead of 
Snapshot for EOS 
M12, EOS 
2.5.  
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA ≥ 50 c/mL 
Over Time by Subgroup (Intervention Phase) –Snapshot 
Analysis 
Include the following subgroups: 
country, implementation arm, sex, 
age group, race group, and CD4 
group as mentioned in Section 
5.4.2. 
M12 


 
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No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
2.6.  
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA < 50 c/mL 
Over Time by Subgroup (Intervention Phase) –Snapshot 
Analysis 
Include the following subgroups: 
country, implementation arm, sex, 
age group, race group, and CD4 
group as mentioned in Section 
5.4.2. 
M12 
CVF 
2.7.  
Safety 
VF1 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Failure Criteria Over Time (Intervention Phase) 
 
HL, M12 
2.8.  
Safety 
VF2 
Proportion of Subjects Meeting Confirmed Virologic Failure 
Criteria Over Time 
 
M12, EOS 
Genotype & Phenotype 
2.9.  
Safety 
201584/primary_17/T7.1 
Summary of the Prevalence of Treatment-Emergent Major 
Resistance Mutations of INI, NRTI, NNRTI and PI Class at 
time of CVF - Plasma Sample 
Known resistance mutations per 
Section 13.5.5.  
Include 95% confidence Intervals 
using Exact (Clopper-Pearson) 
method. 
HL, M12, 
EOS 
2.10. 
Safety 
201584/primary_17/T7.2 Summary of Viral load, Genotypic and Phenotypic data for 
Subjects Who Met Confirmed Virologic Failure Criteria 
 
M12, EOS 
2.11. 
Safety 
201584/primary_17/T7.4 Summary of Viral load, Genotypic and Phenotypic data for 
Subjects Who Did Not Meet Confirmed Virologic Failure 
Criteria  
Only include subjects with available 
genotypic or phenotypic data. 
M12, EOS 
CD4 
2.12. 
Safety 
LB1 
Summary of CD4+ Cell Count (cells/mm^3) by Visit 
 
M12, EOS 
2.13. 
Safety 
LB1 
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit 
 
M12, EOS 


 
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Efficacy: Tables 
No. 
Population 
GSK Standard/ 
Example Shell 
Title  
Programming Notes 
Deliverable 
2.14. 
Safety 
LB1 
Summary of CD4+/CD8+ Ratio Cell Count (cells/mm^3) at 
Baseline & Month 12 
 
M12 
HIV Associated Conditions 
2.15. 
Safety 
CDC2 
Summary of Post-Baseline CDC Stage 3 HIV-1 
Associated Conditions Including Recurrences  
 
M12, EOS 
2.16. 
Safety 
CDC2 
Summary of Post-Baseline CDC Stage 3 HIV-1 
Associated Conditions Excluding Recurrences  
 
M12, EOS 
 
13.12.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
GSK Standard 
 / Example 
Shell 
Title  
Programming Notes 
Deliverable  
Snapshot 
2.1.  
Safety 
SNAPSHOT8 
Percent (95% CI) of Subjects with Plasma HIV-1 RNA ≥ 50 
copies/mL Over Time (Intervention Phase) –Snapshot Analysis 
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals. 
Drop ‘(Intervention Phase)’, Observed 
cases to be used at EOS instead of 
Snapshot 
M12, EOS 
2.2.  
Safety 
SNAPSHOT8 
Percent (95% CI) of Subjects with Plasma HIV-1 RNA < 50 
copies/mL Over Time (Intervention Phase) –Snapshot Analysis 
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals. 
Drop ‘(Intervention Phase)’, Observed 
cases to be used at EOS instead of 
Snapshot 
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Efficacy: Figures 
2.3.  
Safety 
SNAPSHOT10 
Individual HIV-1 RNA Plasma Profiles by Visit for Subjects with 
HIV-1 RNA >= 50 copies/mL at Month 12 per Snapshot 
Algorithm 
The 1st vertical line indicates start of 
study treatment at Intervention Phase. 
The second vertical reference line 
indicates last IP on-treatment study 
day.  i.e. min (last IP injection 
dose+35 days, LTFU HAART start 
date, date of last oral CAB+RPV+1). 
This vertical line is only for subjects 
who withdraw from Intervention 
Phase/Extension phase. 
M12 
2.4.  
Safety 
SNAPSHOT10 
Individual HIV-1 RNA Plasma Profiles by Visit for Subjects 
with Confirmed Virologic Failure 
Same as Figure 2.3. 
M12, EOS 
 
 
 


 
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13.12.7. 
Safety Tables 
Safety: Tables 
No. Population 
GSK Standard/ Example Shell 
Title  
Programming Notes 
Deliverable 
Exposure 
3.1.  
Safety 
207966/primary_15/T3.1 
Summary of Exposure to Study Treatment by 
Implementation Arm (Intervention Phase) 
Includes Oral Bridging 
IA2, M12 
3.2.  
Safety 
207966/primary_15/T3.1 
Summary of Exposure to Study Treatment by 
Implementation Arm 
Includes Oral Bridging 
M12, EOS 
3.3.  
Safety 
SAF_T1 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Country, and Site (Intervention 
Phase) 
See Section 13.5.2 for Covid 
Impact 
 
Remove Covid-19 impact results 
from IA1. 
IA1, IA2, 
HL, M12 
3.4.  
Safety 
SAF_T2 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit and Subgroup (Intervention Phase) 
See Section 13.5.2 for Covid 
Impact 
 
Include all subgroups listed in 
Section 5.4.2 except for Site & 
Country 
HL, M12 
3.5.  
Safety 
SAF_T1 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Country, and Site  
See Section 13.5.2 for Covid 
Impact 
 
EOS 
3.6.  
Safety 
SAF_T2 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit and Subgroup  
See Section 13.5.2 for Covid 
Impact 
 
Include all subgroups listed in 
Section 5.4.2 except for Site & 
Country 
EOS 


 
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Safety: Tables 
3.7.  
Safety 
Study 201584 (primary_02): Table 
3.114 
Summary of Categorized Needle Length and Gauge 
for CAB Injection 
 
M12, EOS 
3.8.  
Safety 
Study 201584 (primary_02): Table 
3.115 
Summary of Categorized Needle Length and Gauge 
for RPV Injection 
 
M12, EOS 
Adverse Events (AEs) 
3.9.  
Safety 
AE99 
Adverse Event Overview by Study Phase and Overall 
High level summary to include 
counts of overall AEs, Serious 
AEs, AEs leading to withdrawal, 
related AEs, AEs related to 
Covid-19, AEs related to Covid-
19 leading to withdrawal, fatal 
AEs 
 
Overall breakdown to be 
condensed to Int + Ext phases. 
HL, M12, 
EOS 
3.10.
Safety 
AE3 
Summary of Adverse Events by Overall Frequency 
ICH E3 
M12, EOS 
3.11.
Safety 
AE5B 
Summary of Adverse Events by System Organ Class 
and Maximum Grade 
ICH E3 
HL, M12, 
EOS 
3.12.
Safety 
AE5B 
Summary of Adverse Events by System Organ Class 
and Maximum Grade — Excluding Study Drug 
Injection Site Reactions  
 
M12, EOS 
3.13.
Safety 
AE5B 
Summary of Adverse Events by System Organ Class 
and Maximum Grade (Oral Lead-in Period)  
 
M12 
3.14.
LTFU 
AE5B 
Summary of Adverse Events by System Organ Class 
and Maximum Grade (Long Term Follow-up Period) 
 
M12, EOS 
3.15.
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by 
Overall Frequency 
ICH E3 
M12, EOS 
3.16.
Safety 
AE3 
Summary of Common (>=1%) Grade 2-5 Adverse 
Events by Overall Frequency 
ICH E3 
M12, EOS 


 
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3.17.
Safety 
201584/primary_7/T3.46 
Summary of Adverse Events by Visit and Maximum 
Severity – Overall and Common 
 
HL, M12, 
EOS 
3.18.
Safety 
AE3 
Summary Drug-Related Adverse Events by Overall 
Frequency 
ICH E3 
M12, EOS 
3.19.
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade 
ICH E3 
 
HL, M12, 
EOS 
3.20.
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade (Oral Lead-in 
Period) 
ICH E3 
 
M12 
3.21.
LTFU 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade (Long Term 
Follow-up Period) 
ICH E3 
 
M12, EOS 
3.22.
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade — Excluding Study 
Drug Injection Site Reactions 
 
M12, EOS 
3.23.
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
FDAAA, EudraCT 
M12, EOS 
3.24.
Safety 
AE3 
Summary of Common (>=1%) Drug-Related Grade 2-
5 Adverse Events by Overall Frequency 
ICH E3 
M12, EOS 
3.25.
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse 
Events by Overall Frequency 
Plain Language Summary 
requirements. 
M12, EOS 
3.26.
Safety 
201584/primary_7/T3.46 
Summary of Drug-Related Adverse Events by Visit 
and Maximum Severity – Overall and Common 
 
M12, EOS 
Serious and Other Significant Adverse Events 
3.27.
Safety 
AE5B 
Summary of Serious Adverse Events by System 
Organ Class and Maximum Grade 
ICH E3 
HL, M12, 
EOS 


 
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3.28.
Safety 
AE5B 
Summary of Serious Adverse Events by System 
Organ Class and Maximum Grade (Oral Lead-in 
Period) 
ICH E3 
M12 
3.29.
LTFU 
AE5B 
Summary of Serious Adverse Events by System 
Organ Class and Maximum Grade (Long Term 
Follow-up Period) 
ICH E3 
M12, EOS 
3.30.
Safety 
AE16 
Summary of Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
FDAAA, EudraCT 
M12, EOS 
3.31.
Safety 
201584/primary_7/T3.46 
Summary of Serious Adverse Events by Visit and 
Maximum Severity – Overall and Common 
 
M12, EOS 
3.32.
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal 
from Study by System Organ Class and Preferred 
Term 
GSK Statistical Display Standard 
HL, M12, 
EOS 
3.33.
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal 
from Study by System Organ Class and Preferred 
Term (Oral Lead-in Period) 
GSK Statistical Display Standard 
M12 
3.34.
LTFU 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal 
from Study by System Organ Class and Preferred 
Term (Long Term Follow-up Period) 
GSK Statistical Display Standard 
M12, EOS 
3.35.
Safety 
201584/primary_7/T3.46 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal 
from Study by Visit and Maximum Severity – Overall 
and Common 
 
M12, EOS 


 
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
1 2 0  
 
S af et y : T a bl e s 
3. 3 6.  
 S af ety  
A E 1  
S u m m ary of S eri ous A dv ers e Ev e nts Le a din g t o 
P er m a n e nt Disc onti n uati o n of St u dy Tr e at m e nt or 
Wit h dr a w al fro m St u dy  by Syst e m Or ga n Cl ass a nd 
Pr ef err e d T er m  
G S K St atistic al Dis pl ay St a n d ar d  
M 1 2, E O S  
L a b orat ory: C h e mi str y  
3. 4 0.  
 S af ety  
L B 1  
S u m m ary of C h e mistry C h a n ges fr o m B as eli n e  
I C H E3 
M 1 2, E O S  
3. 4 1.  
 L T F U  
L B 1  
S u m m ary of C h e mistry C h a n ges fr o m B as eli n e ( Lo n g 
T er m F oll o w -u p P o p ul atio n)  
I C H E3 
M 1 2, E O S  
3. 4 2.  
 S af ety  
L B 1 6  
S u m m ary of C h e mistry R es ults by M axi m u m Gr a de 
I ncr e ase P ost-B as eli n e R el ativ e t o B as elin e  
I C H E3 
H L, M 1 2, 
E O S  
L a b orat ory: He m at ol o g y  
3. 4 3.  
  S af ety  
L B 1  
S u m m ary of H e m atol o gy C h an g es fr o m B as eli n e  
I ncl u d es pr e-s p ecifi e d p ar a m et ers 
r e p e at e d i n c o nv e nti o n al u nits. 
M 1 2, E O S  
3. 4 4.  
  L T F U  
L B 1  
S u m m ary of H e m atol o gy C h an g es fr o m B as eli n e ( L o n g 
T er m F oll o w -u p P o p ul atio n)  
I ncl u d es pr e-s p ecifi e d p ar a m et ers 
r e p e at e d i n c o nv e nti o n al u nits. 
M 1 2, E O S  
3. 4 5.  
 S af ety  
L B 1 6  
S u m m ary of H e m atol o gy R esults by M axi mu m Gr a d e 
I ncr e ase P ost-B as eli n e R el ativ e t o B as elin e  
I C H E3 
H L, M 1 2, 
E O S  
L a b orat ory: He p at o bili ar y ( Li v er)  
C CI


 
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3.46. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
GSK Statistical Display Standard 
M12, EOS 
3.47. 
 Safety 
LIVER10 
Summary of Post Baseline Hepatobiliary Laboratory 
Abnormalities 
GSK Statistical Display Standard 
See hepatobiliary abnormality 
criteria Section 13.7.1  
HL, M12, 
EOS 
3.48. 
 Safety 
LIVER11 
Summary of Liver Restart/Re-Challenges 
GSK Statistical Display Standard  
M12, EOS 
Vital Signs 
3.49. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
Include Baseline values, weight, and 
BMI 
M12, EOS 
Cardiovascular Risk Factors 
3.50. 
Safety 
FH1 
Summary of Family History of Cardiovascular Risk Factors 
GSK Statistical Display Standard  
M12 
3.51. 
Safety 
SU1 
Summary of Substance Use 
GSK Statistical Display Standard  
M12 
COVID-19 Adverse Events 
3.52. 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events 
GSK Statistical Display Standard 
Includes events across all phases 
IA2, M12, 
EOS 
3.53. 
Safety 
PAN2 
Summary of COVID-19 Additional Assessments for Subjects 
with COVID-19 Adverse Events 
GSK Statistical Display Standard 
Includes events across all phases 
M12, EOS 
3.54. 
Safety 
PAN3 
Summary of COVID-19 Symptoms for Subjects with COVID-
19 Adverse Events 
GSK Statistical Display Standard 
Includes events across all phases 
M12, EOS 
3.55. 
Safety 
PAN10 
Incidence of Covid-19 Adverse Events Overall and by 
Subgroup 
Subgroups include Sex, 
Implementation Arm 
Includes events across all phases 
M12, EOS 


 
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Safety: Tables 
Adverse Events of Special Interest 
3.56. 
Safety 
201584/primary_27/T3.140 
Summary of Depression, Anxiety and Suicidal or Suicidal 
Ideation/Behaviour Adverse Events by System Organ Class, 
Maximum DAIDS Toxicity Grade, and History of Depression, 
Anxiety or Suicidal Ideation/Behaviour at Screening  
 
M12, EOS 
3.57. 
Safety 
201584/primary_07/T3.122 
Summary of Depression Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.58. 
Safety 
201584/primary_07/T3.125 
Summary of Anxiety Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.59. 
Safety 
201584/primary_07/T3.128 
Summary of Suicidal Ideation/Behaviour Adverse Events of 
Special Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.60. 
Safety 
201584/primary_07/T3.134 
Summary of Seizures Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.61. 
Safety 
201584/primary_07/T3.137 
Summary of Hepatic Safety Profile: Assessment of Risk of 
Hepatoxicity Adverse Events of Special Interest by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences) 
 
M12, EOS 
3.62. 
Safety 
201584/primary_07/T3.140 
Summary of Hypersensitivity Reactions (HSR) Adverse 
Events of Special Interest by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) 
 
M12, EOS 
3.63. 
Safety 
201584/primary_07/T3.143 
Summary of Rash Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 


 
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3.64. 
Safety 
201584/primary_07/T3.149 
Summary of Bipolar Disorder Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.65. 
Safety 
201584/primary_07/T3.152 
Summary of Psychosis Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.66. 
Safety 
201584/primary_07/T3.155 
Summary of Mood Disorders Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.67. 
Safety 
201584/primary_07/T3.158 
Summary of Sleep Disorders Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.68. 
Safety 
201584/primary_07/T3.161 
Summary of Hyperglycaemia Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.69. 
Safety 
201584/primary_07/T3.161 
Summary of Weight Gain Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.70. 
Safety 
201584/primary_07/T3.164 
Summary of Rhabdomyolysis Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.71. 
Safety 
201584/primary_07/T3.167 
Summary of Pancreatitis Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.72. 
Safety 
201584/primary_07/T3.170 
Summary of Impact on Creatinine Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 


 
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
1 2 4  
 
S af et y : T a bl e s 
3. 7 3.  
 S af ety  
2 0 1 5 8 4/ pri m ary _ 0 7/ T 3. 1 7 3  
S u m m ary of S af ety i n Pr eg n ancy A dv ers e Ev e nts of S p eci al 
I nt er est by Syst e m Or g a n Cl ass a n d Pr ef err e d Ter m 
( Nu m b er of S u bj ects a n d Occurr e nc es) 
 
M 1 2, E O S  
3. 7 4.  
 S af ety  
2 0 7 9 6 6/ pri m ary _ 1 5/ T 3. 1 0 9  S u m m ary of C h ar act eristics of A dv ers e Ev e nts of S p eci al 
I nt er est  
 
M 1 2, E O S  
3. 7 5.  
 S af ety  
A E 9 9  
A dv ers e Ev e nt Ov ervi e w by Stu dy P h as e a n d Su b gr o u p  
R e p e at T a bl e 3. 9 f or all r el ev a nt 
s u b gr o u ps i ncl u di n g c o u ntry, s ex, 
a g e gr o u p, r ac e gr o u p,  a n d C D 4 
gr o u p as m e nti o n e d i n S ecti o n 5. 4. 2 . 
D o n ot i ncl u d e L T F U d at a.  
 
I ncl u d e B MI > = 3 0/ < 3 0 as a 
s u b gr o u p 
M 1 2  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
1 2 5  
 
S af et y : T a bl e s 
3. 8 8.  
 S af ety  
V S 1  
S u m m ary of C h a n ge fr o m D ay 1 W ei g ht V al u es  
R e p e at of T a bl e 3. 4 9 usi n g D ay 1 
v al u es as B as eli n e.  
E O S  
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 3 1 9 9  
 
1 2 6  
 
1 3. 1 2. 8.  
S af et y Fi g ur e s  
S af et y: Fi g ure s  
N o.  
P o p ul ati o n  
G S K St a n d ar d / 
E x a m pl e S h ell  
Titl e   
Pr o gra m mi n g N ot e s  
D eli v er a bl e  
A d v er s e E v e nt s  
3. 1.  
S af ety  
2 0 1 5 8 4/ pri m ary _ 0 7/ F 3. 1 4  
Pl ot of I nci d enc e of St u dy Dr ug I nj ecti o n Sit e R e acti o n 
A dv ers e Ev e nts by I m pl e m e ntati o n Ar m a n d Visit ( Ov er all 
a n d C o m mo n) –  C A B a n d/or R P V  
Sort by C A B + R P V, C A B, t h e n R P V  
I S R o ns et assi g n e d t o m ost r ec e nt 
I M i nj ecti o n Visit 
M 1 2, E O S  
L a b orat ory  
3. 3.  
S af ety  
LI V E R 1 4  
Sc att er Pl ot of M axi mu m vs. Bas elin e f or A L T  
G S K St atistic al Dis pl ay St a n d ar d  
M 1 2, E O S  
3. 4.  
S af ety  
LI V E R 9  
Sc att er Pl ot of M axi mu m T ot al Bilir u bi n vs M axi mu m A L T 
–  e DI S H Pl ot  
G S K St atistic al Dis pl ay St a n d ar d  
M 1 2, E O S  
C CI


 
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13.12.9. 
Other Tables 
Study Visit Length 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable  
4.1 
Safety 
OTR_T1 
Summary of Study Visit Length (minutes) by Visit, 
Country, and Site (Intervention Phase) 
Include overall summary for each 
visit and country. 
IA1, IA2, HL, M12 
4.2 
Safety 
OTR_T2 
Summary of Study Visit Length (minutes) by Visit and 
Subgroup (Intervention Phase) 
Include all subgroups listed in 
Section 5.4.2 except for Site & 
Country 
M12 
4.3 
Safety 
NS1 
Summary of Remote & Nursing Visits by Visit, Country, 
and Site  
Include overall summary for each 
visit and country. 
Add footnote: “All remote visits were 
recorded in response to missed 
visits due to Covid-19.” 
IA2, M12, EOS 
4.4 
Safety 
NS1 
Summary of Remote & Nursing Visits by Visit and 
Subgroup  
Include all subgroups listed in 
Section 5.4.2 except for Site & 
Country 
Add footnote: “All remote visits were 
recorded in response to missed 
visits due to Covid-19.” 
M12, EOS 
 


 
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13.12.10. ICH Listings 
ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Subject Disposition 
1.  
Enrolled 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm 
M12, EOS 
2.  
Enrolled 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm 
HL, M12, EOS 
Protocol Deviations 
3.  
Enrolled 
DV2 
Listing of Important Protocol Deviations 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm  
Add a column on the right for “COVID-
19 Related”. The possible values in this 
column are Y and N, where Y indicates 
the deviation is COVID-19 related and N 
indicates the deviation is non-COVID-19 
related. 
IA1, IA2, M12, 
EOS 
4.  
Enrolled 
DV2 
Listing of Protocol Deviations Related to COVID-19  
Add column for Phase, Visit, and 
Implementation arm 
HL, M12, EOS 
5.  
Enrolled 
DV2 
Listing of Implementation Science Protocol Deviations  
Add column for Phase, Visit, and 
Implementation arm 
HL, M12, EOS 
6.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
M12 
Populations Analysed 
7.  
Enrolled 
SP3 
Listing of Subjects Excluded from Safety Population 
ICH E3 
M12 


 
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ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Demographic and Baseline Characteristics 
8.  
Safety 
DM2 
Listing of Demographic Characteristics 
ICH E3 
M12 
9.  
Safety 
DM9 
Listing of Race 
ICH E3 
M12 
Efficacy 
10.  
Safety 
SNAPSHOT11 
Listing of Qualitative and Quantitative Plasma HIV-1 RNA 
Data 
 
HL, M12 
11.  
Safety 
SNAPSHOT12 
Listing of Study Outcome (50 copies/mL cutoff) at Month 12 
– Snapshot Analysis 
 
HL, M12 
12.  
Safety 
VF4 
Listing of Plasma HIV-1 RNA and CD4+ Cell Count for 
subjects with Confirmed Virologic Failure 
 
M12, EOS 
Exposure and Treatment Compliance 
13.  
Safety 
207966/primary_15/L12 Listing of Exposure Data 
ICH E3 
Remove Phase Day 
M12 
Adverse Events 
14.  
Safety 
AE8  
Listing of All Adverse Events 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm; see 
gsk1265744/mid207966/primary_15/L19 
HL, M12 
15.  
Safety 
AE8  
Listing of Grade 3-5 Adverse Events 
Add column for Phase, Visit, and 
Implementation arm; see 
gsk1265744/mid207966/primary_15/L19 
M12  
16.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
M12 
17.  
Safety 
201584/primary_07/L22 Listing of Changes in Intensity/Grades of Study Drug 
Injection Site Adverse Events 
Remove phase treatment, add visit 
M12, EOS 


 
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ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
18.  
Safety 
AE8  
Listing of COVID-19 Adverse Events 
Add column for Phase, Visit, and 
Implementation arm; see 
gsk1265744/mid207966/primary_15/L19 
Include Y/N column checked if the AE 
lead to discontinuation 
HL, M12 
19.  
Safety 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments 
Add column for Phase and Visit 
M12 
20.  
Safety 
PAN5 
Country Level Listing of Start Dates of COVID-19 
Pandemic Measures   
 
M12, EOS 
Serious and Other Significant Adverse Events 
21.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm 
M12 
22.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm 
M12, EOS 
23.  
Safety 
AE8  
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment 
ICH E3 
Add column for Phase, Visit, and 
Implementation arm 
M12, EOS 
Laboratory 
24.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
Add Category, Phase/Period, Visit 
M12 
 


 
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13.12.11. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition  
25.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
M12 
26.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
M12 
27.  
Enrolled 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
During the Oral Lead-in Period 
Add column for Visit and 
Implementation arm 
M12 
28.  
Safety 
TA1 
Listing of Planned and Actual Treatments by 
Implementation Arm 
GSK Statistical Display Standard 
M12 
29.  
Safety 
TA1 
Listing of Subjects with Missed Visits Due to Covid-19 by 
Implementation Arm 
Add a column indicating whether a 
remote visit was performed (Y/N) 
M12, EOS 
Prior and Concomitant Medications 
30.  
Safety 
207966/primary_15/Listing 
36 
Listing of Prior ART Medications 
Remove the column ‘Phase during 
Which Concomitant’ 
M12 
31.  
Safety 
207966/primary_15/Listing 
37 
Listing of Concomitant ART Medications 
Add column for Phase, Visit, and 
Implementation arm  
Add a column specifying “SOC Oral 
Bridging?” which has values of 
“Yes” and “No”. 
HL, M12, 
EOS 
32.  
Safety 
207966/primary_15/Listing 
38 
Listing of ART Medications Received during Long-term 
Follow-up Phase 
Remove the column ‘Phase during 
Which Concomitant’ 
M12, EOS 
Medical History 
33.  
Safety 
201584/primary_01/L43 
Listing of Medical History of Seizure 
 
M12 
 
 


 
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Efficacy 
34.  
Safety 
CDC4 
Listing of CDC Classification of HIV-1 Infection at 
Baseline 
 
M12 
35.  
Safety 
CDC5 
Listing of CDC Stage 3 HIV-1 Associated Conditions  
Add column for Phase, Visit 
M12, EOS 
Exposure 
36.  
Safety 
EX3 
Listing of Actual Visit Dates and Day Since Last Dose 
Add column for implementation arm 
IA1, IA2, 
M12, EOS 
37.  
Safety 
207966/primary_15/L60 
Listing of Oral Bridging Exposure Data 
Add visit to phase. Add column for 
implementation arm and to identify 
COVID relatedness. 
HL, M12, 
EOS 
38.  
Safety 
207966/primary_15/L60 
Listing of Exposure Data for Subjects Who Received Oral 
Bridging 
Add visit to phase. Add columns for 
implementation arm, Total Volume 
Injected / Duration of Oral 
Treatment 
M12 
Hepatobiliary (Liver) 
39.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
GSK Statistical Display Standard 
Add column for Phase, Visit 
M12, EOS 
40.  
Safety 
LIVER15 
Liver Stopping Event Profile 
GSK Statistical Display Standard 
Add column for Phase, Visit 
M12, EOS 
41.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline 
GSK Statistical Display Standard 
Add column for Phase, Visit 
HL, M12, 
EOS 
42.  
Safety 
LB12 
Listing of ALT, AST, Bilirubin (including Total and Direct 
Bilirubin), INR, and ALP for Subjects Meeting 
Hepatobiliary Lab Abnormality Criteria 
Add column for Phase, Visit 
M12, EOS 
 
 


 
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Other 
43.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Recorded 
ECG Data 
GSK Statistical Display Standard 
Add column for Phase, Visit 
M12 
44.  
Safety 
PREG1 
Listing of Subjects Who Became Pregnant During the 
Study 
GSK Statistical Display Standard 
Add column for Phase, Visit 
M12, EOS 
45.  
Safety 
201584/primary_17/L54 
Listing of Replication Capacity in IN and PR/RT Region 
Add column for Phase, Visit 
M12, EOS 
Vital Signs 
46.  
Safety 
VS5 
Listing of Vital Sign Results 
GSK Statistical Display Standard 
Required for ClinPharm studies 
only. 
M12 
Pharmacokinetic 
47.  
Safety 
PK07 
Listing of Plasma CAB Pharmacokinetic Concentration-
Time Data 
 
M12, EOS 
48.  
Safety 
PK07 
Listing of Plasma RPV Pharmacokinetic Concentration-
Time Data 
 
M12, EOS 
Pregnancy (conditional on incidence of pregnancy) 
49.  
Safety 
PREG_01 
Listing of Pregnancy Details and Outcomes 
Results to be pulled from the 
Pregnancy Notification Form 
EOS 
50.  
Safety 
PREG_02 
Listing of Pregnancy Outcomes 
Results to be pulled from the 
Pregnancy Follow-up Form 
EOS 
51.  
Safety 
207966/primary_15/Listing 
37 
Listing of Concomitant Medications for Pregnant 
Participants During and After Pregnancy 
Results should reconcile with the 
Pregnancy Notification and Follow-
up Forms 
Follow specifications for the current 
Listing 31 
EOS 
52.  
Safety 
SNAPSHOT11 
Listing of Qualitative and Quantitative Plasma HIV-1 RNA 
Data for Pregnant Participants 
Follow specifications for the current 
Listing 10 
EOS 
53.  
Safety 
207966/primary_15/L12 
Listing of Exposure Data for Pregnant Participants 
Follow specifications for the current 
Listing 13 
EOS 


 
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54.  
Safety 
AE8  
Listing of Adverse Events for Pregnant Participants 
During and After Pregnancy 
Follow specifications for the current 
Listing 14 
EOS 
55.  
Safety 
LB5A 
Listing of All Laboratory Data for Pregnant Participants 
During and After Pregnancy 
 
EOS 
56.  
Safety 
PK07 
Listing of Plasma CAB Pharmacokinetic Concentration-
Time Data for Pregnant Participants During and After 
Pregnancy 
Follow specifications for the current 
Listing 43 
EOS 
57.  
Safety 
PK07 
Listing of Plasma RPV Pharmacokinetic Concentration-
Time Data for Pregnant Participants During and After 
Pregnancy 
Follow specifications for the current 
Listing 44 
EOS 
 


 
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13.13. Appendix 13: Example Mock Shells for Data Displays 
Protocol: 213199                                                                                Page 1 of x 
Population: Safety 
                                                 Table DISP_T1 
                             Summary of Subject Disposition at Each Study Phase 
 
 
 
 
Study Phase 
 
CAB Oral + 
RPV Oral 
(N=100) 
CAB LA + RPV 
LA 
(N=100) 
Total 
(N=200) 
 
 
 
 
 
Intervention Phase 
ENTERED 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
COMPLETED 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
WITHDRAWN 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  COVID-19 RELATED 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Completed Intervention 
Phase but Withdrew Prior 
to Extension Phase 
ENTERED 
 
 
xx (xx.x%) 
 
COMPLETED 
 
 
xx (xx.x%) 
 
WITHDRAWN 
 
 
xx (xx.x%) 
 
  COVID-19 RELATED 
 
 
xx (xx.x%) 
 
 
 
 
 
Extension Phase 
ENTERED 
 
 
xx (xx.x%) 
 
COMPLETED 
 
 
xx (xx.x%) 
 
WITHDRAWN 
 
 
xx (xx.x%) 
 
  COVID-19 RELATED 
 
 
xx (xx.x%) 
 
 
 
 
 
Long-term Follow-up Phase ENTERED 
 
 
xx (xx.x%) 
 
COMPLETED 
 
 
xx (xx.x%) 
 
WITHDRAWN 
 
 
xx (xx.x%) 
 
  COVID-19 RELATED 
 
 
xx (xx.x%) 


 
C O N FI D E N TI A L  
 
 
2 1 3 1 9 9  
 
1 3 6  
 
 
 
I n t e r v e n t i o n / E x t e n s i o n  p h a s e  s t a t u s  a n d  r e a s o n  f o r  w i t h d r a w a l  i s  b a s e d  o n  d a t e  a n d  r e a s o n  c o l l e c t e d  i n  
t h e  s t u d y  t r e a t m e n t  d i s c o n t i n u a t i o n  f o r m .  
A  s u b j e c t  i s  c o n s i d e r e d  t o  h a v e  e n t e r e d  t h e  E x t e n s i o n  p h a s e  i f  t h e  s u b j e c t  r e c e i v e d  a  M o n t h  1 4  i n j e c t i o n  
o r  h a d  a n y  a s s e s s m e n t s  c o l l e c t e d  a t  a n y  E x t e n s i o n  p h a s e  n o m i n a l  v i s i t .  
A  s u b j e c t  i s  c o n s i d e r e d  t o  h a v e  e n t e r e d  t h e  L o n g - t e r m  F o l l o w - u p  p h a s e  i f  t h e y  h a v e  r e c e i v e d  a t  l e a s t  o n e  
C A B  a n d / o r  R P V  i n j e c t i o n  a n d  h a v e  s t a r t e d  L o n g - t e r m  F o l l o w - u p  A R T  
L o n g - t e r m  F o l l o w - u p  c o m p l e t i o n / w i t h d r a w a l  i s  b a s e d  o n  d a t a  c o l l e c t e d  i n  t h e  S t u d y  C o n c l u s i o n  f o r m .  
 / a r e n v / a r p r o d / g s k 1 2 6 5 7 4 4 / m i d 2 0 9 4 9 3 / p r i m a r y _ 0 1 / d r i v e r s / t _ s p _ s d _ p h a s e . s a s  0 2 F E B 2 0 2 1  1 1 : 5 8  
P P D


 
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Protocol: 213199                                                                                                    
Page 1 of x 
Population: Safety 
Table DISP_T2 
Summary of Reasons for Withdrawal at Each Study Phase 
 
 
 
Phase 
 
 
Primary Reason[1]/Subreason[2] for Withdrawal 
CAB Oral + RPV 
Oral 
(N=100) 
CAB LA + RPV 
LA 
(N=100) 
Total 
(N=200) 
Intervention 
Phase 
  ADVERSE EVENT 
 xx (xx.x%) 
 xx (xx.x%) 
xx (xx.x%) 
 
    COVID-19 RELATED 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
  LACK OF EFFICACY 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  PROTOCOL DEVIATION 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
    COVID-19 RELATED 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
    PROHIBITED MEDICATION USE 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
    NON-COMPLIANCE WITH STUDY TREATMENT 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
  SUBJECT REACHED PROTOCOL-DEFINED STOPPING 
CRITERIA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  STUDY TERMINATED BY SPONSOR  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  LOST TO FOLLOW-UP 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  INVESTIGATOR SITE CLOSED 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  PHYSICIAN DECISION 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  WITHDRAWAL BY SUBJECT  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
    COVID-19 RELATED 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
    FREQUENCY OF INJECTIONS 
  x  (xx.x%) 
  x  (xx.x%) 
x  (xx.x%) 
 
 
 
 
 
Long-term 
Follow-up 
Phase 
  LOST TO FOLLOW-UP 
 
 
xx (xx.x%) 
 
  WITHDRAWAL BY SUBJECT 
 
 
xx (xx.x%) 
 
    SUBJECT RELOCATED 
 
 
x  (xx.x%) 


 
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138 
 
 
    BURDEN OF PROCEDURES 
 
 
x  (xx.x%) 
 
[1] Subjects may have only one primary reason. 
[2] 
Percentages for subreasons may sum to more or less than 100%. Subjects may have more than one sub-
reason underneath a single primary reason. Subjects are not required to indicate subreasons. 
Intervention/Extension phase: status and reason for withdrawal based on date and reason collected in the 
study treatment discontinuation form. Long term Follow-up: completion/withdrawal based on data collected 
in the Study Conclusion form. 
 
 


 
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Protocol: 213199                                                                                Page 1 of 1 
Population: Safety 
 
Table EFF_T1 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 (Intervention Phase) 
- Snapshot Analysis 
 
Q4W IM 
Outcome 
(N=xx) 
HIV-1 RNA<50 c/mL 
xx (xx%) 
HIV-1 RNA>=50 c/mL 
  Data in window not below threshold  
xx (xx%) 
xx (xx%) 
Discontinued for lack of efficacy 
xx (xx%) 
Discontinued for other reason while not below threshold 
xx (xx%) 
  Change in ART [1] 
xx (xx%) 
No Virologic Data 
xx (xx%) 
  Discontinued study due to AE or Death 
xx (xx%) 
  Discontinued study for Other Reasons 
xx (xx%) 
  On study but missing data in window 
xx (xx%) 
[1] Excludes CAB + RPV Oral Bridging and COVID-19 related temporary oral bridging with SOC. 
 
 


 
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Protocol: mid213199                                                                                Page 1 of 1 
Population: Safety 
 
Table EFF_T2 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 (Intervention Phase) 
- Snapshot Analysis 
 
Q4W IM 
Outcome 
(N=xx) 
HIV-1 RNA<50 c/mL 
xx (xx%) 
HIV-1 RNA>=50 c/mL 
 Data in window not below threshold  
xx (xx%) 
xx (xx%) 
  Non-COVID-19 related 
xx (xx%) 
  Discontinued for lack of efficacy 
xx (xx%) 
  Discontinued for other reason while not below threshold 
xx (xx%) 
COVID-19 related 
xx (xx%) 
  Discontinued for lack of efficacy 
xx (xx%) 
  Discontinued for other reason while not below threshold 
xx (xx%) 
 Change in ART [1] 
xx (xx%) 
No Virologic Data 
xx (xx%) 
  Non-COVID-19 related 
xx (xx%) 
    Discontinued study due to AE or Death 
xx (xx%) 
    Discontinued study for Other Reasons 
xx (xx%) 
    On study but missing data in window 
xx (xx%) 
  COVID-19 related  
    Discontinued study due to AE or Death 
xx (xx%) 
xx (xx%) 
    Discontinued study for Other Reasons 
xx (xx%) 
    On study but missing data in window 
xx (xx%) 
[1] Excludes CAB + RPV Oral Bridging and COVID-19 related temporary oral bridging with SOC. 
 


 
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Protocol: mid213199                                                                                Page 1 of 1 
Population: Safety 
Table SAF_T1                                
Summary of Adherence to CAB LA + RPV LA Dosing Schedule by Visit, Country, Site, and COVID Impacted/Non-
Impacted (Intervention Phase)  
 
Country: xxxxx {Programmer’s Note: repeat for each of 5 countries overall, each individual site, and total} 
Site ID: xxxx  
COVID-19: xxx {non-impacted + impacted/non-impacted/impacted} 
 
Timeliness of Injections Relative to Date of 
Projected Dosing Visits 
Month 2 Month 4 Month 6 Month 8 Month 10 Month 12 Total 
 
 
 
 
 
 
 
 
No. of Expected Injection Visits 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 <-14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 -14 days to – 8 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 -7 days to – 1 days  
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 0 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 1 days to 7 days  
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 8 days to 14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 > 14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed 
Injection 
without 
OB 
(non-COVID-19 
related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection without OB (COVID-1 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection with OB (non-COVID-19 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection with OB (COVID-19 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 
 
 
 
 
 
 
 
Late Out of Window Injections (days outside +7 
day window) 
 
 
 
 
 
 
 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean  
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
Q1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Q3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Min 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 


 
CONFIDENTIAL 
 
 
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142 
 
Timeliness of Injections Relative to Date of 
Projected Dosing Visits 
Month 2 Month 4 Month 6 Month 8 Month 10 Month 12 Total 
Max 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 


 
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Protocol: mid213199                                                                                Page 1 of 1 
Population: Safety 
Table SAF_T2                                
Summary of Adherence to CAB LA + RPV LA Dosing Schedule by Visit, Subgroup, and COVID Impacted/Non-Impacted 
(Intervention Phase)  
 
Subgroup: xxxx {Programmer’s Note: repeat for each subgroup} 
COVID-19: xxx {Programmer’s Note: repeat for non-impacted + impacted/non-impacted/impacted} 
 
Timeliness of Injections Relative to Date of 
Projected Dosing Visits 
Month 2 Month 4 Month 6 Month 8 Month 10 Month 12 Total 
 
 
 
 
 
 
 
 
No. of Expected Injection Visits 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
 <-14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 -14 days to – 8 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 -7 days to – 1 days  
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 0 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 1 days to 7 days  
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 8 days to 14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 > 14 days 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed 
Injection 
without 
OB 
(non-COVID-19 
related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection without OB (COVID-1 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection with OB (non-COVID-19 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 Missed Injection with OB (COVID-19 related) 
xx (%) xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
xx (%) 
 
 
 
 
 
 
 
 
Late Out of Window Injections (days outside +7 
day window) 
 
 
 
 
 
 
 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Mean  
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
SD 
xxx.xx xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
Q1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Q3 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Min 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 


 
CONFIDENTIAL 
 
 
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Timeliness of Injections Relative to Date of 
Projected Dosing Visits 
Month 2 Month 4 Month 6 Month 8 Month 10 Month 12 Total 
Max 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Protocol: mid213199                                                                                               Page 1 of 1 
Population: Safety 
Table OTR_T1 
Summary of Study Visit Length (minutes) by Visit, Country, and Site 
Country 
 
Site 
N 
 
 
Month 1 
Month 2 
Month 6 
Month 8 
Total 
Overall 
 
Overall 
 
Lead Time n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q1 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q3 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Min. 
xx  
xx 
xx  
xx  
xx  
 
 
 
Max. 
xx  
xx 
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
 
Process 
Time 
n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q1 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q3 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Min. 
xx  
xx 
xx  
xx  
xx  
 
 
 
Max. 
xx  
xx 
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
 
Total 
Time 
n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Etc. 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
Lead Time = Actual Start Time of Appointment – Arrival Time.  


 
CONFIDENTIAL 
 
 
213199 
 
145 
 
Process Time = Actual End Time of Appointment – Actual Start Time of Appointment. 
[Programmers Note: repeat for each, country site, and total] 
 
 


 
CONFIDENTIAL 
 
 
213199 
 
146 
 
Protocol: mid213199                                                                                               Page 1 of 1 
Population: Safety 
 
Table OTR_T2 
Summary of Study Visit Length (minutes) by Visit and Subgroup 
Subgroup 
 
Strata 
N 
 
 
Month 1 
Month 2 
Month 6 
Month 8 
Total 
Sex 
 
Male 
 
Lead Time n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q1 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q3 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Min. 
xx  
xx 
xx  
xx  
xx  
 
 
 
Max. 
xx  
xx 
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
 
Process 
Time 
n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q1 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Q3 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Min. 
xx  
xx 
xx  
xx  
xx  
 
 
 
Max. 
xx  
xx 
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
 
Total 
Time 
n 
xxx  
xxx 
xxx  
xxx  
xxx  
 
 
 
Mean 
xx.x  
xx.xx 
xx.x  
xx.x  
xx.x  
 
 
 
SD 
xx.xx  
xx.xx 
xx.xx  
xx.xx  
xx.xx  
 
 
 
Median 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
 
 
 
Etc. 
xx.x  
xx.x 
xx.x  
xx.x  
xx.x  
Lead Time = Actual Start Time of Appointment – Arrival Time.  
Process Time = Actual End Time of Appointment – Actual Start Time of Appointment. 
[Programmers Note: repeat for each Subgroup and Strata] 
 
 


 
C O N FI D E N TI A L  
 
 
2 1 3 1 9 9  
 
1 4 7  
 
Pre g _ 0 1  
 
P r o t o c o l :  2 1 3 1 9 9
P a g e  1  o f  x
P o p u l a t i o n :  S a f e t y
L i s t i n g  4 9
( D a t a  a s  o f :  3 0 M A Y 2 0 1 1 )
L i s t i n g  o f  P r e g n a n c y  D e t a i l s
S i t e  I d . :  
U n i q u e  S u b j e c t  
I d . /
S u b j e c t  
I d . / I m p l e m e n t a t i o
n  A r m
M o t h e r ' s  
Y e a r  o f  
B i r t h
D a t e  o f  
L a s t  
M e n s t r u a l  
P e r i o d /
S t u d y  D a y
E s t i m a t e d  
D a t e  o f  
D e l i v e r y /
S t u d y  D a y
C o n t r a c e p t i o
n ? / C o n t r a c e p
t i o n  
T y p e / C o n c e p t
i o n  T y p e  
( N o r m a l ,  
I V F ) [ 1 ]
R e l e v a n t  L a b  
T e s t s  a n d  
P r o c e d u r e s
P r e - t e r m
F u l l - t e r m
A d d i t i o n a l  F a c r o r s  t h a t  
M a y  I m p a c t  P r e g n a n c y
/ C A B  L A  +  
R P V  L A  A R M - e
x x x x
2 0 1 2 - 
 
T 2 3 : 5 9 /
1
2 0 1 2 - 
 
T 2 3 : 5 9 /
1
Y / B i r t h  
C o n t r o l / N o r m
a l
A m n i o c e n t e s i
s  p e r f o r m e d  
S p o n t a n e o
u s  
A b o r t i o n  
( n ) :  x
N o r m a l  
B i r t h s  
( n ) :  x
E l e c t i v e  
A b o r t i o n  
( n ) :  x
S t i l l b i r t
h s  ( n ) :  x
O t h e r  
( n ) :  x
B o r n  
w / D e f e c t s  
( n ) :  x
/ C A B  L A  +  
R P V  L A  A R M - e
x x x x
2 0 1 2 - 
 
T 2 3 : 5 9 /
1
2 0 1 2 - 
 
T 2 3 : 5 9 /
1
N /  / N o r m a l
S p o n t a n e o
u s  
A b o r t i o n  
( n ) :  x
N o r m a l  
B i r t h s  
( n ) :  x
E l e c t i v e  
A b o r t i o n  
( n ) :  x
S t i l l b i r t
h s  ( n ) :  x
O t h e r  
( n ) :  x
B o r n  
w / D e f e c t s  
( n ) :  x
[ 1 ]  N o r m a l  c o n c e p t i o n  i n c l u d e s  t h e  u s e  o f  f e r t i l i t y  d r u g s .  I V F  =  i n  v i t r o  f e r t i l i z a t i o n .
/ D i r e c t o r y / p r o g r a m . s a s   0 1 J A N 2 0 0 2  1 2 : 0 1
N o .  o f  P r e v i o u s  
P r e g n a n c i e s
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
C O N FI D E N TI A L  
 
 
2 1 3 1 9 9  
 
1 4 8  
 
Pre g _ 0 2  
 
P r o t o c o l :  2 1 3 1 9 9
P a g e  1  o f  x
P o p u l a t i o n :  S a f e t y
L i s t i n g  5 0
( D a t a  a s  o f :  3 0 M A Y 2 0 1 1 )
L i s t i n g  o f  P r e g n a n c y  O u t c o m e s
S i t e  I d . :  
U n i q u e  S u b j e c t  
I d . /
S u b j e c t  
I d . / I m p l e m e n t a t i o
n  A r m
P r e g n a n c y  
S t a t u s  [ 1 ]
F o e t a l / N e o n a t a
l  S t a t u s  
( N o r m a l ,  B r i t h  
D e f e c t ,  O t h e r )
O r i g i n  o f  
B i r t h  
D e f e c t  
K n o w n ?
D a t e  o f  
B i r t h , m i s c a r r i a
g e , t e r m i n a t i o n  
/  S t u d y  D a y  /  
G e s t a t i o n a l  
W e e k s
I n f a n t  
S e x / L e n g t h  
( c m ) / W e i g h t  
( g )
A p g a r  S c o r e  
( 0 - 1 0 )  1 s t  
/  2 n d  
P r e g n a n c y  
D u r -
a t i o n
( d a y s ) [ 2 ]
A d d i t i o n a l  P r e g n a n c y  D e t a i l s
/ C A B  L A  +  
R P V  L A  A R M - e
D e l i v e r y :  
N o r m a l  
B i r t h  D e f e c t
Y e s  :  
x x x x
2 0 1 2 - 
 
T 2 3 : 5 9 /
1  /  3 8
M  /  5 0  /  
2 5 0 0
8 / 8
x x
C A B  L A  +  
R P V  L A  A R M - e
 
N A
N A
2 0 1 2 - 
 
T 2 3 : 5 9 /
1  /  3 6
N A
0
x x
S A E  d e l i v e r y  c o m p l i c a t i o n
[ 1 ]  S t a t u s  o p t i o n s  i n c l u d e  D e l i v e r y :  m e t h o d  s p e c i f i e d ,  S t i l l b i r t h ,  F o e t a l  d e a t h ,  S p o n t a n e o u s  a b o r t i o n ,  E l e c t i v e  a b o r t i o n ,  O t h e r :  s p e c i f i e d .
[ 2 ]  P r e g n a n c y  d u r a t i o n  c a l c u l a t e d  a s  D a t e  o f  B i r t h / M i s c a r r i a g e / T e r m i n a t i o n  -  D a t e  o f  L a s t  M e n s t r u a l  P e r i o d  +  1 .
/ D i r e c t o r y / p r o g r a m . s a s   0 1 J A N 2 0 0 2  1 2 : 0 1
P P D
P P D
P P D
P P D
P P D
P P D


Si g nat ure Pa ge f or  2 1 3 1 9 9 T M F- 1 5 2 1 3 7 1 1 v 1. 0
Si g nat ure Pa ge f or T M F- 1 5 2 1 3 7 1 1 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A
Date of si g nat ure: 1 2- Dec- 2 0 2 2 1 3: 4 0: 2 3 G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A
Date of si g nat ure: 1 2- Dec- 2 0 2 2 1 3: 4 4: 4 1 G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A
Date of si g nat ure: 1 2- Dec- 2 0 2 2 1 5: 3 0: 0 8 G M T + 0 0 0 0
P P D
P P D
P P D

Prot_000.pdf: 
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


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
2 
 
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 
 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
3 
 
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. 
 
 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
4 
 
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. 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
5 
 
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. 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
6 
 
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. 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
7 
 
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. 


TMF-13794092 
CONFIDENTIAL 
 
 
 
213199 
 
8 
 
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. 


TMF-13794092 
CONFIDENTIAL 
 
 
 
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9 
 
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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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  
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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 


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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  
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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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Potential Risk of 
Clinical 
Significance 
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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Potential Risk of 
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Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
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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Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
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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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
 
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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Mitigation Strategy 
 
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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Mitigation Strategy 
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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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 
weeks from the time of the last LA administration. 


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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 
consent. 


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Potential Risk of 
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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 + 
RPV LA injectable treatment. 


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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 
LA given every 4 weeks (Q4W) or every 8 weeks (Q8W), as compared to an oral 3-drug 


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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 
medical monitor for approval of SOC ART as oral bridging, confirm IM restart 


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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 
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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 
decision making on allowing a restart. 


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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 
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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 .  
 
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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.    
 
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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 
to assess the variability of responses by factors 


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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. 
• 
The participant must be informed that his/her medical records may be examined 
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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 
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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 
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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. 


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 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


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 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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11. 
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