A Phase 4, Randomized, Open-label, Two-arm Study Evaluating Implementation Strategies for the Delivery of Cabotegravir in Low and High-volume Pre-exposure Prophylaxis (PrEP) Sites in the U.S. for HIV Uninfected MSM and Transgender Men ≥ 18
Phase: PHASE4
Conditions: HIV Infections
Sponsor: ViiV Healthcare

TMF-15754477 
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ViiV Healthcare group of companies 
 
217710 
 
 
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Information Type: ViiV Healthcare Interventional Study Protocol 
Title: 
A Phase 4, randomized, open-label, two-arm study evaluating 
implementation strategies for the delivery of Cabotegravir in 
low and high-volume pre-exposure prophylaxis (PrEP) sites in 
the U.S. for HIV uninfected MSM and transgender men ≥ 18 
Protocol Number: 
217710/ Amendment 2 
Compound 
Number: 
GSK1265744, Cabotegravir 
Brief Title:  A study evaluating implementation strategies for the delivery of 
Cabotegravir in low and high-volume PrEP site in the U.S. 
Development Phase 
Phase 4 
Acronym:  PILLAR - PrEP Implementation Study for Cabotegravir Long Acting for 
Men in the Real World   
Sponsor Name and Legal Registered Address (excluding US): 
ViiV Healthcare UK Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
US IND Sponsor Legal Registered Address:  
ViiV Healthcare Company 
410 Blackwell Street 
Durham, NC 27701, USA 
Telephone: +1 919 438 2100 
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified 
as Sponsor must be agreed with the global ViiV Healthcare clinical team and signed 
off by the Senior Vice President, Head of Research & Development. 
This study is sponsored by ViiV Healthcare. GSK, Syneos Health and Evidera are 
supporting ViiV Healthcare in the conduct of this study. 
Marketing Authorisation Holder: 
ViiV Healthcare Company 
©2023 ViiV Healthcare and the GSK group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited 

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Regulatory Agency Identifying Number(s):   IND: 109,678 
Medical Monitor Name and Contact Information will be provided separately 
Sponsor Signatory 
Dr Annemiek de Ruiter 
VP & Head of Global Medical Sciences 
ViiV Global Medical 
 
Approval Date: 13 Apr 2023 

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Investigator Protocol Agreement Page 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study. 
• 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study. 
 
Investigator Name:  
_____________________________ 
 
 
 
 
Investigator Signature 
 
Date 
 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment [2] 
13 Apr 2023 
TMF-15754477 
Amendment [1] 
18-February-2022 
TMF-14446771 
Original Protocol (00) 
26-October-2021 
TMF-14064431 
 
Amendment [2] 13 Apr 2023  
Overall Rationale for the Amendment: The protocol has been updated to simplify the 
language used to describe primary, secondary and tertiary endpoints. The information 
removed from the endpoint descriptions was duplicated in the statistical analysis section 
and is more appropriate to be described there. Updates have also been made to the 
diversity targets of the study. Various clarifications to the schedules of assessments have 
been made based on site feedback and ViiV/GSK updated mandatory text has been 
incorporated where appropriate. All changes are considered non-substantial. 
Minor editorial changes for accuracy, clarity, formatting and consistency have been made 
throughout the document and are not included in the description(s) below 
Bold: Newly added text 

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Section 
Current text 
Proposed text 
Rationale for 
change 
Title 
 
ViiV Healthcare Company 
Five Moore Drive 
P.O. 13398 
Research Triangle Park, NC 27709-3398, USA 
 
Sponsor Signatory 
Dr Sherene Shakib Min, MD, MPH 
VP, Head of Clinical Development 
ViiV Research & Development 
 
 
 
ViiV Healthcare Company 
Five Moore Drive 
P.O. 13398 
Research Triangle Park, NC 27709-3398, USA 
410 Blackwell Street 
Durham, NC 27701, USA 
Telephone: +1 919 438 2100 
In some countries, local law requires that the 
Clinical Trial sponsor is a local company 
legal entity.  In these instances, the 
appropriate company to be identified as 
Sponsor must be agreed with the global ViiV 
Healthcare clinical team and signed off by the 
Senior Vice President, Head of Research & 
Development. 
This study is sponsored by ViiV Healthcare. 
GSK, Syneos Health and Evidera are 
supporting ViiV Healthcare in the conduct of 
this study. 
 
Sponsor Signatory 
Dr Annemiek de Ruiter 
VP & Head of Global Medical Sciences 
ViiV Global Medical 
 
Updated Sponsor 
address due to recent 
office relocation.  
 
Added mandatory 
ViiV protocol 
language that was 
omitted from 
previous version in 
error. 
 
Changed Sponsor 
Signatory to reflect 
recent internal 
responsibility 
changes. 
 

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2 – 
Objectives 
and 
Endpoints  
• Objectives 
• Endpoints 
• Primary 
• To evaluate 
feasibility of 
dynamic 
implementation 
(DI) compared to 
routine 
implementation 
(RI) for 
APRETUDE 
administration.  
• Staff study 
participants’ 
(SSPs) mean 
Feasibility of 
Intervention 
Measure (FIM) 
score at M131 by 
study arm, and 
clinic 
characteristics 
(e.g., volume). 
• Secondary  
• To evaluate 
change in 
feasibility of RI 
and DI for 
APRETUDE 
administration 
• Change from 
baseline in SSPs’ 
FIM score at M5 
and M13 by study 
arm and clinic 
characteristics. 
• SSPs perceptions 
of facilitators and 
barriers to RI and 
DI and overall 
implementation of 
PrEP into routine 
• Objectives 
• Endpoints 
• Primary 
• To evaluate 
feasibility of 
dynamic 
implementation 
(DI) compared to 
routine 
implementation 
(RI) for 
APRETUDE 
administration.  
• Staff study 
participants’ 
(SSPs) mean 
Feasibility of 
Intervention 
Measure (FIM) 
score at M131 by 
study arm, and 
clinic 
characteristics 
(e.g., volume). 
• Secondary  
• To evaluate 
change in 
feasibility of RI 
and DI for 
APRETUDE 
administration 
• Change from 
baseline in SSPs’ 
FIM score at M5 
and M13 by study 
arm and clinic 
characteristics. 
• SSPs perceptions 
of facilitators and 
barriers to RI and 
DI and overall 
implementation of 
PrEP into routine 
Multiple endpoints 
have been simplified 
to remove 
information that was 
duplicated in the 
statistical analysis 
section of the 
protocol. 
One new tertiary 
endpoint has been 
added. 

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care assessed by 
semi-structured 
qualitative 
interviews (SSIs), 
implementation 
science 
questionnaire 
(ISQ), FRAME-IS, 
implementation 
monitoring calls 
(IMC)and 
facilitation calls 
through M13. 
• To evaluate 
feasibility and 
acceptability of 
APRETUDE for 
MSM and TGM. 
• Patient Study 
Participants’ 
(PSPs) mean FIM 
and Acceptability 
of Intervention 
Measure (AIM) 
scores as well as IS 
questionnaire 
responses at BL, 
M7(OLI)/M6(DTI) 
and 
M13(OLI)/M12(D
TI) and by study 
arm, clinic 
characteristics, 
initiation method 
(e.g., OLI vs. DTI) 
care assessed by 
semi-structured 
qualitative 
interviews (SSIs), 
implementation 
science 
questionnaire 
(ISQ), FRAME-
IS, 
implementation 
monitoring calls 
(IMC)and 
facilitation calls 
through M13. 
• To evaluate 
feasibility and 
acceptability of 
APRETUDE for 
MSM and TGM. 
• Patient Study 
Participants’ 
(PSPs) mean FIM 
and Acceptability 
of Intervention 
Measure (AIM) 
scores as well as 
IS 
implementation 
science 
questionnaire 
(ISQ) responses at 
BL, 
M7(OLI)/M6(DTI
) and 
M13(OLI)/M12(D

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and patient 
subgroups (e.g., 
race/ethnicity, 
gender). 
• Change from 
baseline in PSPs’ 
AIM and FIM 
scores as well as IS 
questionnaire 
responses FIM 
score at 
M7(OLI)/M6(DTI) 
and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, and 
patient subgroups 
• PSPs perception of 
facilitators and 
barriers to 
feasibility and 
acceptability of 
APRETUDE by 
SSI through 
M13(OLI)/M12(D
TI) by patient 
subgroups 
TI) and by study 
arm, clinic 
characteristics, 
initiation method 
(e.g., OLI vs. 
DTI) and patient 
subgroups (e.g., 
race/ethnicity, 
gender). 
• Change from 
baseline in PSPs’ 
AIM and FIM 
scores as well as 
ISQ questionnaire 
responses FIM 
score at 
M7(OLI)/M6(DTI
) and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, 
and patient 
subgroups.  
• PSPs perception 
of facilitators and 
barriers to 
feasibility and 
acceptability of 
APRETUDE by 

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• To evaluate 
feasibility and 
acceptability of 
telehealth delivery 
for APRETUDE 
administration by 
clinical staff.  
• SSPs’ mean FIM 
and AIM scores as 
well as IS 
questionnaire 
responses for 
telehealth delivery 
at BL, M5 and 
M13 by study arm 
and clinic 
characteristics. 
• Change from 
baseline in SSPs’ 
FIM and AIM 
score as well as IS 
questionnaire 
responses for 
telehealth delivery 
at M5 and M13 by 
study arm and 
clinic 
characteristics. 
• PSPs’ mean FIM 
and AIM scores as 
well as IS 
questionnaire 
responses for 
telehealth delivery 
at BL, 
M7(OLI)/M6(DTI) 
SSI through 
M13(OLI)/M12(D
TI) by patient 
subgroups. 
• To evaluate 
feasibility and 
acceptability of 
telehealth delivery 
for APRETUDE 
administration by 
clinical staff.  
• SSPs’ mean FIM 
and AIM scores as 
well as ISQ 
questionnaire 
responses for 
telehealth delivery 
at BL, M5 and 
M13 by study arm 
and clinic 
characteristics. 
• Change from 
baseline in SSPs’ 
FIM and AIM 
score as well as 
ISQ questionnaire 
responses for 
telehealth delivery 
at M5 and M13 by 
study arm and 
clinic 
characteristics. 
• PSPs’ mean FIM 
and AIM scores as 
well as ISQ 
questionnaire 

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and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, and 
patient subgroups. 
• Change from 
baseline in PSPs’ 
FIM and AIM 
scores as well as 
ISQ responses for 
telehealth delivery 
at 
M7(OLI)/M6(DTI) 
and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, and 
patient subgroups 
• SSPs and PSPs 
perception of 
facilitators and 
barriers to 
feasibility and 
acceptability of 
telehealth use 
assessed by semi-
structured 
qualitative 
responses for 
telehealth delivery 
at BL, 
M7(OLI)/M6(DTI
) and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, 
and patient 
subgroups. 
• Change from 
baseline in PSPs’ 
FIM and AIM 
scores as well as 
ISQ responses for 
telehealth delivery 
at 
M7(OLI)/M6(DTI
) and 
M13(OLI)/M12(D
TI) by study arm, 
clinic 
characteristics, 
and patient 
subgroups 
• SSPs and PSPs 
perception of 
facilitators and 
barriers to 

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interviews (SSIs), 
FRAME-IS and 
facilitation calls 
through M13 and 
M13(OLI)/M12(D
TI), by patient 
subgroups, 
respectively 
• To evaluate 
acceptability and 
utility of DI 
compared to RI 
for APRETUDE 
administration 
• SSPs’ mean AIM 
score and IS 
questionnaire 
responses at BL, 
M5 and M13 by 
study arm, clinic 
characteristics and 
implementation 
strategy 
• Change from 
baseline in SSPs’ 
AIM score and IS 
questionnaire 
responses at M5 
and M13 by study 
arm, clinic 
characteristics and 
implementation 
strategy 
• PSPs’ mean AIM 
score and ISQ 
feasibility and 
acceptability of 
telehealth use 
assessed by semi-
structured 
qualitative 
interviews (SSIs), 
FRAME-IS and 
facilitation calls 
through M13 and 
M13(OLI)/M12(D
TI), by patient 
subgroups, 
respectively 
• To evaluate 
acceptability and 
utility of DI 
compared to RI 
for APRETUDE 
administration 
• SSPs’ mean AIM 
score and ISQ 
questionnaire 
responses at BL, 
M5 and M13 by 
study arm, clinic 
characteristics and 
implementation 
strategy 
• Change from 
baseline in SSPs’ 
AIM score and 
ISQ questionnaire 
responses at M5 
and M13 by study 

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responses by 
implementation 
strategy (e.g., 
transportation 
support, designated 
injection days) at 
BL, 
M7(OLI)/M6(DTI)
. and 
M13(OLI)/M12(D
TI) 
• Proportion of SSPs 
and PSPs that 
respond in 
agreement on 
relevant items on 
the ISQ that each 
implementation 
strategy is fit for 
use through M13 
and 
M13(OLI)/M12(D
TI), respectively, 
and by study arm, 
clinic 
characteristics and 
patient subgroups 
• SSPs perceptions 
of utility of 
implementation 
arm, clinic 
characteristics and 
implementation 
strategy 
• PSPs’ mean AIM 
score and ISQ 
responses by 
implementation 
strategy (e.g., 
transportation 
support, 
designated 
injection days) at 
BL, 
M7(OLI)/M6(DTI
). and 
M13(OLI)/M12(D
TI) 
• Proportion of 
SSPs and PSPs 
that respond in 
agreement on 
relevant items on 
the ISQ that each 
implementation 
strategy is fit for 
use through M13 
and 
M13(OLI)/M12(D
TI), respectively, 

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strategies and 
facilitators and 
barriers to 
acceptability of RI 
and DI through 
SSIs, ISQ 
FRAME-IS, IMC, 
and facilitation 
calls through M13 
and by SSP 
characteristics 
• PSPs perceptions 
of utility of 
implementation 
strategies through 
SSIs through M13 
and by patient 
subgroups  
• To evaluate 
fidelity to 
injection and 
dosing window 
• Proportion of 
injections 
occurring within 
target window 
from target date (- 
7 days for Injection 
dose 2 and ± 7 
days of target date 
for subsequent 
injections) through 
M13 and by study 
and by study arm, 
clinic 
characteristics and 
patient subgroups 
• SSPs perceptions 
of utility of 
implementation 
strategies and 
facilitators and 
barriers to 
acceptability of RI 
and DI through 
SSIs, ISQ 
FRAME-IS, IMC, 
and facilitation 
calls through M13 
and by SSP 
characteristics 
• PSPs perceptions 
of utility of 
implementation 
strategies through 
SSIs through M13 
and by patient 
subgroups  
• To evaluate 
fidelity to 
• Proportion of 
injections 
occurring within 
target window 

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arm, clinic 
characteristics, and 
patient subgroups 
• Proportion of PSPs 
completing target 
number of 
injections through 
M13 and by patient 
subgroups 
• PSPs and SSPs 
perception of 
barriers and 
facilitators to 
fidelity to 
injections as 
assessed by SSIs, 
FRAME-IS, IMC, 
facilitation calls 
and ISQ through 
M13 and by patient 
and provider 
subgroups 
• To evaluate 
fidelity and reach 
of client Sexual 
Health 
Assessment  
• Proportion of 
MSM and TGM 
who take the 
Sexual Health 
Assessment 
through M13 and 
by clinic 
injection and 
dosing window 
from target date 
(± 7 days for 
target date of 
Injection dose 2 
and ± 7 days of 
target date for 
subsequent 
injections) 
through M13 and 
by study arm, 
clinic 
characteristics, 
and patient 
subgroups 
• Proportion of 
PSPs completing 
target number of 
injections through 
M13 and by 
patient subgroups 
• PSPs and SSPs 
perception of 
barriers and 
facilitators to 
fidelity to 
injections as 
assessed by SSIs, 
FRAME-IS, IMC, 
facilitation calls 
and ISQ through 

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characteristics, 
patient subgroups, 
and service 
delivery method 
(e.g., telehealth vs. 
face-to-face in 
clinic) 
• Proportion of 
MSM & TGM who 
report having had 
sex in the last 6 
months through 
M13 on the Sexual 
Health Assessment 
by service delivery 
method  
• Proportion of 
MSM & TGM who 
expressed interest 
in PrEP or never 
heard of PrEP out 
of those who report 
having had sex in 
the last 6 months 
through M13 by 
service delivery 
method 
• Proportion of PSPs 
who initiate 
M13 and by 
patient and 
provider 
subgroups 
• To evaluate 
fidelity and reach 
of client Sexual 
Health 
Assessment  
• Proportion of 
MSM and TGM 
who take the 
Sexual Health 
Assessment 
through M13 and 
by clinic 
characteristics, 
patient subgroups, 
and service 
delivery method 
(e.g., telehealth 
vs. face-to-face in 
clinic) 
• Proportion of 
MSM & TGM 
who report having 
had sex in the last 
6 months through 
M13 on the 
Sexual Health 
Assessment by 
service delivery 
method  

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APRETUDE after 
taking the Sexual 
Health Assessment 
through M13 and 
by clinic 
characteristics, 
patient subgroups, 
and service 
delivery method  
• SSPs and PSPs 
perceptions of 
Sexual Health 
Assessment 
assessed by SSIs, 
FRAME-IS, IMC, 
facilitation calls 
and ISQ through 
M13 and by patient 
and provider 
subgroups 
• To evaluate 
adaptations to any 
implementation 
strategies used in 
clinics to include 
but not limited to 
modifications to 
toolkits, RI and DI 
to support 
• SSIs, ISQ, 
FRAME-IS, IMC 
and facilitation 
calls with SSPs 
through M13 and 
SSIs and ISQ with 
PSPs through 
M13(OLI)/M12(D
TI) 
• Proportion of 
MSM & TGM 
who expressed 
interest in PrEP or 
never heard of 
PrEP out of those 
who report having 
had sex in the last 
6 months through 
M13 by service 
delivery method 
• Proportion of 
PSPs who initiate 
APRETUDE after 
taking the Sexual 
Health 
Assessment 
through M13 and 
by clinic 
characteristics, 
patient subgroups, 
and service 
delivery method  
• SSPs and PSPs 
perceptions of 
Sexual Health 
Assessment 
assessed by SSIs, 
FRAME-IS, IMC, 
facilitation calls 

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APRETUDE 
implementation 
• To evaluate switch 
from oral PrEP to 
APRETUDE 
• Proportion of PSPs 
with history of 
PrEP use that 
complete the 
Sexual Health 
Assessment and 
ISQ and start 
APRETUDE 
through M13 and 
by patient 
subgroups  
• PSPs reasons for 
choosing 
APRETUDE, 
including 
switching, as 
assessed by SSIs 
and ISQ 
questionnaires and 
by patient 
subgroups 
• To evaluate 
perceptions, 
barriers and 
facilitators with 
SSPs and PSPs 
• SSIs, ISQ, 
FRAME-IS, IMC 
and facilitation 
calls assessed with 
SSPs through M13 
and ISQ through 
M13 and by 
patient and 
provider 
subgroups 
• To evaluate 
adaptations to any 
implementation 
strategies used in 
clinics to include 
but not limited to 
modifications to 
toolkits, RI and DI 
to support 
APRETUDE 
implementation 
• Proportion of 
PSPs with history 
of PrEP use that 
complete the 
Sexual Health 
Assessment and 
ISQ and start 
APRETUDE 
through M13 and 
by patient 
subgroups  
• PSPs reasons for 
choosing 
APRETUDE, 
including 
switching, as 
assessed by SSIs 
and ISQ 
questionnaires and 
by patient 
subgroups 
• To evaluate 
switch from oral 
• Proportion of 
PSPs with history 

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and IS 
questionnaires and 
SSIs with PSPs 
through 
M13(OLI)/M12(D
TI) 
• Other / Tertiary 
PrEP to 
APRETUDE 
of PrEP use that 
complete the 
Sexual Health 
Assessment and 
ISQ and start 
APRETUDE 
through M13 and 
by patient 
subgroups  
• PSPs reasons for 
choosing 
APRETUDE, 
including 
switching, as 
assessed by SSIs 
and ISQ 
questionnaires and 
by patient 
subgroups 
• To evaluate 
perceptions, 
barriers and 
facilitators with 
SSPs and PSPs 
• SSIs, ISQ, 
FRAME-IS, IMC 
and facilitation 
calls assessed with 
SSPs through 
M13 and IS 
questionnaires and 
SSIs with PSPs 
through 
CCI

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M13(OLI)/M12(D
TI) 
• PSPs and SSPs 
perception of 
barriers and 
facilitators 
through M13. 
• Other / Tertiary 
CCI
CCI

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CCI

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CCI

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CCI

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CCI

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Section 3.2 
– Study 
Population 
Approximately 220 PSPs will be enrolled. 
We aim for a total of 50% of the enrolled 
PSPs to be Black and Latino. We also aim 
for a total of 2-4% of the enrolled PSPs to be 
TGM, at a minimum. The number of SSPs 
will vary by site and approximately 5 per site 
will be included. 
Approximately 220 PSPs will be enrolled. 
We aim for at least total of 50% of the 
enrolled PSPs to be Black and or Latino. We 
also aim for a total of 2-4% of the enrolled 
PSPs to be TGM, at a minimum. Of the 
total PSPs enrolled, we aim for at least 2-
4% to be TGM. The number of SSPs will 
vary by site and approximately 5 per site 
will be included. 
Text updated to 
clarify diversity 
targets of the study 
to ensure adequate 
enrolment of 
underrepresented 
populations. 
Section 
3.3.1 – 
PSPs 
PSPs meeting all eligibility criteria at the 
screening/enrolment visit will sign the 
informed consent form at the site or through 
virtual administration. Screen failures are 
defined as PSPs who consent to participate in 
the study but are not subsequently entered in 
the study. A minimum set of screen failure 
information will be collected including 
demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
PSPs meeting all eligibility criteria at the 
screening/enrolment visit will sign the 
informed consent form at the site or through 
virtual administration. Screen failures are 
defined as PSPs who consent to participate 
in the study but are not subsequently entered 
in the study. A minimum set of screen 
failure information will be collected 
including demography, screen failure details, 
eligibility criteria, and any serious adverse 
Clarified re-
screening options for 
potential PSPs who 
screen fail due to 
delays in benefits 
verification with no 
other screening 
procedures having 
been performed. Re-
screening for those 
CCI

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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 
ID number for every screening/re-screening 
event. SSPs will not be captured for screen 
failure reporting. 
events. Individuals who do not meet the 
criteria for participation in this study (screen 
failure) post benefits verification may be 
rescreened one time within 4 weeks of the 
date they were determined to have screen 
failed. Individuals who screen fail due to 
benefits verification exceeding the 90-day 
screening window, with no other 
screening assessments having been 
performed, may be rescreened once, to 
take place any time after benefits 
verification has been obtained original 
screening; informed consent will need to be 
reviewed and re-signed for each rescreen. 
Subjects will be issued a new ID number for 
every screening/re-screening event. SSPs 
will not be captured for screen failure 
reporting. 
potential PSPs will 
be permitted any 
time after benefits 
verification is 
confirmed. For any 
other screen failure 
reason, the 4-week 
window for re-
screening still 
applies.  
Section 
4.1.2 
Dynamic 
Implement
ation 
Detail information on the strategies is given 
in the SRM. 
Detail information on the strategies is given 
in the SRM. 
Text removed as 
information on 
strategies are 
captured by the 
implementation 
science vendor. 
Section 
4.1.3.1 – 
Group and 
1:1 
Facilitatio
n 
Group facilitation should occur quarterly, 
Group facilitation should occur quarterly, as 
needed. 
Added information 
to clarify when 
group facilitation 
should occur. 

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Section 5.6 
– 
Qualitativ
e Analyses 
Qualitative data collection and analyses for 
both SSPs and PSPs will be informed by the 
study frameworks – CFIR and Proctor 
outcomes framework. The qualitative data 
are embedded within the quantitative 
outcomes of the study for expansion and 
triangulation of data. 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 will be compiled and 
analyzed. The Implementation Science 
vendor will be responsible for coding all 
qualitative assessments for use in the 
evaluation of the study outcomes. 
Established procedures to enhance validity 
will be used, including development of an 
audit trail documenting analytical decisions, 
agreeing on a threshold for rater agreement, 
and documenting coding decisions. 
Qualitative data collection and analyses for 
both SSPs and PSPs will be informed by the 
study frameworks – CFIR and Proctor 
outcomes framework. SSPs and PSPs 
perceptions on implementation, including 
but not limited to facilitators and 
barriers, implementation of PrEP into 
routine care, quality of care, will be 
assessed by semi-structured qualitative 
interviews, implementation science 
questionnaire, FRAME-IS, 
implementation monitoring calls and 
facilitation calls. The qualitative data are 
embedded within the quantitative outcomes 
of the study for expansion and triangulation 
of data. 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 will be compiled and analyzed. The 
Implementation Science vendor will be 
responsible for coding all qualitative 
assessments for use in the evaluation of the 
study outcomes. Established procedures to 
enhance validity will be used, including 
development of an audit trail documenting 
analytical decisions, agreeing on a threshold 
for rater agreement, and documenting coding 
decisions. 
Added information 
on the types of 
assessments to be 
used to analyse SSP 
and PSPs 
perceptions on 
implementation. 

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Section 6.2 
Participan
t 
Confidenti
ality 
Section 
6.2.1 - 
PSPs 
Not applicable 
Collection of sex, race and ethnicity data 
is necessary to assess and monitor the 
diversity of the trial participants, in order 
to meet the study objectives and to 
determine if the trial participants are 
truly representative of the impacted 
population. 
Added new 
mandatory 
GSK/ViiV protocol 
text regarding 
collection of 
sensitive information 
such as sex, race and 
ethnicity data as part 
of the study. 
Section 6.3 
– 
Informed 
Consent 
Process 
The PrEP Provider or his/her representative 
will explain the nature of the study to the 
participant, or their legally authorized 
representative and answer all questions 
regarding the study.  
• PSPs must be informed that their 
participation is voluntary. PSPs 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.  
• 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 study 
The PrEP Provider or his/her representative will 
explain the nature of the study, including the 
risks and benefits, to the participant, or their 
legally authorized representative and answer all 
questions regarding the study.  
• Potential PSPs must be informed that 
their participation is voluntary. PSPs will 
be required to physically or 
electronically 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.  
• The medical record must include a 
statement that written physical or 
electronic informed consent was 
obtained before the participant was 
enrolled in the study and the date the 
Removed reference 
to written consent 
and added 
clarification that 
consent may be 
given either 
physically or 
electronically  

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site authorized person obtaining the 
informed consent must also sign the ICF. 
• PSPs must be re-consented to the most 
current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to 
the participant or their legally authorized 
representative. 
written physical or electronic consent 
was obtained.  The study site authorized 
person obtaining the informed consent 
must also sign the ICF. 
• PSPs must be re-consented to the most 
current version of the ICF(s) during their 
participation in the study.  
• A physical or electronic copy of the 
ICF(s) must be provided to the 
participant or their legally authorized 
representative. 
Section 
9.1.1 – 
Time 
Period and 
Frequency 
for 
Collecting 
AE and 
SAE 
Informatio
n 
• All SAEs will be collected from the 
signing of the informed consent form 
until the until the PSP completes or 
withdraws from the study. at the 
timepoints specified in the SoA 
(ANNEX 1 and ANNEX 2). AEs that 
begin during the oral lead-in and are 
considered by the PrEP Provider to be 
related to CAB PrEP will be recorded as 
a CAB PrEP related AE after obtaining 
the informed consent. 
• PrEP Providers are not obligated to 
actively seek information on AEs or 
SAEs after conclusion of the study 
participation. However, if the PrEP 
Provider learns of any SAE, including a 
death, at any time after a participant has 
• All AEs that meet the criteria for 
documentation listed in Section 9.1, and 
all SAEs will be collected from the 
signing of the informed consent form 
until the until the PSP completes or 
withdraws from the study. at the 
timepoints specified in the SoA 
(ANNEX 1 and ANNEX 2).  
• AEs that begin during the oral lead-in 
and are considered by the PrEP Provider 
to be related to CAB PrEP will be 
recorded as a CAB PrEP related AE after 
obtaining the informed consent. 
• A poststudy AE/SAE is defined as any 
event that occurs outside of the 
Section updated to 
incorporate new 
mandatory GSK 
protocol language 
for AE reporting.  

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been discharged from the study, and 
he/she considers the event to be 
reasonably related to the study 
intervention or study participation, the 
PrEP Provider must promptly notify the 
sponsor. 
AE/SAE reporting period defined 
earlier in this Section 9.1.1.  
• PrEP Providers are not obligated to 
actively seek information on AEs or 
SAEs after conclusion of the study 
participation. However, if the PrEP 
Provider learns of any SAE, including a 
death, at any time after a participant has 
been discharged from the study, the 
PrEP Provider must record it in the 
medical records. If the PrEP Provider 
and he/she considers the event to be 
reasonably related to the study 
intervention or study participation, the 
PrEP Provider must promptly notify the 
sponsor. 
Section 
11.1 
Annex 1: 
Schedule 
of 
Activities 
– direct to 
injection 
 
 
 
Section 
11.2 
2. Benefits verification should be performed at 
the start of the screening period, which may 
be extended up to 90 days to allow for this 
confirmation. Screening/eligibility 
procedures (excluding informed consent) 
should not be performed prior to receiving 
this confirmation. Additionally, in line with 
the USPI, all patient participants require 
proof of a negative HIV test, dated within 
the 7 days prior to PrEP initiation, regardless 
of any prior negative test results. During 
screening/enrollment, the following will be 
completed for PSPs: 1) Informed consent 
2. Benefits verification should be performed at 
the start of the screening period, which may 
be extended up to 90 days to allow for this 
confirmation. All other 
Sscreening/eligibility procedures (excluding 
informed consent) should not only be 
performed prior to after receiving this 
benefits confirmation. Additionally, in line 
with the USPI, all patient participants 
require proof of a negative HIV test, dated 
within the 7 days prior to PrEP initiation, 
regardless of any prior negative test results. 
During screening/enrollment, the following 
Based on feedback 
from sites, wording 
of this footnote has 
been clarified. PSPs 
should consent to the 
study and a benefits 
verification check 
should be completed 
and benefits 
confirmed before 
any other 
screening/eligibility 

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Annex 2: 
Schedule 
of 
Activities 
– Optional 
oral lead 
in 
form (ICF), 2) Benefits verification, as 
required, 3) Confirm Inclusion and 
Exclusion criteria, 4) Demography 5) 
Medical History, including history of HCV 
infection, and current medical conditions 6) 
required labs per clinical local standard of 
care. Screening/enrollment can occur on the 
same date as the first APRETUDE injection 
as long as a negative HIV test is documented 
within 7 days prior to initiation of 
APRETUDE. Refer to Section 3.3.1 for 
details on re-screening for PSPs who fail 
screening. 
Patient Study Participants 
Participants baseline questionnaires and 
interviews should be completed within two 
weeks prior to or on their D1 visit and before 
receiving the 1st APRETUDE injection. 
Approximately 3 participants per site will be 
interviewed; sites with larger volume of 
participants might have more interviews. 
Participants will be purposely sampled for 
interviews based on demographic characteristics, 
such as race/ethnicity, prior PrEP use. 
Participant Interviews Notes: 
Interviews will be completed on a subset of 
PSPs (see Section 4.1.3.1). Window within 2 
weeks before or 2 weeks following study visit. 
will be completed for PSPs: 1) Informed 
consent form (ICF), 2) Benefits verification, 
as required, 3) Confirm Inclusion and 
Exclusion criteria, 4) Demography 5) 
Medical History, including history of HCV 
infection, and current medical conditions 6) 
required labs per clinical local standard of 
care. Screening/enrollment can occur on the 
same date as the first APRETUDE injection 
as long as a negative HIV test is 
documented within 7 days prior to initiation 
of APRETUDE. Refer to Section 3.3.1 for 
details on re-screening for PSPs who fail 
screening. 
Patient Study Participants 
PSP baseline questionnaires and interviews 
should be completed within two weeks prior to 
or on their D1 visit and before receiving the 1st 
APRETUDE injection. 
 
Participants interviews should be completed 
within two weeks prior to or two weeks 
following their D1 visit and within two weeks 
prior to or two weeks following the target 
dates for their D4 and D7 visits. 
Approximately 3 participants per site will be 
interviewed; sites with larger volume of 
participants might have more interviews. 
Participants will be purposely sampled for 
interviews based on demographic 
procedure is 
performed. 
 
 
 
 
 
 
 
 
 
Removed and added 
text to clarify timing 
of participant 
questionnaires and 
interviews 

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Staff Study Participants 
For sites with both OLI and DTI participants, 
M4/M5 visit will be defined when at least 1 
participant, at their respective site, has 
completed their M4(DTI)/M5(OLI) study visit 
(Dose 3 visit), respectively, whichever comes 
first.  M12/M13 visit will be defined after at 
least 1 participant, at their respective site, has 
completed their M12(DTI)/M13(OLI) study visit 
(Dose 7 visit), whichever comes first. 
SSP questionnaires and/or interviews can be 
completed within 3 of study visits. 
characteristics, such as race/ethnicity, prior 
PrEP use.  
All additional study visits, including those 
where questionnaires and/or interviews are 
administered at M6 and M12, will be anchored 
off of each participants M1 visit, so it reflects 
months in study, regardless of what dose they 
are on and regardless of whether they have 
missed any injections and received oral PrEP. 
Staff Study Participants 
For sites with both OLI and DTI participants, 
M4/M5 visit will be defined by the target date 
when at least 1 participant, at their respective 
site, has completed their M4(DTI)/M5(OLI) 
study visit (Dose 3 visit), respectively, 
whichever comes first.  M12/M13 visit will be 
defined by the target date when at least 1 
participant, at their respective site, has 
completed their M12(DTI)/M13(OLI) study 
visit (Dose 7 visit), whichever comes first.  
Interim and final SSP questionnaires and/or 
interviews can be completed within 3 weeks 
prior to or 3 weeks after study visits. 

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Section 
11.4.5 
Reporting 
of SAE to 
the 
Sponsor – 
Subsection 
SAE 
Reporting 
to the 
Sponsor 
via 
Electronic 
Data 
Collection 
Tool 
Not applicable 
New bullet point: 
• If the site during the course of the study 
or poststudy becomes aware of any 
serious, nonserious AEs, pregnancy 
exposure, related to any GSK non-IMP 
they will report these events to GSK or to 
the concerned competent authority via the 
national spontaneous reporting 
system.  These will be classified as 
spontaneous ICSRs. 
This section has 
been updated to 
include new GSK 
mandatory protocol 
language. 

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TABLE OF CONTENTS 
PAGE 
1. 
BACKGROUND AND RATIONALE ........................................................................ 40 
1.1. 
Background ................................................................................................ 40 
1.2. 
Rationale .................................................................................................... 42 
1.3. 
Benefit/Risk Assessment ............................................................................ 43 
1.3.1. 
Overall Benefit: Risk Conclusion .................................................. 43 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................... 44 
3. 
RESEARCH DESIGN ............................................................................................. 51 
3.1. 
Study Design .............................................................................................. 51 
3.2. 
Study Population ......................................................................................... 52 
3.2.1. 
Eligibility Criteria .......................................................................... 53 
3.3. 
Study Groups and Duration ........................................................................ 54 
3.3.1. 
PSPs ........................................................................................... 54 
3.3.2. 
SSPs ........................................................................................... 55 
4. 
IMPLEMENTATION RESEARCH METHODS ........................................................ 58 
4.1. 
Study Arms Overview ................................................................................. 58 
4.1.1. 
Routine Implementation ............................................................... 58 
4.1.2. 
Dynamic Implementation ............................................................. 59 
4.1.3. 
Implementation Assessments ...................................................... 65 
4.1.4. 
Primary Endpoint ......................................................................... 69 
4.1.5. 
Telehealth Strategy ...................................................................... 69 
4.2. 
Scientific Rationale for Study Design and Research Methods ..................... 71 
4.2.1. 
Implementation Frameworks ........................................................ 71 
5. 
STATISTICAL CONSIDERATIONS ........................................................................ 73 
5.1. 
Statistical Hypotheses................................................................................. 73 
5.2. 
Study Size .................................................................................................. 73 
5.3. 
Essential Analysis ....................................................................................... 80 
5.4. 
Secondary Analysis .................................................................................... 81 
5.5. 
Other/Tertiary Endpoints ............................................................................. 84 
5.6. 
Qualitative Analyses ................................................................................... 86 
5.7. 
Limitations of the Research Methods .......................................................... 87 
6. 
PROTECTION OF HUMAN SUBJECTS ................................................................ 88 
6.1. 
Ethical Approval and Participant Consent ................................................... 88 
6.2. 
Participant Confidentiality ........................................................................... 88 
6.2.1. 
PSPs ........................................................................................... 88 
6.2.2. 
SSPs ........................................................................................... 89 
6.3. 
Informed Consent Process ......................................................................... 89 
7. 
CAB PREP AND CONCOMITANT THERAPY ........................................................ 90 
7.1. 
Missed APRETUDE Injections .................................................................... 90 
7.2. 
Treatment of an Overdose .......................................................................... 90 
7.3. 
Concomitant Therapy.................................................................................. 91 
8. 
DISCONTINUATION OF CAB PREP AND PARTICIPANT 
DISCONTINUATIONS ............................................................................................ 91 

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8.1. 
Discontinuation of CAB PrEP ...................................................................... 91 
8.2. 
Temporary Discontinuation ......................................................................... 91 
8.3. 
Participant Discontinuation / Withdrawal from the Study ............................. 92 
8.4. 
Lost to Follow-up ........................................................................................ 92 
9. 
SPECIFIC ADVERSE EVENTS, SERIOUS ADVERSE EVENTS (SAES) 
AND OTHER SAFETY REPORTING ..................................................................... 93 
9.1. 
Specific Adverse Events to be Documented in this Study ........................... 93 
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 94 
9.1.2. 
Method of Detecting AEs and SAEs ............................................. 95 
9.1.3. 
Follow-up of AEs and SAEs ......................................................... 95 
9.1.4. 
Regulatory Reporting Requirements for SAEs ............................. 95 
9.2. 
Safety Assessments ................................................................................... 95 
9.2.1. 
Clinical safety laboratory assessments ........................................ 96 
9.2.2. 
Liver Chemistry Monitoring .......................................................... 96 
9.3. 
Adverse Events (AEs), Pregnancy Exposure and Incident Reporting .......... 96 
9.3.1. 
Definition of adverse events ......................................................... 96 
9.3.2. 
Reporting of AEs and timelines .................................................... 97 
9.3.3. 
Pregnancy ................................................................................... 97 
9.3.4. 
Cardiovascular and Death Events ................................................ 98 
9.3.5. 
Medical Device Deficiencies ........................................................ 99 
10. REFERENCES ..................................................................................................... 100 
11. ANNEX ................................................................................................................. 103 
11.1. 
ANNEX 1: Schedule of Activities – Direct to injection ................................ 103 
11.2. 
ANNEX 2: Schedule of Activities – Optional oral lead in ........................... 112 
11.3. 
ANNEX 3. List of Stand-Alone Documents ................................................ 121 
11.4. 
ANNEX 4. AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 122 
11.4.1. 
Definition of AE .......................................................................... 122 
11.4.2. 
Definition of SAE ........................................................................ 124 
11.4.3. 
Definition of Cardiovascular Events ........................................... 125 
11.4.4. 
Recording and Follow-Up of AE and SAE .................................. 126 
11.4.5. 
Reporting of SAE to the Sponsor ............................................... 127 
11.5. 
ANNEX 5:  Medical device reporting Definition of Medical Device 
AE and ADE ............................................................................................. 129 
11.5.1. 
Definition of Device Deficiency ................................................... 129 
11.5.2. 
Reporting of Medical Device Deficiencies .................................. 129 
11.6. 
ANNEX 6:  COVID-19 Pandemic and Clinical Trial Continuity ................... 130 
11.6.1. 
Changes to Study Visits and Study Procedures ......................... 130 
11.6.2. 
Changes to Informed Consent ................................................... 130 
11.6.3. 
COVID-19 Specific Data Capture ............................................... 131 
11.7. 
ANNEX 7: Regulatory, Ethical and Study Oversight Considerations ......... 134 
11.7.1. 
Financial Disclosure ................................................................... 134 
11.7.2. 
Dissemination of Clinical Study Data ......................................... 134 
11.7.3. 
Data Quality Assurance ............................................................. 135 
11.7.4. 
Source Documents .................................................................... 136 
11.7.5. 
Study and Site Start and Closure ............................................... 136 
11.7.6. 
Publication Policy ....................................................................... 137 
11.8. 
ANNEX 8: Protocol Amendment History ................................................... 138 

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LIST OF ABBREVIATIONS  
AE 
adverse event 
AIM 
Acceptability of Intervention Measure 
ART 
Antiretroviral therapy 
CAB LA for PrEP  
(hereafter referred to as APRETUDE) 
CAB PrEP 
Oral Cabotegravir (CAB) tablets and CAB long acting 
(LA) extended-release suspension for injection for pre-
exposure prophylaxis (PrEP) 
CBO 
community-based organization 
CDC 
Centers for Disease Control and Prevention 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
COVID-19 
Coronavirus Disease of 2019 
DDI 
drug-drug interaction 
DI 
dynamic implementation 
DSMB 
Data and Safety Monitoring Board 
DTI 
direct to injection 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FDA 
Food and Drug Administration 
FIM 
Feasibility of Intervention Measure 
FTC 
Emtricitabine 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
HPTN 
HIV Prevention Trials Network 
HR 
Hazard ratio 
ICF 
informed consent form 
ID 
Identifier 
IM 
Intramuscular 
IMC 
Implementation monitoring calls 
IRB 
Institutional review board 
IS 
Implementation science 
ISQ 
Implementation science questionnaire 
ISF 
Investigator Site File 
LA 
long acting 
LMP 
Last menstrual period 
MSM 
men who have sex with men 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OLI 
oral lead-in 
PrEP 
pre-exposure prophylaxis 
PSP 
patient study participant 
RI 
routine implementation 

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RPV 
rilpivirine 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
Schedule of Activities 
SSI 
semi-structured interview 
SSP 
Staff study participant 
STI 
sexually transmitted infections 
TDF 
tenofovir disoproxil fumarate 
TGM 
Transgender men 
TGW 
Transgender women 
U.S. 
United States 
USPI 
United States Prescribing Information 
VHC 
ViiV Healthcare 
 
 
Trademark Information 
Trademarks of ViiV Healthcare  
 
Trademarks not owned by ViiV 
Healthcare 
APRETUDE 
 
NONE 
 

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Abstract 
Background/Rationale:  Oral Cabotegravir (CAB) tablets and CAB long acting (LA) 
extended-release suspension for injection for pre-exposure prophylaxis (PrEP) has been 
developed to reduce the risk of sexually acquired HIV-1 infection in at-risk individuals 
(adults and adolescents) weighing at least 35 kg, hereafter referred to as CAB PrEP. The 
blinded portion of both pivotal studies, HPTN 083 and HPTN 084, were stopped based 
on Data and Safety Monitoring Board (DSMB) review of available interim data.  HPTN 
083 demonstrated the efficacy of CAB LA when compared to daily, oral emtricitabine 
(FTC)/ tenofovir disoproxil fumarate (TDF) in cisgender men who have sex with men 
(MSM) and transgender women (TGW) who have sex with men and HPTN 084 
demonstrated the efficacy of CAB LA when compared to daily, oral FTC/TDF in 
cisgender women. 
CAB LA for PrEP (hereafter referred to as APRETUDE) will provide people who are at 
higher risk of HIV acquisition with a new prevention option. It also has several appealing 
features that could contribute to reducing disparities in HIV infections and PrEP 
utilization, including superiority vs a daily oral PrEP regimen (FTC/TDF), less frequent 
dosing and is more discreet; the latter may decrease stigma associated with daily dosing 
and a pill bottle. However, these features will not overcome the critical existing and new 
health delivery implementation challenges that must be rapidly addressed when 
introducing the first injectable HIV prevention option into real-world settings for 
populations vulnerable to HIV and their providers.  
Implementation of APRETUDE will require layering onto existing PrEP models of care 
(e.g., clinics and health centers) as well as expanding an injectable delivery to alternative 
models of care that are already used for oral PrEP (e.g., telemedicine-supported PrEP 
delivery and community-based organization delivered PrEP). 
In this study, an innovative set of implementation strategies will be used to address 
anticipated challenges associated with feasibility of APRETUDE delivery.  
Objectives: The primary objective is to evaluate the feasibility of dynamic 
implementation (DI) compared to routine implementation (RI) for APRETUDE 
administration. 
The secondary objectives include 
• To evaluate change in feasibility of RI and DI for APRETUDE administration  
• To evaluate feasibility and acceptability for APRETUDE for MSM and 
transgender men (TGM). 
• To evaluate feasibility and acceptability of telehealth delivery for APRETUDE 
administration by clinical staff.  
• To evaluate acceptability and utility of DI compared to RI for APRETUDE 
administration 
• To evaluate fidelity to injection and dosing window 

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• To evaluate fidelity and reach of client Sexual Health Assessments for 
APRETUDE 
• To evaluate adaptations to any implementation strategies used in clinics to 
include, but not limited to, modifications to toolkits, RI and DI to support 
APRETUDE implementation 
• To evaluate switch from oral PrEP to APRETUDE 
• To evaluate perceptions, barriers and facilitators with Staff Study Participants 
(SSPs) and Patient Study Participants (PSPs) 
Study Design:  This post-approval, Phase 4 study is designed to evaluate the impact of 
two implementation strategy conditions – dynamic implementation and routine 
implementation – on the feasibility of delivering APRETUDE in high and low volume 
current PrEP sites for MSM and TGM over 12 months. Approximately 18 sites will be 
randomized 2:1 in the Dynamic (DI) or Routine (RI) implementation arms. 
Randomization will occur at the level of study sites and the study will enroll the staff at 
the study site (who are enrolled as “Staff Study Participants”).  Approximately 220 HIV 
negative individuals will be enrolled once CAB PrEP is prescribed to them (“Patient 
Study Participants”); at least 50% will be Black or Latino. Patients Study Participants 
will start APRETUDE using commercial product as prescribed by the PrEP provider. The 
study will not use a central laboratory, and all laboratory assessments will be performed 
according to the Centers for Disease Control and Prevention (CDC) clinical management 
guidelines for PrEP [Centers for Disease Control and Prevention, 2021] and APRETUDE 
USPI using sites local laboratories [APRETUDE, 2021]. 
Sites randomized to RI will have access to the standard CAB LA for PrEP toolkits for 
providers and patients to use as needed. Sites randomized to DI will receive enhanced 
toolkits for providers and patients, a digital health end to end implementation strategy, 
and implementation facilitation.   
Implementation science methodology using both quantitative and qualitative measures 
will be used to assess the outcomes, to determine effective implementation strategies and 
to identify barriers and facilitators (including solutions). The implementation outcomes 
will be assessed from the perspectives of SSPs and PSPs.  Clinical data will be collected 
from PSPs to monitor safety and efficacy. 
Analysis Methods:  The primary endpoint in terms of feasibility is SSPs’ mean FIM 
score at Month 13 under Dynamic Implementation (DI) arm and Routine Implementation 
(RI) arm respectively, and the difference of SSPs’ mean FIM scores between two arms at 
Month 13. Descriptive statistics including 95% confidence intervals (CI) for these 
estimates will be displayed. A hypothesis test will be conducted to determine if the 
observed difference is statistically significant. To address the potential intra-cluster 
correlation effect due to the cluster randomization design, classical methods such as 
mixed effects linear regression model or Generalized Estimating Equations will be 
utilized. Besides the analysis on the subject level, the stratification analysis will be 
performed at the site level to evaluate the impact of the capacity of sites (high volume vs 
low volume) in responding to two implementation strategies imposed on SSPs. 
Exploratory analysis will be undertaken to assess the variability of responses by other 

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factors such as subset of implementation strategies. In addition to summary of FIM scores 
of SSPs at different timepoints, the change in FIM scores of each item from baseline will 
be analyzed at the designated timepoints. For the specific Telehealth implementation 
strategy on SSPs, the subgroup analysis on FIM scores including change from baseline 
will be conducted.  
The FIM scores of PSPs will be summarized in the same way as those of SSPs. In 
addition, subgroup analysis on PSPs will include factors such as demographic, baseline 
characteristics and initiation method. To address the potential differential dropout rates of 
PSPs between arms, appropriate imputation methods will be undertaken to handle 
missing data of different type. 
The analysis methods for the secondary endpoints of acceptability, utility, reach, fidelity 
and adaptations will be similar to that of the feasibility endpoints. 

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1. 
BACKGROUND AND RATIONALE 
1.1. 
Background 
Cabotegravir (CAB, GSK1265744) is an HIV-1 integrase strand transfer inhibitor 
(INSTI).  CAB, as one component of a dual antiretroviral maintenance therapy regimen 
in combination with the long acting (LA) formulation of rilpivirine (RPV LA- Janssen), 
has been approved in countries including the U.S., European Union (EU), Canada and 
Australia for the treatment of HIV-1 infection in adults.  Hereafter, CAB + RPV will be 
referred to as CAB Treatment. 
ViiV Healthcare has developed oral CAB tablets and CAB LA extended-release 
suspension for injection for pre-exposure prophylaxis (PrEP) to reduce the risk of 
sexually acquired HIV-1 infection in individuals (adults and adolescents) at higher risk of 
HIV acquisition weighing at least 35 kg, hereafter referred to as CAB PrEP.  As a 
component of the CAB PrEP regimen, CAB tablets (hereafter referred to as CAB tablets 
for PrEP) may be used as optional oral lead in (OLI) to assess tolerability of CAB prior to 
administration of CAB LA (hereafter referred to as APRETUDE) and as oral PrEP in 
individuals who will miss planned dosing with APRETUDE injection. 
Two pivotal studies, HPTN 083 and HPTN 084, have been conducted by the HIV 
Prevention Trials Network (HPTN) under Sponsorship of the Division of Acquired 
Immunodeficiency Syndrome (DAIDS), National Institute of Allergy and Infectious 
Diseases (NIAID)/ National Institutes of Health (NIH).  These studies are intended to 
assess the safety and efficacy of CAB PrEP when compared to the active comparator 
daily, oral tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC) for HIV PrEP in the 
most key affected populations globally (i.e., men who have sex with men (MSM) and 
transgender women (TGW) [enrolled in HPTN 083] and cisgender women [enrolled in 
HPTN 084]). 
The blinded portion of both pivotal studies were stopped based on Data and Safety 
Monitoring Board (DSMB) review of available interim data. On 14 May 2020 at a pre-
planned interim review of trial data, the DSMB recommended that the blinded phase of 
HPTN 083 be stopped due to the demonstration of efficacy of APRETUDE when 
compared to daily, oral FTC/TDF (Hazard Ration [HR] 0.34, two-sided superiority p = 
0.0005) in MSM and TGW and that participants randomized to the active FTC/TDF 
group be offered APRETUDE [HIV Prevention Trials Network, 2020a; Landovitz, 
2021]. On 05 November 2020 at a pre-specified interim analysis, the DSMB 
recommended that the blinded phase of HPTN 084 be stopped due to the demonstration 
of efficacy of APRETUDE when compared to daily, oral FTC/TDF (HR 0.11, two-sided 
superiority p = 0.000042) in cisgender women and that participants randomized to the 
active FTC/TDF group be offered APRETUDE [HIV Prevention Trials Network, 2020b]. 
On May 4, 2021, a New Drug Application was submitted to the US Food and Drug 
Administration (FDA) for CAB PrEP in the United States [ViiV Healthcare, 2021]. 
CAB PrEP will provide people who are at higher risk of HIV acquisition with a new 
prevention option and could contribute to reducing disparities in HIV infections and PrEP 
utilization. Of the 37,000 new cases of HIV infection in the US, 65% were among men 

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who have sex with men (MSM) and among all MSM, 67% of diagnoses were among 
African American/Black and Hispanic/Latino MSM [Centers for Disease Control and 
Prevention, 2021] 
Centers for Disease Control and Prevention, 2021; Centers for Disease Control and 
Prevention, 2018].  The Southern US accounted for 50% of all diagnoses of HIV 
infection among MSM, which the largest being among African American/Black (48%), 
followed by Hispanic/Latino (26%) and White (23%) MSM. In terms of PrEP, Centers 
for Disease Control and Prevention (CDC) reported PrEP awareness and use were lower 
in Black and Hispanic MSM as compared to White MSM [Jones, 2021; Kanny, 2019].  
The Southern US represented only 30 percent of all PrEP users despite accounting for 
more than half of new HIV diagnoses in the country [Sullivan, 2018]. Further, 3.2% of 
transgender men (TGM) are living with HIV but TGM has largely been left out of the 
HIV discourse [Centers for Disease Control and Prevention, 2019].  
The existing PrEP disparities are driven by several factors that affect effective 
implementation, including geography, stigma, medical mistrust, low perception of risk, 
low awareness of PrEP, lower prescribing behaviors in certain geographies, low 
healthcare system capacity and low health literacy [Trost, 2020; Jones, 2021; Sullivan, 
2018].  CAB PrEP has several appealing features that might overcome a few of these 
challenges, including superiority, more discretion, and less frequent dosing when 
compared to a daily oral PrEP regimen (FTC/TDF); CAB PrEP’s dosing frequency may 
decrease stigma associated with daily dosing and a pill bottle. However, these features 
will not overcome the critical existing and new health delivery implementation 
challenges that must be rapidly addressed when introducing the first injectable HIV 
prevention option into real-world settings for populations vulnerable to HIV and their 
providers.  
Implementation of CAB PrEP will require layering onto existing PrEP models of care 
(e.g., clinics and health centers) as well as expanding to alternative models of care (e.g., 
pharmacy-based PrEP, telemedicine-supported PrEP delivery and community-based 
organization delivered PrEP) in order to reach populations vulnerable to HIV, especially 
in the Southern US [Sullivan, 2018].  Community-based organizations (CBOs) have been 
critical to the delivery of HIV prevention methods, especially when provided with the 
right implementation supports, because of their reach and trusted relationship with 
populations who are vulnerable to HIV, including MSM [Smith, 2016]. Clinical CBOs 
are more prepared to support expansion of biomedical interventions than nonclinical 
CBOs [Smith, 2016]. The Coronavirus Disease of 2019 (COVID-19) pandemic has 
significantly expanded the use of alternative models of care. For example, in response to 
the COVID-19 pandemic, many clinical practices shifted non-essential in-person medical 
appointments online to reduce the spread of the virus and the rollout of the COVID-19 
vaccines has benefited from pharmacy delivery. These alternative models of care are 
being used for oral PrEP delivery [Hoth, 2019] and can likely be adopted to support the 
administration of CAB PrEP.  
As CAB PrEP is introduced to consumers, early development and implementation of 
strategies to addresses challenges associated with feasibility of its delivery will be 

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important to removing barriers to uptake and persistence by populations vulnerable to 
HIV.  
1.2. 
Rationale 
This post-approval, Phase 4 study is designed to evaluate the impact of two 
implementation strategy conditions – dynamic implementation and routine 
implementation – on the feasibility of delivering APRETUDE in high and low volume 
current PrEP sites for MSM and transgender men over 12 months. Volume will be 
defined using all clinic feasibility data. One or a combination of the following approaches 
will be considered: absolute PrEP volume; average number of established PrEP patients; 
PrEP to need ratio vs. clinic ratio; and established providers of PrEP services (e.g., hub, 
referral site) vs. new to PrEP sites.     
Clinical sites will be randomized 2:1 in the Dynamic (DI) or Routine (RI) 
implementation arms. Clinics randomized to RI will have access to the standard toolkits 
for providers and patients that will be available for APRETUDE to use as needed. Clinics 
randomized to DI will receive enhanced toolkits for providers and patients, a digital 
health end to end implementation strategy, and implementation facilitation.   
Implementation science methodology using both quantitative and qualitative measures 
will be used to assess whether DI as opposed to RI results in higher feasibility in 
delivering APRETUDE. The study will also evaluate reach, utility, fidelity to and 
acceptability of the implementation strategies; and identify barriers and facilitators to 
implementation. The implementation outcomes will be assessed from the perspectives of 
individuals receiving CAB PrEP who are enrolled as “Patient Study Participants” and the  
staff at the study site (who are enrolled as “Staff Study Participants”) -- see below for 
definitions of participants). Clinical data will be collected from Patient Study Participants 
to monitor safety and efficacy (Refer to Section 7; Section 8 and Section 9). 
There are two types of participants in the study: 
 
• “Patient Study Participants” (PSPs) will refer to individuals who are enrolled in 
the study and who will receive commercially available CAB PrEP via prescription 
from the PrEP provider (see below) at the corresponding site. PSPs will be 
monitored according to usual standard care for CAB PrEP recipients at the PrEP 
provider’s discretion. 
 
• “Staff Study Participants” (SSPs) will refer to site staff who are involved in 
administrative and clinical aspects of offering and administering PrEP to PSPs 
and participate in the staff study assessments. SSPs may include healthcare 
providers, nurses, staff performing injections, clinic administrators, pharmacists 
and laboratory staff (if labs are being done on site). The staff who will be 
recruited for participation in the study as SSPs will vary by site size, site structure, 
site workflow and staffing structure. As SSPs, they will complete implementation 
assessments on the implementation strategies at their site. At a minimum, SSPs at 
each site will include at least one qualified personnel (referred as “PrEP 

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provider”) who will prescribe PrEP regimens, including CAB PrEP, and be 
responsible for standard of care clinical management and protocol-specified 
assessments for PSPs during the duration of the study (Refer to Section 7 and 
Section 8).    
 
The study will examine the impact of the dynamic and routine implementation on the 
delivery of CAB PrEP in high and low volume current PrEP sites. As a result, the study 
will identify strategies that are or are not successful in the delivery of CAB PrEP. 
 
1.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of CAB PrEP may be found in the United 
States Prescribing Information [APRETUDE, 2021]. 
1.3.1. 
Overall Benefit: Risk Conclusion 
The results of this study are anticipated to be beneficial or useful for individuals receiving 
CAB PrEP and physicians providing CAB PrEP. 

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2. 
OBJECTIVES AND ENDPOINTS  
• Objectives 
• Endpoints 
• Primary 
• To evaluate feasibility of dynamic 
implementation (DI) compared to 
routine implementation (RI) for 
APRETUDE administration.  
• Staff study participants’ (SSPs) mean 
Feasibility of Intervention Measure 
(FIM) score at M131. 
• Secondary  
•  
• To evaluate change in feasibility of RI 
and DI for APRETUDE administration 
• Change from baseline in SSPs’ FIM 
score at M5 and M13. 
• SSPs perceptions of facilitators and 
barriers to RI and DI and overall 
implementation of PrEP into routine 
care assessed through M13. 
• To evaluate feasibility and 
acceptability of APRETUDE for MSM 
and TGM. 
• Patient Study Participants’ (PSPs) 
mean FIM and Acceptability of 
Intervention Measure (AIM) scores as 
well as implementation science 
questionnaire (ISQ) responses at BL, 
M7(OLI)/M6(DTI) and 
M13(OLI)/M12(DTI). 
• Change from baseline in PSPs’ AIM 
and FIM scores as well as ISQ 
responses FIM score at 
M7(OLI)/M6(DTI) and 
M13(OLI)/M12(DTI).  
• PSPs perception of facilitators and 
barriers to feasibility and acceptability 
of APRETUDE through 
M13(OLI)/M12(DTI). 
• To evaluate feasibility and 
acceptability of telehealth delivery for 
APRETUDE administration by clinical 
staff.  
• SSPs’ mean FIM and AIM scores as 
well as ISQ responses for telehealth 
delivery at BL, M5 and M13. 
• Change from baseline in SSPs’ FIM 
and AIM score as well as ISQ 
responses for telehealth delivery at 
M5 and M13 . 

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• Objectives 
• Endpoints 
• PSPs’ mean FIM and AIM scores as 
well as ISQ  responses for telehealth 
delivery at BL, M7(OLI)/M6(DTI) and 
M13(OLI)/M12(DTI)  
• Change from baseline in PSPs’ FIM 
and AIM scores as well as ISQ 
responses for telehealth delivery at 
M7(OLI)/M6(DTI) and 
M13(OLI)/M12(DTI). 
• SSPs and PSPs perception of 
facilitators and barriers to feasibility 
and acceptability of telehealth use 
through M13 and M13(OLI)/M12(DTI) 
respectively. 
• To evaluate acceptability and utility of 
DI compared to RI for APRETUDE 
administration 
• SSPs’ mean AIM score and ISQ 
responses at BL, M5 and M13 . 
• Change from baseline in SSPs’ AIM 
score and ISQ responses at M5 and 
M13. 
• PSPs’ mean AIM score and ISQ 
responses by implementation strategy 
at BL, M7(OLI)/M6(DTI). and 
M13(OLI)/M12(DTI) 
• Change from baseline in PSPs’ mean 
AIM score and ISQ responses by 
implementation strategy at 
M7(OLI)/M6(DTI) and 
M13(OLI)/M12(DTI) 
• Proportion of SSPs and PSPs that 
respond in agreement on relevant 
items on the ISQ that each 
implementation strategy is fit for use 
through M13 and M13(OLI)/M12(DTI), 
respectively.  
• SSPs perceptions of utility of 
implementation strategies and 
facilitators and barriers to acceptability 
of RI and DI through M13  

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• Objectives 
• Endpoints 
• PSPs perceptions of utility of 
implementation strategies through 
SSIs through M13. 
• To evaluate fidelity to injection and 
dosing window 
• Proportion of injections occurring 
within target window from target date 
(±7 days for target date of Injection 
dose 2 and subsequent injections) 
through M13  
• Proportion of PSPs completing target 
number of injections through M13 
• PSPs and SSPs perception of barriers 
and facilitators to fidelity to injections 
through M13  
• To evaluate fidelity and reach of client 
Sexual Health Assessment  
• Proportion of site staff who administer 
Sexual Health Assessment through 
M13. 
• Proportion of eligible PSPs for which 
Sexual Health Assessment are 
administered through M13 
• Proportion of MSM and TGM who take 
the Sexual Health Assessment 
through M13  
• Proportion of MSM & TGM who report 
having had sex in the last 6 months 
through M13 on the Sexual Health 
Assessment  
• Proportion of MSM & TGM who 
expressed interest in PrEP or never 
heard of PrEP out of those who report 
having had sex in the last 6 months 
through M13 
• Proportion of PSPs who initiate 
APRETUDE after taking the Sexual 
Health Assessment through M13  
• SSPs and PSPs perceptions of Sexual 
Health Assessment through M13  
• To evaluate adaptations to any 
implementation strategies used in 
clinics to include but not limited to 
• Summarize components adapted and 
changes made using FRAME-IS at 

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• Objectives 
• Endpoints 
modifications to toolkits, RI and DI to 
support APRETUDE implementation 
pre-implementation and monthly 
through M13 
• SSPs and PSPs perceptions of 
adaptations to implementation 
strategies through M13  
• To evaluate switch from oral PrEP to 
APRETUDE 
• Proportion of PSPs with history of 
PrEP use that complete the Sexual 
Health Assessment and ISQ and start 
APRETUDE through M13  
• PSPs reasons for choosing 
APRETUDE, including switching, as 
assessed by SSIs and ISQ  
• To evaluate perceptions, barriers and 
facilitators with SSPs and PSPs 
• PSPs and SSPs perception of barriers 
and facilitators through M13.  
• Other / Tertiary 
CCI

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• Objectives 
• Endpoints 
CCI

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• Objectives 
• Endpoints 
CCI

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• Objectives 
• Endpoints 
• 
1 If the site has only DTI patients, endpoints will be a month prior for SSPs. 
 
CCI

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3. 
RESEARCH DESIGN  
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 
3.1. 
Study Design 
This is a Phase 4, randomized, open-label, two-arm study evaluating the impact of two 
implementation strategy conditions – dynamic implementation and routine 
implementation – on the delivery of CAB PrEP in low and high-volume PrEP sites in the 
U.S. for MSM and Transgender men ≥ 18 years of age.  MSM and transgender men who 
tested HIV-1 negative at the sites prior to initiation of CAB PrEP (Section 3.2.1) will be 
enrolled. Approximately eighteen clinics – about 9 high and about 9 low volume – will be 
randomized 2:1 to either dynamic implementation or routine implementation.  This study 
is being conducted following FDA approval and commercial availability of CAB PrEP in 
the U.S.  
Eligible and consenting PSPs will be followed for 12 calendar months from the time of 
enrollment and receipt of the first administration of CAB tablets for PrEP oral lead in or 
APRETUDE (for direct to injection PSPs). The study includes a screening period of up to 
90 days to allow sufficient time for any benefit verification checks to be completed, as 
required. PSPs will be initiated on CAB PrEP as soon as their eligibility is confirmed. 
The screening period is followed by a 11-month or 12-month administration period of 
CAB PrEP depending on whether an optional 1-month oral lead-in of CAB tablets for 
PrEP is administered, followed by APRETUDE IM injections every two months after the 
one-time loading dose (i.e., first 2 IM doses 1 month apart and 2 months apart thereafter). 
All PSPs will receive a total of 7 APRETUDE IM injections, with the last IM injection 
visit being their last study visit. After 11-month (direct to injection) or 12-month (with 
OLI) treatment period, PSPs will complete the study and will be offered PrEP regimen as 
per site standard of care. When PSPs complete their M12/M13 assessments, irrespective 
of missed injections, they will be a completer. Consenting SSPs at the site will participate 
in study quantitative and qualitative study assessments to evaluate the impact of the two 
implementation strategy conditions on the feasibility of delivering APRETUDE.  When 
SSPs completes their M13 study assessments, they will be a completer.  The end of study 
is defined when the last PSP and SSP have completed their implementation science 
assessments. For a detailed Schedule of Activities (SoA) refer to ANNEX 1 and ANNEX 
2.  CAB PrEP dosing information can be found in the prescribing information for CAB 
PrEP. 

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Figure 1 
Study Design Schematic 
 
3.2. 
Study Population 
Approximately 220 PSPs will be enrolled. We aim for at least 50% of the enrolled PSPs 
to be Black or Latino. Of the total PSPs enrolled, we aim for at least 2-4% to be TGM. 
The number of SSPs will vary by site and approximately 5 per site will be included. 
During the screening period, PSPs who enroll into the study will complete informed 
consent and confirmation of inclusion and exclusion criteria will be conducted. Each PSP 
being screened for study enrollment evaluation will be assigned a PSP number at the 
screening visit (refer to the SRM for details). Completion of study assessments will occur 
prior to receipt of Dose 1(D1) of intramuscular (IM) injections. 
SSPs will be selected in advance of the investigator meeting and will be enrolled and 
assigned an SSP number (refer to the SRM for details) around the time of the site 
initiation visit, prior to the site’s first subject visit.  

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3.2.1. 
Eligibility Criteria 
3.2.1.1. 
Inclusion Criteria for PSP 
Age:  
1 
Participant must be ≥ 18 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2 
HIV negative test result at screening 
3 
No prior history of receiving CAB PrEP (Note: prior or active use of non-CAB PrEP 
([FTC/TDF or FTC/TAF]) at screening is allowed). 
4 
PrEP provider deems CAB PrEP use to be appropriate per the applicable CAB PrEP 
prescribing information prior to enrollment in the study. 
Sex 
5 
Men who have sex with Men or Transgender Men. 
Informed Consent 
6 
Capable of giving signed informed consent as described in Section 6.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
3.2.1.2. 
Exclusion Criteria for PSP 
Medical Conditions  
1 
HIV indeterminate or positive test result during screening and prior to initiation of 
CAB PrEP (CAB tablets for PrEP or APRETUDE). 
Prior/Concomitant Therapy 
2 
Refer to the current U.S. Prescribing Information for CAB PrEP, i.e., for CAB 
tablets for PrEP and APRETUDE 
Prior/Concurrent Clinical Study Experience 
3 
A participant of concurrent interventional clinical or implementation science study 
at any time during the study 
Other exclusions 
4 
Cis-gender or Transgender female 
5 
As dictated in the Prescribing Information for CAB PrEP in consultation with the 
prescriber.  

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3.2.1.3. 
Inclusion Criteria for SSPs 
An SSP will be eligible for inclusion in this study if:  
7 
They are site employees responsible for administrative (for administrative SSPs)/ or 
clinical (for clinical SSPs) aspects of offering and administering CAB PrEP at the 
site. 
8 
Has the required qualifications according to their role and delegated the appropriate 
responsibilities by the PrEP Provider. 
9 
Be able to understand and comply with protocol requirements, instructions, and 
restrictions. 
10 
Understand the long-term commitment to the study, have adequate resource to 
complete assessments for the duration of the study at the point of enrollment. 
 
3.2.1.4. 
Exclusion Criteria for SSPs 
An SSP will be ineligible for inclusion in this study if:  
6 
Engaged or planned engagement in an implementation science study with similar 
strategies on long acting PrEP injectables at any time during the study. 
7 
SSP does not have adequate resource to complete study assessments. 
 
3.3. 
Study Groups and Duration 
This study will enroll the following groups:  MSM and transgender men who are not 
living with HIV (as PSPs) and staff at sites offering PrEP (i.e., as SSPs).  Sites will be 
randomized to RI or DI prior to study participant enrolment.  
Assessments can be found in ANNEX 1 and ANNEX 2.   
3.3.1. 
PSPs 
MSM and transgender men who are HIV negative prior to initiation of CAB PrEP and 
who have either not previously received PrEP (i.e., PrEP naïve) or are current or prior 
users of oral PrEP (e.g., FTC/TDF, FTC/TAF, generic FTC/TDF) and meet CDC 
eligibility for PrEP initiation, including documentation of a negative HIV test per CDC 
guidelines [Centers for Disease Control and Prevention, 2021], are allowed in the study 
as PSPs. 
Administration of CAB PrEP will be in accordance with the prescribing information in 
the US. PSPs will either receive or not receive optional oral lead-in (OLI) of CAB PrEP 
prior to their first APRETUDE IM injection based on participant or PrEP provider 
preference, which will be recorded in the eCRF. PSPs who receive optional OLI should 

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receive oral CAB tablets for PrEP for approximately 1 month (at least 28 days) prior to 
their first injection of APRETUDE.  
PSPs meeting all eligibility criteria at the screening/enrolment visit will sign the informed 
consent form at the site or through virtual administration. Screen failures are defined as 
PSPs who consent to participate in the study but are not subsequently entered in the 
study. A minimum set of screen failure information will be collected including 
demography, screen failure details, eligibility criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
post benefits verification may be rescreened 1 time within 4 weeks of the date they were 
determined to have screen failed. Individuals who screen fail due to benefits verification 
exceeding the 90-day screening window, with no other screening assessments having 
been performed, may be rescreened once, to take place any time after benefits 
verification has been obtained; informed consent will need to be reviewed and re-signed 
for each rescreen. Subjects will be issued a new ID number for every screening/re-
screening event. SSPs will not be captured for screen failure reporting.  
For PSPs receiving optional OLI, the final dose should be taken on the same day as the 
APRETUDE IM injections are started. CAB tablets for PrEP and APRETUDE dosing 
will be performed in accordance with the corresponding CAB PrEP prescribing 
information.  
If a PSP plans to miss the injections by more than 7 days from a scheduled APRETUDE 
injection, then in consultation with the PrEP provider, CAB tablets for PrEP may be 
taken daily until the PSP restarts IM injections as per the US prescribing information for 
CAB PrEP. For oral PrEP duration greater than two months, the decision to use other 
recommended oral PrEP regimens [Saag, 2020] in this clinical setting will be made by 
the PrEP provider.  Dosing of oral PrEP regimen used in such cases of missed 
APRETUDE injections will be recorded in the eCRF. 
The total duration of study participation for PSPs is approximately 12 calendar months 
from the time of enrolment to the receipt of the final administration of APRETUDE IM 
injection.  A PSP is considered to have completed the study if the PSP has finished all 
protocol-specified (i.e., Month 12 for PSPs who started CAB PrEP without optional OLI, 
and Month 13 for PSPs who started CAB PrEP with OLI) assessments and receive the 
last injection of APRETUDE during the study.  
3.3.2. 
SSPs 
SSPs will complete assessments as outlined in ANNEX 1 and agree to data privacy 
requirements prior to the completion of study assessments. Assessments will include 
questionnaires and interviews at baseline, M5 and M13; baseline questionnaires with 
SSPs should be completed prior to the enrolment of the first participant at their site, 
which might vary by site depending on whether the first PSP started CAB PrEP with or 
without optional OLI. They will also participate in monthly FRAME-IS assessments. 
Sites in the DI arm will participate in quarterly group and monthly one-on-one facilitation 
calls.  
 

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The PrEP provider at the site will manage and remain responsible for all clinical aspects 
of the PSPs enrolled at the site during the study.   
• During the screening period, the site will obtain the PSP’s informed consent and 
confirm inclusion and exclusion criteria prior to enrolling in the study/M1. The 
site will also complete demography and vital signs and required labs per clinical 
local standard of care. 
• (See SoA for specific laboratory test results that should be documented in the 
eCRF, e.g., HIV testing results and any positive STI clinical diagnoses (defined 
for this study as syphilis (any stage), gonorrhea, chlamydia, or trichomonas)  at 
Screening and at any time point during the study, laboratory abnormalities 
associated with AEs leading to study discontinuations, positive pregnancy test 
results). The site will explain to the PSPs that medical records may be requested 
from other medical facilities to support complete reporting of SAEs or other 
events if they occur during the study. 
• For PSPs diagnosed with incident HIV-1 infections (defined as newly diagnosed 
HIV infection following enrolment and during the study), the site may perform 
additional tests, including but not limited to HIV-1 viral load, CD4 count, 
genotype/phenotype tests, and recency assays, and initiate antiretroviral therapy 
(ART) as per the site’s standard of care.  See SoA for collection of available 
results as well as the start date of ART and classes of ART regimen used for PSPs 
with incident HIV-1 infection. 
 
• The PrEP provider at the site will prescribe CAB tablets for PrEP to PSPs who 
will receive optional OLI and administer APRETUDE IM injections as per 
approved prescribing information.  
• The site will be responsible for scheduling the monthly and every 2 months 
injections, reminding participants when they are scheduled to receive their 
injections, and rescheduling missed injections.  
• The PrEP provider will be notified that CRO staff and/or the Medical Monitor 
may request additional information, including medical records if required, on AEs 
and SAEs assessed by the PrEP Provider as related to CAB PrEP, or other 
assessments (e.g., pregnancies). 
• The PrEP provider will monitor all visits (planned, missed, and any unplanned 
visits) and will determine when to start oral PrEP for planned missed doses, or to 
restart APRETUDE according to the USPI [APRETUDE, 2021]. 
• If the PrEP provider cannot contact the PSP following missed injections of 
APRETUDE and a PSP misses two consecutive scheduled APRETUDE 
injections, this should be documented in the participants medical record and they 
will be discontinued from the study.   
 
Optional oral lead-in (OLI), every injection visit and if applicable, early discontinuation, 
should be recorded as a study visit in the PSP medical record and the eCRF.  Additional 
PSP contacts should be documented in the medical records but will not need to be entered 

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as a study visit in the eCRF, unless the contact results in any safety information that is 
required to be documented for the study (refer to Section 9).  
The site is responsible for the completion of all data entry accurately transcribed from the 
source documentation in the PSPs medical records, including the reporting of AEs and 
SAEs assessed by the PrEP Provider as related to CAB PrEP. (see Section 9.3 for 
additional information). All study assessments and events should be kept in the PSP 
source documentation (refer to Section 11.7.4). 
Total duration of study participation for SSPs is approximately 12 calendar months, at the 
time of enrollment of the last PSP at their site (questionnaires and monthly injections). In 
the event of turnover in SSPs, replacement staff will undergo study training and continue 
staff study activities per SOA. The number of SSPs will vary by site and will be 
approximately 5 per site.   
 

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4. 
Implementation Research Methods 
4.1. 
Study Arms Overview 
The two study arms are routine implementation and dynamic implementation.  Clinics 
will be randomized to the two study arms in a 2:1 distribution, whereby about 12 clinics 
will be in the dynamic implementation arm and about 6 clinics will be in the routine 
implementation arm (Note: Number of clinics may vary depending on recruitment).  
Clinics receiving routine implementation will receive standard provider and patient 
toolkits that will be available when CAB PrEP is commercially available. Clinics 
receiving dynamic implementation will receive enhanced toolkits, a digital health end to 
end implementation strategy, and implementation facilitation. An overview of the RI and 
DI implementation strategies are outlined in Table 1 and Table 2 in terms of six 
dimensions as recommended by Proctor and colleagues [Proctor, 2013]: actor, the action, 
action targets, dose, implementation outcomes addressed, and theoretical justification.    
4.1.1. 
Routine Implementation 
The RI arm will evaluate the feasibility of APRETUDE delivery without implementation 
supports. Sites randomized to RI will have access to the standard toolkits for providers 
and patients that will be available for APRETUDE to use as needed. An overview of 
example materials contain in the toolkits is provided in Table 1. Detail information on the 
toolkits is given in the SRM. SSPs in the RI arm will participate in study training, 
FRAME-IS assessments and implementation monitoring. 
• Study Training: In preparation for the study, all SSPs and other relevant site staff 
will receive study training including information on safety and effectiveness of 
APRETUDE, study procedures, and information and/or training on 
implementation strategies. Study training requirements will be described in the 
study training plan and evidence of training will be filed in the Investigator Site 
File (ISF). Initial study training will be covered in the Investigator meeting, other 
virtual sessions, via on demand learning or and at the site initiation visits. SSPs 
should complete all study training applicable to their role. 
 
• FRAME-IS Assessments: SSPs in the RI arm most knowledgeable of the study, 
clinic operations and modifications will participate in monthly FRAME-IS 
assessments, which are administered via email and takes maximum 15 minutes to 
complete. All SSPs will be asked to complete the FRAME-IS in order to 
understand implementation from the perspective of the different roles. The 
Framework for Reporting Adaptations and Modifications to Evidence-based 
Implementation Strategies (FRAME-IS) provides a systematic way of 
documenting and tracking modifications to implementation strategies in 
traditional healthcare settings, allowing for a better understanding of how the 
strategies influence outcomes [Miller, 2021]. The assessments will provide 
understanding of implementation challenges and successes as well as 
modifications made, if any, to overcome identified challenges at each clinical site.  
 

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• Implementation monitoring: Implementation monitoring focuses on 
understanding each site’s integration of CAB PrEP rather than intervening and is 
not considered an implementation strategy. The information collected can be used 
to develop lessons-learned to promote sustainability and scale-up in future clinics.  
Monitoring may include brief monthly or quarterly calls with the designated site 
implementation lead at each RI site or a written form that assesses implementation 
progress. At least one consistent SSP from each site should participate in all 
implementation monitoring. This SSP should be aware of how implementation is 
going and be willing and able to report out on behalf of the clinic and 
communicate back to the team at the clinic.   
SSPs and PSPs will complete all assessments per the SoA (ANNEX 1 and ANNEX 2).   
Table 1 
Routine Arm Implementation Strategies 
  
 Toolkits 
  
Provider Toolkit 
Patient Toolkit 
Action 
Office Starter Guide, Instructions for Use, 
Guidance on Pausing/Stopping, Discussion 
Points Checklist; Injection Education Video. 
Treatment Scheduler, Dosing and Admin 
Guide, Implementation Video, ViiV Connect 
Materials, Demo Packs 
Patient Appointment Reminder 
Cards; Welcome Brochure; FAQs 
Actor 
ViiV developed, delivered with IS vendor 
support  
ViiV developed, delivered with IS 
vendor support 
Action target 
Improved provider knowledge of CAB PrEP 
and access to implementation resources 
Improve patient knowledge about 
CAB PrEP and support retention in 
care 
Dose 
As needed 
As needed 
Outcome  
Feasibility, acceptability, utility 
Feasibility, acceptability, utility 
Justification 
Clinicians needs logistic support to 
integrate new modality into clinics 
Patients may benefit from support 
materials to be aware of CAB PrEP 
as well as with initiation and 
adherence 
 
4.1.2. 
Dynamic Implementation  
The DI arm will evaluate the feasibility of APRETUDE delivery with implementation 
supports; specifically determining whether DI results in higher feasibility in delivering 
APRETUDE.  Clinics randomized to DI will receive: 1) enhanced toolkits, 2) a digital 
health end to end implementation strategy; and 3) implementation facilitation.  Figure 2 
depicts an example of how these strategies support the CAB PrEP clinical experience and 
the PrEP care continuum. The description of strategies according to Proctor reporting 
domains [Proctor, 2013] is presented in Table 2.  

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Figure 2 
Dynamic Implementation Pathway 
 
• Enhanced toolkits: PSPs and relevant site staff, inclusive of SSPs will have 
access to the standard toolkit items as in the routine implementation arm in 
addition to enhanced items. Enhanced provider items will include but not limited 
to a video on using ViiV Connect, training module on providing inclusive care, 
and a patient-provider decision making tool. Enhanced patient items might 
include text appointment reminders and videos on what to expect. All items – 
standard and enhanced - may be available and accessible to site staff and PSPs in 
a mobile application with web-enabled capabilities. Site staff will receive 
information and/or training on the patient & provider toolkit items as these items 
provide product information and education. PSPs could be informed of toolkit 
information and the mobile application from their clinicians and will be available 
on the digital platform. Toolkit items will be used as needed. 
 
• Digital health end to end implementation strategy: As depicted in Figure 2, 
digital health end to end implementation strategy supports relevant site staff, 
inclusive of SSPs, in implementing APRETUDE from identification of 
APRETUDE eligible individuals to the enrolment, adherence, persistence and 
retention of PSPs who are on APRETUDE. The Sexual Health Assessment tool 
may help individuals to self-identify their need for APRETUDE rather than rely 
solely on clinician identification. The tool is intended to be integrated into 
standard clinic operations and be a part of routine care offered to all men who 
seek health services at the site. As such, site staff may integrate the tool into clinic 
operations and may send the tool digitally to all men seeking care before their 
clinical visit throughout the study period.  Any data collected in the tool from men 
will be collected following agreement to data sharing and privacy; site staff may 
review the tool results with their patients as part of routine care, which may 
support site staff in linking men, including MSM and TGM, to PrEP and 

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prescribing PrEP.  Any data reported for study purposes (e.g., shared with 
Sponsor/ CRO) from the Sexual Health Assessment will be in aggregate form at 
the site level and be de-identified individual data. 
 
Site staff may develop a plan to make APRETUDE injections accessible by the 
implementation of designated injection days and a choice of prescheduled 
appointments and drop-in visits. These options will support PSPs in getting their 
initial injection and subsequent injections within target windows at times 
convenient to them. All clinics using the telehealth platform (see Section 4.1.5) 
will provide a drop-in visit option.  
 
Site staff may provide PSPs with information about transportation available to 
transport them to their initial and follow-up injection visits, aiding in adherence to 
target injection windows and retention in care. PSPs requesting transportation will 
receive digital support to acquire the transportation. 
 
A sub-group of clinics will use a telehealth platform (see Section 4.1.5) to 
implement CAB PrEP. All the digital strategies will be delivered on the platform 
and may influence uptake, adherence, retention and persistence on APRETUDE.  
A sub-group, rather than all DI clinics, will allow for focused iterative feedback 
and refinement of the platform throughout the study.  
 
• Implementation Facilitation: As depicted in Figure 2, implementation 
facilitation supports the dynamic implementation strategies. The purpose of 
implementation facilitation is to provide the help and support needed to improve 
clinical care and patient outcomes through a process of interactive problem-
solving within a context of a recognized need for improvement and a supportive 
interpersonal relationship [Ritchie, 2020].  An external facilitator, an expert in 
implementation science and knowledgeable of the protocol and the study’s 
implementation strategies, will lead group facilitation calls focused on the 
exchanging of knowledge, identification of barriers to implementation and 
identification of solutions to overcome the barriers.  The grouping of clinics on 
the facilitation calls will be determined once sites have been selected; clinics can 
be grouped by geography, PrEP volume, or another meaningful characteristic that 
would be helpful for clinics.  
 
Tailoring implementation strategies to individual settings in the context of 
applying diverse implementation strategies is important. Individual facilitation 
can result in effective implementation. SSPs in the DI arm will be offered one-on-
one facilitation calls to help problem solve implementation barriers specific to 
their health facility, including reminding SSPs of the availability of toolkit items 
that might support them.  
 
SSPs in the DI arm might participate in quarterly group and monthly one-on-one 
facilitation calls. Monthly one-on-one calls will not occur in the months the 
quarterly groups meet. At least one consistent SSP from each site should 
participate in both one-on-one and quarterly facilitation calls. This SSP should be 

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aware of how implementation is going and be willing and able to report out on 
behalf of the clinic and communicate back to the team at the clinic.   
  
Additionally, DI arm clinics will complete the brief monthly FRAME-IS assessments and 
participate in the study training. All SSPs in the DI arm will be asked to complete the 
FRAME-IS in order to understand implementation from the perspective of the different 
roles. SSPs and PSPs will complete all assessments per the SoA (ANNEX 1 and ANNEX 
2).  
 
 

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Table 2 
Dynamic Arm Implementation Strategies 
 
Enhanced Toolkits 
Implementation 
Facilitation 
Digital Health End to End Implementation  
Provider Toolkit 
Patient Toolkit 
Group & 1:1 Calls 
Sexual Health 
Assessment 
Designated 
Injection Days 
Transportation 
Support 
Telehealth 
Platform 
Action 
Enhanced ViiV 
connect Materials;  
inclusive training 
module and forms; 
patient-provider 
decision making 
tool 
+ RI arm resources 
Text/App 
Reminder, What 
to Expect Video, 
Mobile App (with 
web enabled 
features)  
Interactive group 
problem solving 
and one-on-one 
implementation 
support 
Patients self-
assessment of 
HIV risk and PrEP 
need. 
Clinics have 
designated injection 
days, and a choice 
of prescheduled 
appointments or 
drop-in visits 
Provision of 
digital 
transportation 
support for 
patient 
appointment 
keeping. 
All CAB PrEP 
clinical services 
except injection 
offered through a 
telehealth 
platform 
Actor 
ViiV developed, 
delivered with IS 
vendor support  
ViiV developed, 
Clinic staff 
delivered 
IS Vendor 
Participants 
Clinic Staff 
Clinic Staff 
Participants 
CRO 
Clinic Staff 
Participants 
CRO 
Clinic Staff 
Participants 
Action 
target 
Enhanced 
resources to 
improve provider 
knowledge of CAB 
PrEP and 
implementation 
guidance  
Use digital 
resources to 
improve 
participant 
knowledge about 
CAB PrEP and 
support retention 
in care 
Clinics learn best 
implementation 
practices in group 
sessions and 
clinics overcome 
implementation 
barriers in one-on-
one sessions  
Improve 
participant 
identification of 
HIV risk and 
linkage to PrEP 
care and clinician 
identification of 
eligible PrEP 
patients. 
Support clinics in 
providing timely 
CAB PrEP services 
for patients to 
support CAB PrEP 
initiation, adherence 
and retention in 
care. 
Support patients 
in initiating, 
adhering and 
retaining in CAB 
PrEP services. 
Understand how 
best to implement 
CAB PrEP using 
telehealth by 
supporting a sub-
group of clinics 
through the 
process  
Dose 
As needed 
As needed 
Group: quarterly 
(60-90 mins); 1:1 - 
monthly (1hr)  
Before or at 
clinical visits  
Daily  
As needed 
Daily, as needed 

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Enhanced Toolkits 
Implementation 
Facilitation 
Digital Health End to End Implementation  
Provider Toolkit 
Patient Toolkit 
Group & 1:1 Calls 
Sexual Health 
Assessment 
Designated 
Injection Days 
Transportation 
Support 
Telehealth 
Platform 
Outcome  
Feasibility, 
acceptability, utility 
Feasibility, 
acceptability, 
utility, adherence 
Feasibility, 
acceptability 
Reach, fidelity, 
feasibility, 
acceptability 
Feasibility, reach, 
adherence fidelity, 
acceptability  
Acceptability, 
uptake, 
adherence, 
retention, utility 
Feasibility, 
acceptability, 
uptake, 
adherence, 
retention, utility 
Justification 
Clinicians need 
added logistic 
support to integrate 
new modality into 
clinics and support 
working with new 
population 
demographics 
Patients may 
benefit from 
support 
materials to be 
aware of CAB 
PrEP as well as 
with initiation 
and adherence 
delivered via a 
different 
modality 
Clinics may benefit 
from best practice 
sharing while 1:1 
support can aid 
clinics in 
addressing their 
unique 
implementation 
challenges 
Clinicians need to 
unbiasedly 
assess patients' 
eligibility for CAB 
PrEP and patients 
need a 
mechanism to 
evaluate their 
own PrEP need. 
Clinics may benefit 
from strategies to 
reduce care burden 
but support 
accessibility and 
reach to support 
adherence 
Patients may 
benefit from 
transportation 
support to 
expand 
accessibility, 
adherence and 
retention. 
Telehealth may 
help expand 
accessibility and 
reach of PrEP to 
patients who 
prefer non-
traditional care. 
 
 
 
 

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4.1.3. 
Implementation Assessments 
Implementation outcomes align with the study’s objectives and Proctor and colleague’s 
[Proctor, 2011] implementation outcome recommendations.  The administration of 
assessments for SSPs and PSPs, including facilitation calls and FRAME-IS, is outlined in 
Table 3. Baseline assessments should be completed prior to the enrollment of first 
participant.  Implementation information may also be gathered from or about site staff 
members who are administering APRETUDE to non-PSPs. 
One or more interim analysis will be conducted to provide early evaluation of the 
implementation science primary and key secondary objectives. The timing of the 
interim/s will be based on when a sufficient number of SSPs and/or PSPs questionnaires 
and interviews have been completed. 
 
Table 3 
Implementation Assessments  
Outcome 
Assessment Level 
Measurement 
OLI/DTI Time point 
Feasibility- 
Overall 
Staff Study Participants 
FIM 
BL, M5, M13 
 
Staff ISQ 
BL, M5, M13 
 
SSI 
M5, M13 
Patient Study 
Participants 
FIM 
M13(OLI)/M12(DTI) 
 
Patient ISQ 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
SSI 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Acceptability- 
Overall 
Staff Study Participants 
AIM 
BL, M5, M13 
 
 
SSI 
M5, M13 
Feasibility - 
Telehealth 
Staff Study Participants 
FIM 
BL, M5, M13 
 
SSI 
M5, M13 
 
Staff ISQ 
BL, M5, M13 
Patient Study 
Participants 
FIM 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
SSI 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
Patient ISQ 
BL, M7(OLI)/M6(DTI), 
M13M13(OLI)/M12(DTI) 
Acceptability - 
Telehealth 
Staff Study Participants 
AIM 
BL, M5, M13 
 
SSI 
M5, M13 
 
Staff ISQ 
BL, M5, M13 
Patient Study 
Participants 
AIM 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
SSI 
BL, M7(OLI)/M6(DTI), 
M13M13(OLI)/M12(DTI) 
 
Patient ISQ 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Acceptability – 
Cabotegravir LA 
Patient Study 
Participants 
AIM 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 

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Outcome 
Assessment Level 
Measurement 
OLI/DTI Time point 
 
 
SSI 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
 
Patient ISQ 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Fidelity 
Patient Study 
Participants 
Adherence to Target date (7 
days), eCRF 
Monthly 
 
Patient ISQ 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
SSI 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Staff Study Participants 
Staff ISQ 
BL, M5, M13 
 
SSI 
BL, M5, M13 
 
# clinical staff-initiated 
assessments/ # eligible pts 
Monthly 
Cross Study1 
Composite measure*: 
• adherence to target date 
• assessments given 
• missed appointments  
BL-M13 
Reach 
Staff Study Participants 
# pts receiving 1st injection / 
#eligible pts based on 
assessments 
Monthly 
Awareness 
Staff Study Participants 
Assessment tool 
Monthly 
 
 
Staff ISQ 
BL, M5 
 
SSI 
BL, M5 
Patient Study 
Participants 
Assessment tool 
BL 
 
Patient ISQ 
BL 
 
SSI 
BL 
Uptake 
Staff Study Participants 
Assessment tool 
Monthly 
 
 
Clinic administrative records 
Monthly 
 
Staff ISQ 
BL, M5, M13 
Patient Study 
Participants 
Assessment tool 
Monthly 
 
Patient ISQ 
BL 
 
SSI 
BL 
Persistence, 
Retention 
Staff Study Participants 
Assessment tool 
Monthly 
 
 
Clinic administrative records 
Monthly 
 
Adherence to Target date (7 
days), admin records 
Monthly 
 
Staff ISQ 
BL, M5, M13 
Patient Study 
Participants 
Adherence to Target date (7 
days), eCRF 
Monthly 
 
Patient ISQ 
M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
 
SSI 
M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Process 
evaluation of 
implementation 
Staff Study Participants,  
SSI 
BL, M5, M13 

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Outcome 
Assessment Level 
Measurement 
OLI/DTI Time point 
strategies and 
toolkits 
 
Patient Study 
Participants 
SSI 
BL, M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Perceptions, 
barriers & 
facilitators 
Staff Study Participants,  
SSI, Staff ISQ 
BL, M5, M13 
 
Patient Study 
Participants 
SSI, Patient ISQ 
M7(OLI)/M6(DTI), 
M13(OLI)/M12(DTI) 
Abbreviations: FIM: Feasibility of Intervention Measure; AIM: Acceptability of Intervention Measure; SSI: 
Semi-Structured Interviews; M: Month; DTI: Direct to Injection; OLI: Optional Oral Lead In 
*Composite measure to be developed in consultation with stats; example of measures provided 
1Measures taken from both SSPs and PSPs across the study implementation period; to be further refined 

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4.1.3.1. 
Timepoint Definitions for Completion of Questionnaires and Interviews 
PSPs:   
• PSPs who are started on oral Cabotegravir PrEP as optional OLI will receive their 
first dose of oral CAB in Month 1.  PSPs who are started on APRETUDE 
injections (direct to injection) will receive their first dose of APRETUDE 
injection in Month 1.   
• Each administration of APRETUDE injection will be categorized by the 
sequential number, e.g., Dose 1 visit (first injection), Dose 2 visit (second 
injection); and the corresponding Study Month will be recorded. 
• Baseline IS assessment is defined as the first assessment taken on or before 
receiving Dose 1 of APRETUDE injection. Baseline questionnaires should be 
completed within two weeks of or on their Dose 1 visit and before receiving the 
first APRETUDE injections. 
• For each PSP, the last APRETUDE injection is to occur at the last study visit.  
• All study visits, including those where questionnaires and/or interviews are 
administered at M7(OLI)/M6(DTI) and M13(OLI)/M12(DTI), will be anchored 
off of each PSP M1, so it reflects months in study, regardless of what dose they 
are on and regardless of whether they have missed any injections and received 
oral CAB tablets for PrEP. 
• Approximately 3 PSPs per site will participate in SSIs; number of SSIs might 
vary by site. Participants will be purposely sampled for interviews based on 
demographic characteristics, such as race/ethnicity, prior PrEP use.  
• Interviews should be conducted with all PSPs who discontinue participation 
within one month of discontinuation, when possible.  
SSPs: 
• Baseline IS assessment is defined as the first assessment taken prior to 
administering the first APRETUDE injection at each site. Baseline questionnaires 
should be completed by all SSPs within 1-2 weeks of the site’s initiation.  
• For sites with both OLI and DTI participants, M4/M5 visit will be defined when 
at least 1 participant, at their respective site, has completed their 
M4(DTI)/M5(OLI) study visit (Dose 3 visit), respectively, whichever comes first.  
M12/M13 visit will be defined after at least 1 participant, at their respective site, 
has completed their M12(DTI)/M13(OLI) study visit (Dose 7 visit), whichever 
comes first.  
o Questionnaires and/or interviews can be completed within 3 weeks of the 
respective study visits. 
• For a site with only DTI patients, the visits will be defined at M4 and M12, 
respectively.  For a site with only OLI patients, the visits will be defined at M5 
and M13, respectively. 

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Group and 1:1 Facilitation:  
• SSPs in the DI arm will meet as a group to actively discuss problem solving for 
implementation barriers encountered.   
o At least 1 consistent SSP from each site will be required to attend. Sites 
will be encouraged to send the most knowledgeable and involved 
individuals in the implementation to the meetings.  
o Group facilitation should occur quarterly, as needed.  
• SSPs in the DI arm will be offered one-on-one facilitation calls to help problem 
solving for individual implementation barriers.  
o At least 1 consistent SSP will participate in the one-on-one calls. 
o One-on-one facilitation calls will be up to monthly as needed except for 
the months when group facilitation occurs.   
FRAME-IS: 
• SSPs at each site will complete the FRAME-IS questionnaire each month, which 
will be sent via email. Additional details on the FRAME-IS are provided in the 
SRM. 
The full SoA can be found in ANNEX 1 and ANNEX 2.   
4.1.4. 
Primary Endpoint 
The primary endpoint is Feasibility of Intervention Measure score assessed from SSP 
Month 13. The secondary implementation endpoints include the feasibility in PSPs, 
feasibility and acceptability of specific implementation components, reach, fidelity, and 
utility.  Additional secondary measures will assess awareness, uptake, adherence and 
retention of APRETUDE, adaptations to existing toolkits, and the process of acquiring 
Cabotegravir. Quantitative and qualitative data as well as facilitation calls and FRAME-
IS output will be triangulated to inform final study results.  
4.1.5. 
Telehealth Strategy 
Telehealth is a unique strategy within the dynamic implementation arm requiring its own 
standard operating procedures. Telehealth delivery of APRETUDE is new and is likely to 
be complex with no similar benchmarks with which to compare. It is important to 
understand and resolve the known and unknown challenges that may accompany 
telehealth delivery of APRETUDE before attempting to scale as unresolved challenges 
can lead to significant opportunity costs. For these reasons, the telehealth strategy will be 
approached from a developmental evaluation lens, which is an approach that supports 
continuous adaptation in complex environments, emphasizing iterative, real-time data 
collection and regular reflection to support adaptation [Fagen, 2011].  Developmental 
evaluation creates a road map to ensure the right people are reflecting on the right data at 
the right time to inform changes and that careful, ongoing documentation is occurring in 
the implementation process.  

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The approach may provide the foundation for producing the essential information, such 
as development and design, and optimal strategies for the possible scale-up of telehealth 
delivery of APRETUDE. The telehealth strategy may be a simulated digital environment 
or a hybrid system of integrating telehealth components/modules into existing clinic 
telehealth systems. This will be done in a sub-group of clinics in the study. 
Certain functions within the telehealth platform will be made available to potential 
patients of the PrEP provider as part of routine care and is independent of study 
participation. Some patients, however, may subsequently become study participants if 
eligible. Potential patients may take a web-based/online questionnaire, such as the Sexual 
Health Assessment Tool, that is being implemented as routine care for all men within a 
clinic. Any questionnaire data collection will only be done following the patient’s 
agreement to consent to data sharing and privacy terms within the platform. Data 
collected from potential patients will be key coded and reviewed by the provider in order 
to provide appropriate PrEP care to their patient. Data collected for study purposes (i.e., 
shared with CRO) will be de-identified in aggregate form only at the site level data is not 
connected to any individual. Once a patient is linked to a PrEP provider for consideration 
and provision (including prescribing and administration of APRETUDE injections), then 
the site staff may consider initiating a discussion around involvement in the study and 
initiation of study consent discussions. The telehealth strategy may include, but is not 
limited to:  
• Patient web-based/online PrEP questionnaires (e.g. Sexual Health assessment, this 
does not include the questionnaires noted in the SoA). 
• Online appointment scheduling for providers. 
• Initial patient-provider interaction through telehealth. 
• Provider ability to provide an HIV test or schedule a lab draw (at local lab) during 
the initial telehealth visit. 
• Electronic submission of the HIV test result or result of the lab draw to the PrEP 
provider. 
• Electronic submission of optional oral lead-in prescription from provider (if 
needed)  
• Electronic scheduling of first IM dose for patient from a choice of sites. Potential 
locations for injection visits at clinic (scheduled or drop-in), or patient home (if 
allowed). 
• Patient benefits verification process (e.g., insurance) 
• Home nursing option for home administration (if feasible). 
• PSP injection visit scheduling at chosen location.  
• Follow-up visits occur with provider via telehealth. 
The digital environment developed for this study could be utilized to support future 
telehealth strategies and designs.  Implementation assessments (e.g., facilitation calls, 
FRAME-IS) may also document the telehealth processes to help inform future scale up. 
Detail information on the telehealth strategy is given in the SRM. 

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4.2. 
Scientific Rationale for Study Design and Research Methods 
The HPTN 083 and HPTN 084 studies demonstrated that the efficacy of APRETUDE 
was statistically superior to daily oral FTC/TDF for PrEP at preventing HIV acquisition 
in cisgender men who have sex with men and transgender women as well as cisgender 
women, respectively. Yet, clinical efficacy of a product often does not translate to real-
world effectiveness, including awareness, knowledge, demand, acceptability and use. 
Research shows that just because an effective treatment exists, translation into routine 
care is slow and often never occurs [Bauer, 2020]. For long acting injectables for HIV 
prevention, however, early acceptability research has shown preference for an injectable 
prevention method over other methods by end-users [Philbin, 2021; Tolley, 2020]. 
However, as the first injectable HIV prevention modality, APRETUDE will require 
changes to the current routine of prescribing oral PrEP therapy, including but not limited 
to workflow, staffing needs, delivery platform considerations, and training needs [Pleuhs, 
2020].  Therefore, implementation research will be used to identify and understand the 
strategies that will enhance the delivery and/or integration of APRETUDE into existing 
and new PrEP delivery systems and programs is critical to its access and use.  
Implementation research focuses on systematic uptake of research findings into routine 
practice in order to improve health services. The study will be guided by a set of 
evidence-based implementation frameworks to ensure the robustness of the research.  
Implementation outcomes will be identified and measured at the service and patient level 
in order to determine how effectively and efficiently APRETUDE is being integrated and 
delivered within the identified clinics. The study will identify the barriers and facilitators 
to effective implementation while allowing for the tailoring and adapting of strategies to 
fit the needs of each clinical setting.  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 study design utilizes unequal randomization ratio of 2:1, whereby twice as many 
clinics are allocated to the DI arm than the RI arm. Unequal allocation is chosen due to 
the unequal distribution of implementation resources between the two arms. The DI arm 
will receive several enhanced supports relative to the RI arm and therefore, unequal 
allocation is recommended [Dumville, 2006].  
4.2.1. 
Implementation Frameworks 
The study is guided by 3 Gold Standard Implementation Science Frameworks (covering 
evaluation, determinants, and process): the Proctor [Proctor, 2011] Outcomes 
Framework, the Consolidated Framework for Implementation Research (CFIR) 
[Damschroder, 2009] and the Framework for Reporting Adaptations and Modifications to 
Evidence-based Implementation Strategies (FRAME-IS) [Miller, 2021].   
The Proctor outcomes framework will provide guidance on study design and outcomes 
[Proctor, 2011].  The framework distinguishes between three distinct but interrelated 
types of outcomes – implementation, services and client health outcomes. Improvements 

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in client health outcomes (e.g., remaining HIV uninfected) and service outcomes (e.g., 
on-time APRETUDE injections) are impacted by the implementation process and 
implementation outcomes. The framework will be used to guide measurement decisions 
for the key outcomes that will be assessed: feasibility, fidelity, acceptability, utility and 
reach.  
Figure 3 
Proctor & CFIR Integration Application  
 
CFIR will be integrated with the Proctor outcomes framework to serve as the process and 
determinant’s framework. CFIR provides a repository of standardized implementation-
related constructs organized across five major domains that influence implementation and 
implementation effectiveness - intervention characteristics, outer setting, inner setting, 
characteristics of individuals involved, and the process of implementation. These 
constructs can be used in a range of applications and for this study, CFIR will be integral 
to systematically identifying and assessing barriers and facilitators to APRETUDE 
implementation via the implementation strategies. The framework can be used to develop 
data collection approaches and therefore, will be used to guide the qualitative interviews 
with study participants and Study Staff Participants.  
Adaptations made to the toolkits, RI and DI will be captured using the FRAME-IS 
[Miller, 2021]. The FRAME-IS provides a systematic way of documenting and tracking 
modifications to implementation strategies in traditional healthcare settings, allowing for 
a better understanding of how the strategies influence outcomes. It is modular, capturing 
what is modified, the nature of the modification, and the rationale for the modifications. 
There are also optional modules to capture when modifications occurred, whether they 
were planned, who participated in the decision making and how widespread they were.  

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5. 
Statistical Considerations  
The statistical analysis plan will be finalized prior to any interim or final database lock 
(DBL) and it will include a more technical and detailed description of the statistical 
analyses described in this section.  This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and key secondary endpoints.   
Baseline analyses will be conducted when a sufficient number of SSPs and PSPs 
complete their baseline assessments. Interim analyses will be conducted when a sufficient 
number of staff study and/or patient study participant complete study assessments up to 
the Month 5 time point for SSPs and the Month 7(OLI)/Month 6(DTI) time point for 
PSPs. Additional interim analysis may be performed as required and will be detailed in 
the Statistical Analysis Plan (SAP). The purpose of these interim analyses will be to 
provide early evaluation of the implementation science primary and key secondary 
objectives.  
Completed SSP and PSP 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 clinical 
datasets from the eCRF will be included in order to describe the characteristics of the 
patient study participants enrolled. No formal criteria for stopping or amending the study 
based on interim analysis results will be made. The SAP will describe the planned 
analyses in greater detail. 
5.1. 
Statistical Hypotheses 
The primary hypothesis on the quantitative aspects of this study is that there is a 
difference between the dynamic implementation (DI) strategy and the routine 
implementation (RI) strategy in terms of staff study participants’ (SSPs) mean FIM score 
at Month 13, i.e., 
                            𝐻10 : µ(DI) = µ(RI) vs  𝐻11 : µ(DI) ≠ µ(RI), 
and the secondary hypothesis is that there is a difference between the dynamic 
implementation (DI) strategy and the routine implementation (RI) strategy in terms of 
patient study participants’ (PSPs) mean FIM score at Month 13, i.e., 
                            𝐻20 : µ(DI) = µ(RI) vs  𝐻21: µ(DI) ≠ µ(RI). 
The two-way ANOVA will be used to test each of the above hypothesis with clinic 
volume as the stratification factor, where no multiplicity adjustment is planned.  
5.2. 
Study Size 
The study is designed to mainly evaluate feasibility and acceptability of some 
implementation strategies from the feedbacks of SSPs and PSPs using implementation 
science measures. The study size for SSPs and PSPs will be investigated on the basis of 
analysis of the standardized effect size   
𝑑= µ(DI) − µ(RI)
𝜎
 
which is defined as the ratio of difference of mean FIM scores between two arms to the 
standard deviation 𝜎. To accommodate various scenarios of the mean difference between 

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arms and the assumed standard deviation, the standardized effect size d is considered 
without taking into account the effect of ICC (Intra-Cluster Correlation). 
 
Sample Size of SSPs: 
 
For SSPs, its size consideration consists of two parts: one is based on practical 
considerations in terms of feasibility of enrolling an adequate number of sites on each 
implementation strategy with the desire to have interventions tested across two types of 
study sites (high vs low), and the other is to enroll an adequate number of SSPs in each 
site to achieve the targeted power to detect the various differences between two arms (DI 
vs RI) in term of their mean FIM score with the cap 90 on the number of SSPs to be 
enrolled.  
 
With the cap 90 on the number of SSPs and the allocation of SSPs between DI arm and 
RI arm being 2:1, the absolute value of d will range approximately from 0.63 to 0.73 if 
the study power changes from 0.80 to 0.90, as shown in Table 4 below, where Figure 4 
illustrates the relationship between d>0 and the study power.  
 
Table 4 
Sensitivity of the Absolute Value of Standardized Effect Size to 
Study Power for SSPs 
 
Power 
N1 
N2 
N 
Absolute Value of d 
0.8 
30 
60 
90 
0.63 
0.81 
30 
60 
90 
0.64 
0.82 
30 
60 
90 
0.65 
0.83 
30 
60 
90 
0.66 
0.84 
30 
60 
90 
0.67 
0.85 
30 
60 
90 
0.68 
0.86 
30 
60 
90 
0.69 
0.87 
30 
60 
90 
0.7 
0.88 
30 
60 
90 
0.71 
0.89 
30 
60 
90 
0.72 
0.9 
30 
60 
90 
0.73 
 

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Figure 4 
Relationship between Standardized Effect Size and Study Power for 
SSPs 
 
 
 
Results from study CUSTOMIZE (209493) have shown that the estimated mean score of 
FIM for SSPs was 4.46 with standard deviation (SD) 0.59 at Month 12. Assuming these 
results remain valid in our RI arm (N1=30) at Month 13 when 90 SSPs are enrolled in DI 
and RI with ratio 2:1, to achieve 80% power, the mean score µ(DI) of FIM at Month 13 
for DI arm should be at least 4.83  if DI arm behaves better than RI arm, or at most 4.09 
if vice versa, as the absolute mean difference |µ(DI) − µ(RI)| will be 0.37≈0.59*0.63 
(=𝜎*d). The mean FIM score of DI arm at Month 13 will be at most 4.06 if µ(DI) < µ(RI) 
or at least 4.86 if µ(DI) > µ(RI) to have 85% power. The other scenarios of µ(DI) are 
summarized for the range of detectable standardized effect size and the corresponding 
powers in Table 5. 
 
Table 5 
The Mean FIM Score of DI Arm at Month 13 Assuming µ(RI)=4.46 and 
SD=0.59 for SSPs 
 
Absolute Value of d 
Power 
µ(DI) if µ(DI) < µ(RI) 
 µ(DI) if µ(DI) > µ(RI) 
0.63 
0.8 
4.09 
4.83 
0.64 
0.81 
4.08 
4.84 
0.65 
0.82 
4.08 
4.84 
0.66 
0.83 
4.07 
4.85 
0.67 
0.84 
4.06 
4.86 
0.68 
0.85 
4.06 
4.86 
0.69 
0.86 
4.05 
4.87 
0.7 
0.87 
4.05 
4.87 

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Absolute Value of d 
Power 
µ(DI) if µ(DI) < µ(RI) 
 µ(DI) if µ(DI) > µ(RI) 
0.71 
0.88 
4.04 
4.88 
0.72 
0.89 
4.04 
4.88 
0.73 
0.9 
4.03 
4.89 
 
If we consider a series of standardized effect size d, Figure 5 below summarizes the 
corresponding minimum sample size N1 of RI arm needed to achieve three target powers 
(80%, 85%, 90%). For the exact sample size of SSPs and their allocation to each arm for 
d ranging from 0.6 to 0.75, please refer to Table 6. For instance, if we expect the 
standardized effect size to be 0.66 which is a little larger than 0.63 discussed above, then 
a total of 84 SSPs is required with 28 in RI arm and 56 in DI arm to achieve 80% power. 
And approximately 96 SSPs are needed to have 85% power, where 32 SSPs are allocated 
to RI arm and 64 to DI arm. 
 
 
Table 6 
Sensitivity of Sample Size to Standardized Effect Size for SSPs 
d 
Target Power  
Actual Power 
N1 for RI 
N2 for DI 
Total N 
0.6 
0.8 
0.81 
34 
68 
102 
0.6 
0.85 
0.86 
39 
78 
117 
0.6 
0.9 
0.9 
45 
90 
135 
0.63 
0.8 
0.81 
31 
62 
93 
0.63 
0.85 
0.85 
35 
70 
105 
0.63 
0.9 
0.9 
41 
82 
123 
0.66 
0.8 
0.8 
28 
56 
84 
0.66 
0.85 
0.85 
32 
64 
96 
0.66 
0.9 
0.9 
37 
74 
111 
0.69 
0.8 
0.81 
26 
52 
78 
0.69 
0.85 
0.85 
29 
58 
87 
0.69 
0.9 
0.9 
34 
68 
102 
0.72 
0.8 
0.81 
24 
48 
72 
0.72 
0.85 
0.85 
27 
54 
81 
0.72 
0.9 
0.91 
32 
64 
96 
0.75 
0.8 
0.81 
22 
44 
66 
0.75 
0.85 
0.86 
25 
50 
75 
0.75 
0.9 
0.9 
29 
58 
87 
 
 

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Figure 5 
Relationship between Minimum Sample Size Required for RI Arm 
and the Assumed Standardized Effect Size for SSPs 
 
 
Sample Size of PSPs: 
 
For PSPs, its sample size will be considered in a similar way to that of SSPs. With the 
cap 220 on the number of enrolled PSPs and the assumption on the dropout rate about 
15% across arms, a series of targeted power will be investigated to determine the number 
of PSPs needed in each arm that will ensure the detection of the various differences 
between two arms (DI vs RI) in term of mean FIM score of PSPs at Month 13.   
 
With the dropout rate 15%, at most 187 out of the capped 220 PSPs will remain in both 
DI arm and RI arm with the ratio 2:1 at Month 13, and the absolute value of standardized 
effect size d will range from 0.44 to 0.51 when the study power increases from 0.80 to 
0.90 as shown in Table 7, where Figure 6 illustrates the relationship between d>0 and the 
study power.  
 
Table 7 
Sensitivity of the Absolute Value of Standardized Effect Size to 
Study Power for PSPs 
 
Power 
N1 
N2 
N 
 Absolute Value of d 
0.8 
62 
125 
187 
0.44 
0.81 
62 
125 
187 
0.44 
0.82 
62 
125 
187 
0.45 
0.83 
62 
125 
187 
0.46 
0.84 
62 
125 
187 
0.46 
0.85 
62 
125 
187 
0.47 
0.86 
62 
125 
187 
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Power 
N1 
N2 
N 
 Absolute Value of d 
0.87 
62 
125 
187 
0.48 
0.88 
62 
125 
187 
0.49 
0.89 
62 
125 
187 
0.5 
0.9 
62 
125 
187 
0.51 
 
Figure 6 
Relationship between Standardized Effect Size and Study Power for 
PSPs 
 
 
 
Interim Results from study CARISEL (213199) have shown that the estimated mean 
score of FIM for PSPs in standard arm was 4.7 with standard deviation (SD) 0.49 at 
Month 4. Assuming these results remain valid in our RI arm at Month 13 when a total of 
220 PSPs are enrolled in DI and RI with ratio 2:1, to achieve 80% power, the mean score 
of FIM at Month 13 for DI arm should be at least 4.92 if DI arm behaves better than RI 
arm, or at most 4.48 if vice versa, as the absolute mean difference |µ(DI) − µ(RI)| will be 
0. 22 ≈ 0.49*0.44. The mean FIM score of DI arm at Month 13 will be at most 4.47 if 
µ(DI) < µ(RI) or at least 4.93 if µ(DI) > µ(RI) to have 85% power. The other scenarios of 
µ(DI) are summarized for the range of detectable standardized effect size and the 
corresponding powers in Table 8. 
 

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Table 8 
The Mean FIM Score of DI Arm at Month 13 Assuming µ(RI)=4.7 and 
SD=0.49 for PSPs 
Absolute Value of d 
Power 
µ(DI) if µ(DI) < µ(RI) 
µ(DI) if µ(DI) > µ(RI) 
0.44 
0.8 
4.48 
4.92 
0.44 
0.81 
4.48 
4.92 
0.45 
0.82 
4.48 
4.92 
0.46 
0.83 
4.47 
4.93 
0.46 
0.84 
4.47 
4.93 
0.47 
0.85 
4.47 
4.93 
0.47 
0.86 
4.47 
4.93 
0.48 
0.87 
4.46 
4.94 
0.49 
0.88 
4.46 
4.94 
0.5 
0.89 
4.46 
4.95 
0.51 
0.9 
4.45 
4.95 
  
 
If we consider a series of standardized effect size d, Figure 7 below summarizes the 
corresponding minimum sample size N1 of RI arm needed to achieve three target powers 
(80%, 85%, 90%). For the exact sample size of PSPs and their allocation to each arm for 
d ranging from 0.44 to 0.51, please refer to Table 9 below, where N1’ is the Dropout-
Inflated enrollment sample size for RI arm, N2’ is the Dropout-Inflated enrollment 
sample size for DI arm and N’ is the total enrollment sample size for PSPs with dropout 
rate 15% across arms. 
 
For instance, if we expect the standardized effect size to be 0.45 which is slightly higher 
than 0.44 discussed above, then a total of 209 PSPs is required to be enrolled with 70 in 
RI arm and 139 in DI arm to achieve 80% power, while 59 PSPs and 118 PSPs are 
remained in each arm respectively at Month 13. And approximately 240 PSPs are needed 
in the enrollment to have 85% power, where 80 PSPs are allocated to RI arm and 160 to 
DI arm, and 68 PSPs and 136 PSPs are retained in each arm respectively at Month 13. 
 
Table 9 
Sensitivity of Sample Size to Standardized Effect Size for PSPs 
 
d 
Target Power  
 Actual Power 
N1 
N1' 
N2 
N2' 
N 
N' 
0.44 
0.8 
0.8 
62 
73 
124 
146 
186 
219 
0.44 
0.85 
0.85 
71 
84 
142 
168 
213 
252 
0.44 
0.9 
0.9 
83 
98 
166 
196 
249 
294 
0.45 
0.8 
0.8 
59 
70 
118 
139 
177 
209 
0.45 
0.85 
0.85 
68 
80 
136 
160 
204 
240 
0.45 
0.9 
0.9 
79 
93 
158 
186 
237 
279 
0.46 
0.8 
0.8 
57 
68 
114 
135 
171 
203 
0.46 
0.85 
0.85 
65 
77 
130 
153 
195 
230 
0.46 
0.9 
0.9 
76 
90 
152 
179 
228 
269 
0.47 
0.8 
0.8 
54 
64 
108 
128 
162 
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d 
Target Power  
 Actual Power 
N1 
N1' 
N2 
N2' 
N 
N' 
0.47 
0.85 
0.85 
62 
73 
124 
146 
186 
219 
0.47 
0.9 
0.9 
72 
85 
144 
170 
216 
255 
0.48 
0.8 
0.8 
52 
62 
104 
123 
156 
185 
0.48 
0.85 
0.86 
60 
71 
120 
142 
180 
213 
0.48 
0.9 
0.9 
70 
83 
140 
165 
210 
248 
0.49 
0.8 
0.8 
50 
59 
100 
118 
150 
177 
0.49 
0.85 
0.85 
57 
68 
114 
135 
171 
203 
0.49 
0.9 
0.9 
67 
79 
134 
158 
201 
237 
0.5 
0.8 
0.8 
48 
57 
96 
113 
144 
170 
0.5 
0.85 
0.85 
55 
65 
110 
130 
165 
195 
0.5 
0.9 
0.9 
64 
76 
128 
151 
192 
227 
0.51 
0.8 
0.8 
46 
55 
92 
109 
138 
164 
0.51 
0.85 
0.85 
53 
63 
106 
125 
159 
188 
0.51 
0.9 
0.9 
62 
73 
124 
146 
186 
219 
 
Figure 7 
Relationship between Minimum Sample Size Required for RI Arm 
and the Assumed Standardized Effect Size for PSPs 
 
5.3. 
Essential Analysis 
The primary endpoint in terms of feasibility is SSPs’ mean FIM score at Month 13 under 
Dynamic Implementation (DI) arm and Routine Implementation (RI) arm respectively, 
and the difference of their mean FIM scores between arms. For FIM of SSPs and the 
difference between arms, descriptive statistics including 95% confidence intervals will be 
displayed for these estimates. Mean FIM scores will be compared between the two 
implementation arms to test if the observed difference is statistically significant. In 

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addition, distribution of FIM items scores will also be compared. P-values will be 
reported for these comparisons. 
To address the potential intra-cluster correlation effect due to the cluster randomization 
design, classical methods such as mixed effects linear regression model or Generalized 
Estimating Equations will be utilized. Besides the analysis on the subject level, the 
stratification analysis will be performed at the site level to evaluate the impact of the 
capacity of sites (high volume vs low volume) in responses to two implementation 
strategies imposed on SSPs. Exploratory analysis will be undertaken to assess the 
variability of responses by other factors such as subset of implementation strategies.  
In addition to summary of mean FIM scores of SSPs at different timepoints, the change in 
mean FIM scores from baseline will be analyzed at the designated timepoints. For the 
specific Telehealth implementation strategy on SSPs, the subgroup analysis on FIM 
scores including change from baseline will be conducted.  
The FIM scores of PSPs will be summarized in the same way as those of SSPs. In 
addition, subgroup analysis on PSPs will include, but not limited to, factors such as 
demographic, baseline characteristics, study arm, clinic characteristics and APRETUDE 
initiation method. To address the potential differential dropout rates of PSPs between 
arms, appropriate imputation methods will be undertaken to handle missing data of 
different type. 
 
5.4. 
Secondary Analysis 
Key secondary outcomes include  
• Acceptability and feasibility of telehealth delivery: The mean Acceptability of 
Intervention Measure (AIM) score and Feasibility of Intervention Measure (FIM) 
score for SSPs and PSPs will be calculated. The scores will be calculated at 
Baseline, Month 5 and Month 13 for SSPs, and at Baseline, Month 7 (OLI)/Month 
6(DTI), and Month 13(OLI)/Month 12(DTI) for PSPs. Change from Baseline of 
mean score in the AIM and FIM scores at the respective time points from SSPs 
and PSPs will also be calculated. Descriptive statistics will be used including 95% 
confidence intervals.  Exploratory analyses will be undertaken to assess the 
variability of responses by factors including but not limited to clinic 
characteristics, SSP role and study arm. 
 
Additional analyses will assess SSPs and PSPs responses to acceptability and 
feasibility questions posed in the IS questionnaires. The finalization of the 
questionnaires will inform the latter analyses.  
 
Other secondary outcomes to evaluate include: 
• Change from baseline in SSPs’ FIM score of RI and DI for APRETUDE 
administration over time  

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• SSPs perceptions of facilitators and barriers to RI and DI and overall 
implementation of PrEP into routine care assessed over time 
• PSPs mean FIM and AIM score as well as ISQ responses for APRETUDE over 
time 
• Change from baseline in PSPs’ AIM score and FIM score as well as ISQ 
responses for APRETUDE over time  
• PSPs perception of facilitators and barriers to feasibility and acceptability of 
APRETUDE over time` 
• SSPs’ mean AIM score and ISQ responses for RI and DI for APRETUDE 
administration over time  
• Change from baseline in SSPs’ AIM score and ISQ responses for RI and DI for 
APRETUDE administration over time  
• PSPs’ mean AIM score and ISQ responses by implementation strategy over time 
• Change from baseline in PSPs’ mean AIM score and ISQ responses by 
implementation strategy over time 
• Proportion of SSPs and PSPs that agree or completely agree on the ISQ that each 
implementation strategy is fit for use over time 
• SSPs and PSPs perceptions of utility of implementation strategies and PSPs 
perceptions of facilitators and barriers to acceptability of RI and DI over time 
• Proportion of injections occurring within target window from target date (± 7 days 
for Injection dose 2 and ± 7 days of target date for subsequent injections) over 
time 
• Proportion of PSPs completing target number of injections through M13  
• PSPs and SSPs perception of barriers and facilitators to fidelity to injections 
window over time 
• Proportion of site staff who administer Sexual Health Assessment for 
APRETUDE over time 
• Proportion of eligible PSPs for which Sexual Health Assessment for APRETUDE 
are administered over time 
• Proportion of MSM and TGM who take the Sexual Health Assessment over time 
• Proportion of MSM & TGM who report having had sex in the last 6 months on 
Sexual Health Assessment over time 
• Proportion of MSM & TGM who expressed interest in PrEP or never heard of 
PrEP out of those who report having had sex in the last 6 months over time 
• Proportion of PSPs who initiate APRETUDE after taking the Sexual Health 
Assessment over time 
• SSPs and PSPs perceptions of Sexual Health Assessment over time 

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• Summarize components adapted and changes made using FRAME-IS at pre-
implementation and over time 
 
• SSPs and PSPs perceptions of barriers and facilitators over time 
• Proportion of PSPs with history of PrEP use that complete the Sexual Health 
Assessment and ISQ and start APRETUDE over time  
• PSPs reasons for choosing APRETUDE, including switching, as assessed by SSIs 
and ISQ  
• SSIs, FRAME-IS and facilitation calls assessed qualitatively with SSPs and SSIs 
with PSPs over time  
 
In general, descriptive summaries will include number of subjects, means, standard 
deviations, median, first and third quartiles, as well as the minimum and maximum values 
for continuous outcomes; and counts and proportions are presented for categorical 
measures for outcomes in endpoints above. Unless otherwise stated, a 95% confidence 
interval (CI) will be provided for means and proportions. 
Analyses of the implementation outcomes for SSPs and PSPs will use standardized 
measures, such as the FIM and AIM, as well as items from the ISQ that measure these 
outcomes using different terminology (Table 10) [Proctor, 2011, Weiner, 2017, Aarons, 
2015]. SSPs analyses will also be conducted by factors including but not limited to study 
arm, staff role, and clinic characteristics. PSPs analyses will also be conducted by factors 
including but not limited to study arm, clinic characteristics, APRETUDE initiation 
method, PrEP use before initiation on CAB PrEP, service delivery method, and patient 
subgroups if sufficient data are available. 
 

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Table 10 
Definitions of Implementation Outcomes  
5.5. 
Other/Tertiary Endpoints 
Implementation 
Outcomes 
Definition  
Additional terminology  
 
Acceptability (Proctor, 
2011, Weiner, 2017) 
Acceptability is the perception among 
implementation stakeholders that a given 
treatment, service, practice, or innovation 
is agreeable, palatable, or satisfactory 
meets my approval, seems good, meets 
my needs, is satisfactory, is appealing, I 
like, I welcome the use of 
 
 
satisfaction with various aspects of the 
innovation; examples include content, 
complexity, comfort, delivery, and 
credibility, 
Feasibility (Proctor, 
2011, Weiner, 2017) 
Feasibility is defined as the extent to 
which a new treatment, or an innovation, 
can be successfully used or carried out 
within a given agency or setting. 
practical, realistic, workable, 
implementable, possible, viable, doable, 
easy to use, challenging (reverse score) 
 
 
Actual fit, suitability for everyday use, 
convenience* 
Utility (Aarons, 2015) 
Seen as being useful and helpful in day-
to-day operations and in implementing 
change and EBP 
Useful, helpful 
*Convenience is synonymous with published literature terminology and used in this study to measure 
feasibility 
CCI

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CCI

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5.6. 
Qualitative Analyses 
Qualitative data collection and analyses for both SSPs and PSPs will be informed by the 
study frameworks – CFIR and Proctor outcomes framework. SSPs and PSPs perceptions 
on implementation, including but not limited to facilitators and barriers, implementation 
of PrEP into routine care, quality of care, will be assessed by semi-structured qualitative 
interviews, implementation science questionnaire, FRAME-IS, implementation 
monitoring calls and facilitation calls. The qualitative data are embedded within the 
quantitative outcomes of the study for expansion and triangulation of data. 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 will be compiled 
and analyzed. The Implementation Science vendor will be responsible for coding all 
qualitative assessments for use in the evaluation of the study outcomes. Established 
procedures to enhance validity will be used, including development of an audit trail 
documenting analytical decisions, agreeing on a threshold for rater agreement, and 
documenting coding decisions.  
 
The goals, objectives and key research questions will guide all aspects of the qualitative 
analyses. Using content analysis, analytical categories to describe and explain 
observations will be identified. Codes will be derived deductively by identifying 
categories at the beginning of the research using the study framework and interview 
guides as well as 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 
CCI

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lead to further refinement. Qualitative and quantitative data may be integrated for 
expansion, development, and convergence to assist in the understanding of processes and 
characteristics that may influence implementation outcomes of APRETUDE.  
 
 
5.7. 
Limitations of the Research Methods 
The two arms are randomized with ration 2:1 on the site level, which leads to the 
unbalance of subjects under different interventions. This might reduce the study power 
with a fixed sample size. 

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6. 
Protection of Human Subjects 
6.1. 
Ethical Approval and Participant Consent 
The protocol, protocol amendments, ICF, and other relevant documents (e.g., 
advertisements) must be submitted to an Institutional Review Board (IRB) and reviewed 
and approved by the IRB before the study is initiated.  
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The PrEP Provider will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB. 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
• Providing oversight of the conduct of the study at the PrEP site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations. 
6.2. 
Participant Confidentiality 
6.2.1. 
PSPs 
PSPs will be assigned a unique identifier.  Any PSP records or datasets that are 
transferred to the sponsor or third party working with the Sponsor to conduct the study 
will contain the identifier only; PSP names or any information which would make the 
participant identifiable will not be transferred.  
Collection of sex, race and ethnicity data is necessary to assess and monitor the 
diversity of the trial participants, in order to meet the study objectives and to 
determine if the trial participants are truly representative of the impacted 
population. 
The PSP must be informed that their 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 PSP who will be required to give consent for their data to be used as 
described in the informed consent.  

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The PSP must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
All study site staff will ensure protection of PSP personal data and will not include PSPs’ 
names on any sponsor forms, reports, publications, or in any other disclosures, except 
where required by laws. 
6.2.2. 
SSPs 
SSPs will be assigned a unique identifier.  Any SSPs datasets that are transferred to the 
sponsor or third party working with the Sponsor to conduct the study will contain the 
identifier only; SSP names or any information which would make the SSP identifiable 
will not be transferred.  
SSPs must be informed that their study assessment data will be used by the sponsor in 
accordance with local data protection law. SSPs will agree to data privacy requirements 
prior to data collection. 
 
6.3. 
Informed Consent Process 
The PrEP Provider or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant, or their legally authorized representative and 
answer all questions regarding the study.  
• Potential PSPs must be informed that their participation is voluntary. PSPs will be 
required to physically or electronically 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.  
• The medical record must include a statement that physical or electronic informed 
consent was obtained before the participant was enrolled in the study and the date 
the physical or electronic consent was obtained.  The study site authorized person 
obtaining the informed consent must also sign the ICF. 
• PSPs must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A physical or electronic copy of the ICF(s) must be provided to the participant or 
their legally authorized representative.  
The Sponsor (alone or working with others) may use participant’s coded study data and 
other information to carry out this study; understand the results of this study; learn more 
about Cabotegravir or about the study disease; and publish the results of these research 
efforts.   
The ICF contains a separate section that addresses the use of PSPs for optional further 
research. The PrEP Provider or authorized designee will inform each participant of the 

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possibility of further research not related to the study/disease. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to 
document a participant's agreement to allow any participant data and/or remaining 
leftover samples to be used for further research not related to the study/disease. 
Participants who decline further research will tick the corresponding “No” box. 
7. 
CAB PrEP and Concomitant Therapy 
The protocol only requires that the PSPs receive marketed CAB tablets for PrEP and 
APRETUDE, dosed in accordance with the approved label; no CAB PrEP or any other 
PrEP will be provided by ViiV Healthcare.  No dose reductions, modifications, or 
changes in the frequency of any components of CAB PrEP, i.e., CAB tablet for PrEP or 
APRETUDE will be allowed during the study beyond what is allowed within the 
approved CAB PrEP labels. 
The PrEP Provider should follow the APRETUDE USPI for the preparation and 
administration of APRETUDE [APRETUDE, 2021]. 
7.1. 
Missed APRETUDE Injections 
Adherence to the APRETUDE injection dosing schedule is strongly recommended.  If a 
PSP misses a scheduled injection visit, the PrEP Provider should follow the USPI 
guidance for oral PrEP and schedule for restart of IM injections.  The PrEP 
provider is responsible for all clinical management decision for participants after a 
missed dose, as described in the USPI.   
Any changes in a PSP’s CAB PrEP regimen must be recorded in the eCRF.  This 
includes CAB tablets for PrEP or other approved oral PrEP to ensure PrEP coverage 
during a planned or unplanned missed injection visit. 
PSPs receiving CAB PrEP may be at risk for acquiring HIV and development of 
virologic resistance (USPIs for CAB tablets for PrEP and APRETUDE) [APRETUDE, 
2021]. PrEP providers should refer to the USPI [APRETUDE, 2021] and CDC PrEP 
guidelines [Centers for Disease Control and Prevention, 2021] for the appropriate 
management of incident HIV infection (i.e., HIV infection identified following start of 
CAB PrEP). 
7.2. 
Treatment of an Overdose 
For this study, any dose of CAB PrEP greater than listed in the USPI will be considered 
an overdose [APRETUDE, 2021].  All overdoses and any treatment for the overdosage 
should be recorded in the eCRF. 
There is no known specific treatment for overdose with CAB PrEP.  If overdose occurs, 
monitor the participant and apply standard supportive treatment as required, including 
monitoring of vital signs as well as observation of the clinical status of the patient, and 
record in the participants source documentation.  Consider the prolonged exposure to 
cabotegravir following injections when assessing treatment needs and recovery.   

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In the event of an overdose, the site must: 
1. Take action according to the USPI and notify and consult the primary Medical 
Monitor [APRETUDE, 2021]. 
2. Document the timing and the quantity of the excess dose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the PrEP 
provider  
7.3. 
Concomitant Therapy 
PrEP providers will monitor concomitant medications per the USPI, especially regarding 
concomitant medications that are contraindicated with CAB PrEP and medications with a 
potential for drug-drug interactions with CAB PrEP [APRETUDE, 2021]. 
The PrEP provider will note all new concomitant medications and determine if any new 
contraindicated or concomitant medications with the potential for drug interactions are 
noted prior to administering CAB PrEP.  Contraindicated or concomitant medications 
with the potential for drug interactions according to the CAB PrEP USPI must be 
recorded in the eCRF at each visit [APRETUDE, 2021].   
8. 
Discontinuation of CAB PrEP and Participant 
Discontinuations 
8.1. 
Discontinuation of CAB PrEP 
It may be necessary for a PSP to permanently discontinue CAB PrEP.  If CAB PrEP is 
permanently discontinued, the PSP will not remain in the study.  See the SoA (ANNEX 1 
and ANNEX 2) and for data to be collected at the time of discontinuation of CAB PrEP.  
All study and CAB PrEP discontinuations will be captured in the eCRF. 
A PSP may have to discontinue CAB PrEP due to moderate to severe (as clinically 
determined by the PrEP provider) COVID-19 infection (suspect, probable, or confirmed 
using the most recent version of the World Health Organization (WHO) case definition 
[World Health Organization, 2020]. 
All study and CAB PrEP discontinuations will be recorded in the CRF. 
8.2. 
Temporary Discontinuation  
If CAB PrEP is temporarily discontinued for any reason, then the PrEP provider will: 1) 
record temporary discontinuations and restart information in the eCRF; and 2) will be 
responsible for clinical decision and management regarding the use of another 
recommended PrEP regimen to maintain PrEP coverage.  If the PSP does not restart CAB 
PrEP, i.e., if CAB PrEP is permanently discontinued, then such PSP will no longer be 
eligible to continue the study.  

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8.3. 
Participant Discontinuation / Withdrawal from the Study 
A PSP may discontinue CAB PrEP and withdraw from the study at any time at their own 
request or may be withdrawn at any time at the discretion of the PrEP providers for safety 
(i.e., AE, SAE), behavioral, or compliance reasons (i.e., protocol deviation) or their own 
decision (consent withdrawal).   
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. The SoA includes the data to be collected at 
the time of study discontinuation, i.e. for safety monitoring purposes. 
If the PSP withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  
A SSP may withdraw from the study at any time at their own request. If the SSP is 
changing roles, the individual assuming the role will be enrolled in the study. If the SSP 
is retaining the role, reasons for withdrawal will be ascertained. 
8.4. 
Lost to Follow-up 
A PSP will be considered lost to follow-up if they fail to return for one or more scheduled 
visits and is unable to be contacted by the PrEP provider.  
The following actions must be taken if a PSP fails to return to the site for a required study 
visit: 
• The PrEP provider must attempt to contact the PSP and reschedule the missed 
visit as soon as possible and counsel the PSP on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the PSP wishes to and/or 
should continue on study and receiving injections at the site.   
• Before a PSP is deemed lost to follow up, the PrEP provider must make every 
effort to regain contact with the PSP.  These contact attempts should be 
documented in the PSP’s medical record. 
• Should the PSP continue to be unreachable, they will be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”.  
A SSP will be considered lost to follow-up only if that SSP role in the clinic is 
eliminated. Else, an SSP who leaves their role will be replaced with the SSP who 
assumes the role to complete subsequent assessments.  

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9. 
Specific Adverse Events, Serious Adverse Events 
(SAEs) and Other Safety Reporting 
The definitions of adverse events (AEs) or serious adverse events (SAEs) can be found in 
ANNEX 4. For adverse events (AEs), only those that are considered related to CAB 
PrEP, or that caused the PSPs to discontinue the study are required to be reported (See 
Section 9.1.). 
The definitions of unsolicited and solicited adverse events can be found in ANNEX 4. 
The definitions of device-related safety events, adverse device effects (ADEs) and serious 
adverse device effects (SADEs), can be found in ANNEX 5. Device deficiencies are 
covered in Section 9.3.5. 
AEs will be reported by the PSP (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The PrEP Provider and any qualified designees are responsible for detecting, 
documenting, and recording 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 PSP to discontinue CAB PrEP (see Section 
9.1).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in ANNEX 4. 
Please refer to ANNEX 6 for study management information during the COVID-19 
pandemic. 
9.1. 
Specific Adverse Events to be Documented in this Study 
Please refer to the USPIs for CAB tablets for PrEP and APRETUDE for additional safety 
information [APRETUDE, 2021].  
Adverse events that occur during the trial should be evaluated by the PrEP provider and 
graded according to the Division of AIDS (DAIDS) toxicity scales Version 2.1 July 
2017. 
AEs and SAEs that are required to be recorded as defined in the eCRF include:  
• AEs/ADRs considered related to CAB PrEP  
o Note: Non-serious injection site reactions do not have to be reported to the 
CRO.. 
• AEs/Adverse drug reactions (ADRs) reported at the Baseline/Month 1 visit that 
are considered related to CAB tablets for PrEP (if used as optional oral lead-in) 
• All AEs, including ISRs, whether considered related or not, that cause the 
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• All SAEs whether related to CAB PrEP or not 
The PrEP provider are obliged to collect and report from the time of informed consent to 
PSP’s completion of study or study withdrawal, all non-serious ADRs, (excluding non-
serious ISRs), AEs leading to withdrawal and all SAEs listed above, to the CRO. 
As ISRs have been well characterized throughout the clinical development program for 
CAB PrEP and are considered common adverse drug reactions for CAB PrEP, therefore 
only serious ISRs and ISRs leading to discontinuation are required to be reported  as 
described in above. 
Non serious AEs that are considered not related to CAB PrEP by the SSP or do not lead 
to withdrawal, should be documented in the source documents but will not be 
documented in the eCRF, as this information has been extensively collected in PrEP 
clinical trials, no further information is needed to characterize these events. 
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• AEs that meet the criteria for documentation listed in Section 9.1, and all SAEs 
will be collected from the signing of the informed consent form until the PSP 
completes or withdraws from the study, at the timepoints specified in the SoA 
(ANNEX 1 and ANNEX 2).  
 
• AEs that begin during the oral lead-in and are considered by the PrEP Provider to 
be related to CAB PrEP will be recorded as a CAB PrEP related AE after 
obtaining the informed consent.  
• All other events that begin before the administration of CAB PrEP but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions section of the case report form (CRF) not as AEs. 
• All non-serious ADRs will be collected from Day 1 until the follow-up visit at the 
time points specified in the SoA (ANNEX 1 and ANNEX 2). 
• AEs 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 ANNEX 
4. The PrEP Provider will submit any updated SAE data to the sponsor within 24 
hours of it being available. 
• A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined earlier in this Section 9.1.1.  

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• PrEP Providers are not obligated to actively seek information on AEs or SAEs 
after conclusion of the study participation. However, if the PrEP Provider learns 
of any SAE, including a death, at any time after a participant has been discharged 
from the study, the PrEP Provider must record it in the medical records. If the 
PrEP Provider considers the event to be reasonably related to the study 
intervention or study participation, the PrEP Provider must promptly notify the 
sponsor. 
9.1.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
9.1.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the PrEP provider is required to proactively follow each 
PSP at subsequent visits/contacts.  All SAEs will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.4).  Further information on follow-up procedures is given in the SRM. 
9.1.4. 
Regulatory Reporting Requirements for SAEs 
The definition of serious adverse events (SAEs) can be found in ANNEX 4.  Prompt 
notification by the site to the sponsor of an SAE is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of CAB PrEP are 
met. All SAEs need to be reported within 24 hours of documentation sent by an 
automated, electronic safety alert within the CRF. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of CAB PrEP.  The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB) and PrEP providers with participants in this 
study. 
The site which receives a safety report describing an SAE or other specific safety 
information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with the required study documents and will notify the IRB, if appropriate 
according to local requirements. 
Safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded 
to participating PrEP providers as necessary. 
9.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA. 

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9.2.1. 
Clinical safety laboratory assessments 
Local laboratory assessments for this study will be performed at local laboratories.  The 
PrEP provider must review the laboratory reports and should follow local or CDC PrEP 
management guidelines for laboratory assessments during PrEP 
• The PrEP provider will determine if any laboratory tests have values considered 
clinically significant and will be responsible for the participant clinical 
management. The laboratory reports must be filed with the source documents. 
Testing for HIV-1 and liver chemistries (if performed at the discretion of the PrEP 
provider) will be analyzed by the local labs (refer to SRM for further details). Additional 
tests may be performed at any time during the study as determined necessary by the PrEP 
provider and in accordance with the current CDC PrEP guidelines [Centers for Disease 
Control and Prevention, 2021]. 
9.2.2. 
Liver Chemistry Monitoring 
The decision whether to discontinue CAB PrEP in the presence of abnormal liver tests 
should be made by the PrEP provider in accordance with the PrEP CDC clinical 
management guidelines [Centers for Disease Control and Prevention, 2021] and the US 
prescribing information for CAB tablet for PrEP and APRETUDE [APRETUDE, 2021] 
In cases where the PrEP provider suspects a PSP has an event of hepatotoxicity, the liver 
eCRF forms will also need to be completed, in addition to any corresponding AE or SAE 
form. The additional forms will gather further details of the liver event and should be 
completed in a timely manner.Section 9.2.1 
9.3. 
Adverse Events (AEs), Pregnancy Exposure and Incident 
Reporting 
All PSP clinical safety data will be collected as outlined in the eCRF. No clinical safety 
data will be collected for SSPs.  
9.3.1. 
Definition of adverse events  
An AE is any untoward medical occurrence in a PSP, temporally associated with the use 
of CAB PrEP, whether or not considered related to a 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 CAB PrEP. 
AEs will be reported by the PSP (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative [LAR]) and be collected and stored in the 
participants source documentation.   
The PrEP provider should assess all reported AEs and SAEs for follow-up medical 
management and to determine relatedness to CAB PrEP.  When a causality relationship is 

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determined by the PrEP provider to be related to CAB PrEP, this must be recorded as a 
treatment related AE or SAE.  
Adverse events that occur during the trial should be evaluated by the SSP and graded 
according to the Division of AIDS (DAIDS) toxicity scales Version 2.1 July 2017. 
Further details of the definitions of adverse events (AE) or serious adverse events (SAEs) 
can be found in ANNEX 4. 
9.3.1.1. 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is defined as a noxious and unintended response to a 
medication related to any doses where there is at least a reasonable possibility, or the 
relationship cannot be ruled out, that it is related to CAB PrEP. 
9.3.1.2. 
Injection Site Reactions 
Injection site reactions (ISRs) are considered drug related as they are related to the 
administration of CAB PrEP.  ISRs may include redness, itching, pain or swelling or 
discomfort at the site of the reaction.  
As ISRs have been well characterized throughout the clinical development program for 
CAB PrEP and are considered common adverse drug reactions for CAB PrEP, therefore 
only serious ISRs and ISRs leading to discontinuation are required to be reported to 
Sponsor or designee as described in ANNEX 4. 
9.3.2. 
Reporting of AEs and timelines  
All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, All AEs listed in Section 9.1.1 will 
require reporting within 3 days.  
If the eCRF is unavailable at the time of notification of these events, a paper form 
will need to be completed and sent to the Sponsor or designee. 
Prompt notification by the site to the sponsor of these events is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of CAB PrEP are met.  
9.3.3. 
Pregnancy 
Pregnancy testing will be managed by the PrEP Provider and in accordance with CDC 
PrEP guidelines. 
If a pregnancy is reported, the site will record pregnancy information on the 
appropriate form and submit it to the Sponsor or designee within 24 hours of 
learning of the pregnancy. Pregnancies will also be directly reported to the 
Antiretroviral Pregnancy Registry (APR) by the PrEP provider. The procedure for 
reporting is outlined in the SRM. 

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Whilst pregnancies are not part of the study they will be reported to the Sponsor or 
designee within 24 hours of awareness and documented in the eCRF.  All 
pregnancies will be followed up until outcome (including premature terminations and 
complications) for both mother and child. 
The PrEP Provider will be provided with necessary “pregnancy notification” and 
“pregnancy follow up” forms and supported by clinical monitor and/or Sponsor medical 
team in complying with regular pregnancy reporting procedures.  Pregnancies will also 
be reported to the Antiretroviral Pregnancy Registry (APR) by the Sponsor.  The PrEP 
Provider must not report to APR, to avoid duplication. 
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 SAEs. 
Any SAE occurring in association with a pregnancy brought to the site’s attention after 
the PSP has completed the study and considered by the PrEP Provider as possibly linked 
to CAB PrEP exposure, must be promptly reported to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the PrEP Provider will be reported to the Sponsor (refer to SRM for 
details). While the PrEP Provider is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• 
The Sponsor’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/index.htm. 
Prior to continuation of CAB PrEP following pregnancy, the following must occur: 
• PrEP Provider confirms CAB PrEP can be continued and this documentation is 
stored in the PSP’s source documents. 
• The site agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
 
9.3.4. 
Cardiovascular and Death Events 
All deaths will be reported as SAEs. In addition, all deaths will be required to have the 
eCRF death forms completed by the site.  These sections include questions regarding the 
death (including sudden cardiac death and non-cardiovascular death).  
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up eCRF reports regarding death must be completed 
within one week of when the death is reported. 

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For any cardiovascular events detailed in ANNEX 4 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.   
9.3.5. 
Medical Device Deficiencies 
To fulfil regulatory reporting obligations worldwide, the SSP is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that 
occur during the study with such devices.  
The definition of a medical device deficiency can be found in ANNEX 5 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in ANNEX 4 of the protocol.  
9.3.5.1. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be reported during all 
periods of the study in which the medical device is used.  
• If the SSP learns of any device deficiency at any time after a participant has been 
discharged from the study, and such a device deficiency is considered reasonably 
related to a medical device provided for the study, the PrEP Provider will 
promptly notify the Sponsor. 
9.3.5.2. 
Prompt Reporting of Medical Device Deficiencies to the Sponsor 
• Device deficiencies will be reported to the sponsor within 24 hours after the SSP 
determines that the event meets the protocol definition of a device deficiency. 
• The method of reporting of Medical device deficiencies is outlined in ANNEX 5. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
9.3.5.3. 
Regulatory Reporting Requirements for Device Deficiencies 
• The SSP will promptly report all device deficiencies occurring with any medical 
device provided for use in the study 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 SSP, 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. 
 
 

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10. 
REFERENCES 
Aarons, GA, Ehrhart, MG, Farahnak, LR, et al. (2015) Leadership and organizational 
change for implementation (LOCI): A randomized mixed method pilot study of a 
leadership and organization development intervention for evidence-based practice 
implementation. Implementation Science, 10(1), Article 
11. https://doi.org/10.1186/s13012-014-0192-y 
APRETUDE Prescribing Information (APRETUDE USPI). Dec 2021. 
Becker D, Koenig MA, Mi Kim Y, Cardona K, et al. (2007) The quality of family 
planning services in the United States: Findings from a literature review. Perspectives on 
Sexual and Reproductive Health. 39(4):206–215 
Bauer MS, Kirchner J. (2020) Implementation science: What is it and why should I care? 
Psychiatry Research. 283:112376. 
Centers for Disease Control and Prevention. (2018) HIV Surveillance Report, 2018 
(Updated); vol. 31. http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. 
Published May 2020. Accessed July 21, 2021/ 
Centers for Disease Control and Prevention. (2019, April) HIV and Transgender 
Communities. Issue Brief. Retrieved from HIV and Transgender Communities (cdc.gov) 
Centers for Disease Control and Prevention. (2021) US Public Health Service: 
Preexposure prophylaxis for the prevention of HIV infection in the United States—2021 
Update: a clinical practice guideline. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-
guidelines-2021.pdf. Published December 2021. 
Centers for Disease Control and Prevention. (2021) Monitoring selected national HIV 
prevention and care objectives by using HIV surveillance data—United States and 6 
dependent areas, 2019. HIV Surveillance Supplemental Report 26(No. 2). 
http://www.cdc.gov/hiv/library/reports/ hiv-surveillance.html. Published May 2021. 
Accessed September 12, 2021. 
Damschroder, L. J., Aron, D. C., Keith, R. E., et al. (2009). Fostering implementation of 
health services research findings into practice: a consolidated framework for advancing 
implementation science. Implementation science, 4(1), 1-15. 
Dumville, J. C., Hahn, S., Miles, J. N. V., et al. (2006). The use of unequal randomisation 
ratios in clinical trials: a review. Contemporary clinical trials, 27(1), 1-12. 
Fagen, M. C., Redman, S. D., Stacks, J., et al. (2011). Developmental evaluation: 
Building innovations in complex environments. Health Promotion Practice, 12(5), 645-
650. 
HIV Prevention Trials Network (HPTN). (2020a, July 7) HPTN 083 Study demonstrates 
superiority of cabotegravir for the prevention of HIV. Retrieved from 

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https://www.hptn.org/news-and-events/press-releases/hptn-083-study-demonstrates-
superiority-cabotegravir-prevention-hiv.  
HIV Prevention Trials Network (HPTN). (2020b, Nov 9) HPTN 084 Study Demonstrates 
Superiority of Injectable Cabotegravir to Oral FTC/TDF for the Prevention of HIV in 
Cisgender Women in Sub-Saharan Africa. Retrieved from https://www.hptn.org/news-
and-events/announcements/hptn-084-study-demonstrates-superiority-of-injectable-
cabotegravir-to 
Hoth, A. B., Shafer, C., Dillon, D. B., et al. (2019). Iowa TelePrEP: a public-health-
partnered telehealth model for human immunodeficiency virus preexposure prophylaxis 
delivery in a rural state. Sexually transmitted diseases, 46(8), 507-512. 
Jones, J. T., deCastro, B. R., August, E. M., et al. (2021). Pre-exposure prophylaxis 
(PrEP) awareness and prescribing behaviors among primary care providers: DocStyles 
survey, 2016–2020, United States. AIDS and Behavior, 25(4), 1267-1275. 
Kanny, D., Jeffries IV, W. L., Chapin-Bardales, J., et al. (2019). Racial/ethnic disparities 
in HIV preexposure prophylaxis among men who have sex with men—23 urban areas, 
2017. Morbidity and Mortality Weekly Report, 68(37), 801. 
Landovitz, R. J., Donnell, D., Clement, M. E., et al. (2021). Cabotegravir for HIV 
prevention in cisgender men and transgender women. New England Journal of 
Medicine, 385(7), 595-608. 
Miller, C., Barnett, M.L., Baumann, A.A. et al. The FRAME-IS: a framework for 
documenting modifications to implementation strategies in healthcare. Implementation 
Sci 16, 36 (2021).  
Philbin MM, Parish C, Kinnard EN, et al. Interest in Long-Acting Injectable Pre-
exposure Prophylaxis (LAI PrEP) Among Women in the Women's Interagency HIV 
Study (WIHS): A Qualitative Study Across Six Cities in the United States. AIDS Behav. 
2021 Mar;25(3):667-678.  
Pleuhs, B., Quinn, K. G., Walsh, J. L., et al. (2020). Health care provider barriers to HIV 
pre-exposure prophylaxis in the United States: a systematic review. AIDS Patient Care 
and STDs, 34(3), 111-123 
Proctor, E., Silmere, H., Raghavan, R., et al. (2011). Outcomes for implementation 
research: conceptual distinctions, measurement challenges, and research agenda. 
Administration and Policy in Mental Health and Mental Health Services Research, 38(2), 
65-76 
Proctor, E.K., Powell, B.J. & McMillen, J.C. (2013) Implementation strategies: 
recommendations for specifying and reporting. Implementation Sci 8, 139.  
Ritchie MJ, Dollar KM, Miller CJ, et al. Using Implementation Facilitation to Improve 
Healthcare (Version 3). Veterans Health Administration, Behavioral Health Quality 
Enhancement Research Initiative (QUERI), 2020 

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Saag, M. S., Gandhi, R. T., Hoy, J. F., et al. (2020). Antiretroviral drugs for treatment and 
prevention of HIV infection in adults: 2020 recommendations of the International 
Antiviral Society–USA Panel. Jama, 324(16), 1651-1669. 
Smith, D. K., Maier, E., Betts, J., et al. (2016). What community-based HIV prevention 
organizations say about their role in biomedical HIV prevention. AIDS Education and 
Prevention, 28(5), 426-439. 
Sullivan, P. S., & Siegler, A. J. (2018). Getting pre-exposure prophylaxis (PrEP) to the 
people: opportunities, challenges and emerging models of PrEP implementation. Sexual 
health, 15(6), 522-527. 
Tolley, E.E., Zangeneh, S.Z., Chau, G. et al. Acceptability of Long-Acting Injectable 
Cabotegravir (CAB LA) in HIV-Uninfected Individuals: HPTN 077. AIDS 
Behav 24, 2520–2531 (2020).  
Trost, S. L., Onwubiko, U. N., Wilson, D. B., et al. (2020, May). Health Care–Seeking 
Behaviors and Perceptions of Provider-Initiated Discussion of Pre-exposure Prophylaxis 
Among PrEP-Naïve HIV-Negative Men Who Have Sex With Men in Atlanta, Georgia. 
In Open forum infectious diseases (Vol. 7, No. 5, p. ofaa165) 
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.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables 
ViiV Healthcare. (2021, May 4). ViiV Healthcare initiates rolling submission of new 
drug application with US FDA for long-acting cabotegravir for prevention of HIV. 
Retrieved from https://viivhealthcare.com/en-gb/media/press-releases/2021/may/viiv-
healthcare-initiates-rolling/ 
Weiner BJ, Lewis CC, Stanick C, et al. (2017) 12:108 DOI 10.1186/s13012-017-0635-3 
World Health Organization. (2020, December). WHO COVID-19: Case Definitions 
Updated in Public health surveillance for COVID-19. Available from: 
file:///C:/Users/nap27946/Downloads/WHO-2019-nCoV-Surveillance_Case_Definition-
2020.2-eng.pdf 
 
 

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11. 
ANNEX 
11.1. 
ANNEX 1: Schedule of Activities – Direct to injection 
Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
1. 
The timing and number of planned study assessments, specifically interviews with SSPs and PSPs, may be altered during the study based on newly available data. Brief 
interviews may be held at other times based on learnings during implementation.   
2. 
Benefits verification should be performed at the start of the screening period, which may be extended up to 90 days to allow for this confirmation. All other screening/eligibility 
procedures (excluding informed consent) should only be performed after receiving this benefits confirmation. Additionally, in line with the USPI, all patient participants require 
proof of a negative HIV test, dated within the 7 days prior to PrEP initiation, regardless of any prior negative test results. During screening/enrollment, the following will be 
completed for PSPs: 1) Informed consent form (ICF), 2) Benefits verification, as required, 3) Confirm Inclusion and Exclusion criteria, 4) Demography 5) Medical History, 
including history of HCV infection, and current medical conditions 6) required labs per clinical local standard of care. Screening/enrollment can occur on the same date as the 
first APRETUDE injection as long as a negative HIV test is documented within 7 days prior to initiation of APRETUDE. Refer to Section 3.3.1 for details on re-screening for 
PSPs who fail screening. 
3. 
Dose 1(D1) is defined as the date of first APRETUDE injection. The following sequence of events must be followed for participants at the D1 visit: 1) complete questionnaires 
and assessments prior to or at the visit, and 2) Receive first intramuscular (IM) injections at the visit.  
4. 
The treatment period is based on 12 calendar months. The last APRETUDE injection is to occur at the last study visit. 
5. E.D. = early discontinuation/ withdrawal: This visit should only be conducted if the participant discontinues from the study prior to completing the Study at Month 12, and the 
discontinuation/withdrawal reason should be recorded. For SSPs, this visit will only occur if the SSP withdraws and remains in the role for which they were enrolled and no 
replacement is possible.  
 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Clinical and Other Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed 
consent must be 
obtained from 
each potentially 
eligible participant 
by site personnel 
prior to the 
initiation of any 
M1 procedures as 
outlined in this 
protocol. 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
will be assessed 
during screening. 
Benefits 
verification, as 
needed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current Medical 
Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Laboratory 
assessments 
X – needed 
at BL, M6 
and end of 
study, can 
be just HIV 
test and STI 
testing, but 
shouldn’t be 
completely 
non-
prescriptive.   
Lab assessments, including HIV testing and STI clinical diagnoses (defined for this study as syphilis (any stage), 
gonorrhea, chlamydia, or trichomonas) at Screening and during PrEP should be performed using local 
laboratories and should be in accordance with the CDC PrEP clinical management guidelines and the USPI or 
per clinical local standard of care.  All lab reports must be stored in the participants source documentation at the 
clinical sites with only the protocol-specified test results to be reported in the eCRF*.  
For PSPs with incident HIV-1 infections, all available HIV-1 test results (HIV Test Result (positive, Negative and 
Indeterminate), HIV Test Type (HIV-1 Antibody/Antigen test and HIV-1 RNA)) conducted by the site as standard 
of care and, if applicable and available, the start date of ART and ART regimen (by category) used will be 
reported in the eCRF. 
 
x 
*All performed HIV 
test results 
(regardless of 
result, including 
positive, negative, 
or indeterminate) 
and HIV test type 
will be reported in 
the eCRF.  
Study Treatment: Participants who are started on oral CAB PrEP as optional oral lead in will receive their first dose of oral CAB on M1.  Participants who are started on 
APRETUDE injections (direct to injection) will receive their first dose of APRETUDE injection on M1. 
 
All injections will be administered according to the APRETUDE USPI. 
Cabotegravir LA 
PrEP IM Initiation 
injection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Cabotegravir LA 
PrEP IM 
Maintenance 
injections 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
IM dosing is 
expected to occur 
on the same date 
of the month as 
determined by 
Dose 1 - 
Treatment Target 
Date.  Dosing 
window is (+ or -) 
a 7-day window, 
as per the USPI. 
Concomitant 
medication review 
X 
 
======================================================→ 
X 
Record in CRF if; 
contraindicated 
medications, 
concomitant 
medications with a 
potential for a 
drug-drug 
interaction (DDI) 
per the CAB tablet 
for PrEP or 
APRETUDE 
USPI;  

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Adverse Event 
(AE) Review 
 
X 
 
======================================================→ 
X 
Only drug related 
AEs and AEs 
leading to CAB 
Prep 
discontinuation 
will be collected in 
the eCRF. 
Serious AEs 
(SAEs) 
X 
 
 
======================================================→ 
X 
All SAEs 
regardless of 
relatedness will be 
collected in the 
eCRF. 
Pregnancy status 
X 
======================================================→ 
X 
Ask person of 
childbearing 
potential at each 
visit if they are 
pregnant and ask 
for the date of 
their LMP. 
Questionnaires and Interviews: Questionnaires and Interviews should be completed before receiving APRETUDE IM injections 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Patient Study Participants 
PSP baseline questionnaires should be completed within two weeks prior to or on their D1 visit and before receiving the 1st APRETUDE injection. 
 
Participants interviews should be completed within two weeks prior to or two weeks following their D1 visit and within two weeks prior to or two weeks following the target dates for 
their D4 and D7 visits. Approximately 3 participants per site will be interviewed; sites with larger volume of participants might have more interviews. Participants will be purposely 
sampled for interviews based on demographic characteristics, such as race/ethnicity, prior PrEP use.  
All additional study visits, including those where questionnaires and/or interviews are administered at M6 and M12, will be anchored off of each participants M1 visit, so it reflects 
months in study, regardless of what dose they are on and regardless of whether they have missed any injections and received oral PrEP. 
PSP 
Questionnaires  
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
To be completed 
prior to injection. 
Participant 
Interviews  
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Interviews will be 
completed on a 
subset of PSPs 
(see Section 
4.1.3.1). Window 
within 2 weeks 
before or 2 weeks 
following study 
visit. 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Staff Study Participants: Month 1 questionnaires should be completed prior to the first participant is enrolled 
 
Baseline IS assessment is defined as the first assessment taken prior to administering the first IM injection to the first participant at each site. 
Baseline questionnaires should be completed by all SSPs within 1-2 weeks of their site initiation. 
For sites with both OLI and DTI participants, M4/M5 visit will be defined by the target date when at least 1 participant, at their respective site, has completed their M4(DTI)/M5(OLI) 
study visit (Dose 3 visit), respectively, whichever comes first.  M12/M13 visit will be defined by the target date when at least 1 participant, at their respective site, has completed their 
M12(DTI)/M13(OLI) study visit (Dose 7 visit), whichever comes first.  
If the site only has DTI patients, the visits will be defined at M4 and M12, respectively.  If a site has only OLI patients, the SSP assessment follows the OLI SOA in ANNEX 2.   
Interim and final SSP questionnaires and/or interviews can be completed within 3 weeks prior to or 3 weeks after study visits.  
Implementation facilitation, implementation monitoring, and FRAME-IS can begin after baseline questionnaires have been completed by all SSPs. Sexual Health Assessment and 
aggregate clinic PrEP-related data collection can start prior to participant enrolment. 
SSP 
Questionnaires 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
At least 1 
participant must 
include an SSP 
who prescribes 
APRETUDE. 
SSP Interviews 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Implementation 
Facilitation Calls 
(DI Arm Only) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Group - Quarterly: 
At least 1 
consistent SSP 
knowledgeable of 
implementation.    
One-on-one - 
monthly: At least 1 
consistent SSP 
knowledgeable of 
implementation. 
Implementation 
Monitoring (RI Arm 
Only) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
At least 1 
consistent SSP 
knowledgeable of 
implementation to 
participate. 
FRAME-IS 
Questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
All SSPs in the RI 
and DI arms will 
be asked to 
complete. 
Sexual Health 
Assessment (DI 
Arm Only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Procedure1 
Screening/ 
Enrollment 
Up to 90 
days2 
Treatment Period4 
Month(M)/Dose(D) 
E.D.5 
Notes 
 
 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
 
 
 
 
D13 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Site level PrEP 
Information 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Quarterly 
aggregate clinic 
PrEP-related data. 
 
 
 

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11.2. 
ANNEX 2: Schedule of Activities – Optional oral lead in 
 
Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
1. 
The timing and number of planned study assessments, specifically interviews with SSPs and PSPs, may be altered during the study based on newly available data. Brief 
interviews may be held at other times based on learnings during implementation.   
2. 
Benefits verification should be performed at the start of the screening period, which may be extended up to 90 days to allow for this confirmation. All other screening/eligibility 
procedures (except informed consent) should only be performed after receiving this benefits confirmation. Additionally, in line with the USPI, all patient participants require 
proof of a negative HIV test, dated within the 7 days prior to PrEP initiation, regardless of any prior negative test results. During screening/enrollment, the following will be 
completed for PSPs: 1) Informed consent form (ICF), 2) Benefits verification, as required, 3) Confirm Inclusion and Exclusion criteria, 4) Demography 5) Medical History, 
including history of HCV infection, and current medical conditions 6) required labs per clinical local standard of care. Screening/enrollment can occur on the same date as the 
start of OLI as long as a negative HIV test is documented within 7 days prior to initiation of CAB PrEP. Refer to Section 3.3.1 for details on re-screening for PSPs who fail 
screening. 
3. 
Dose 1 (D1) is defined as the date of first APRETUDE injection. The following sequence of events must be followed for participants for the D1 visit: 1) complete questionnaires 
and assessments prior to or at the visit, and 2) Receive first intramuscular (IM) injections at the visit.     
4. 
The treatment period is based on 12 calendar months. The last APRETUDE injection is to occur at the last study visit. 
5. 
E.D. = early discontinuation/ withdrawal: This visit should only be conducted if the participant discontinues from the study prior to completing the Study at Month 12, and the 
discontinuation/withdrawal reason should be recorded.  For SSPs, this visit will only occur if the SSP withdraws and remains in the role for which they were enrolled and no 
replacement is possible. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Clinical and Other Assessments 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written informed 
consent must be 
obtained from each 
potentially eligible 
PSP by site 
personnel prior to 
the initiation of any 
procedures as 
outlined in this 
protocol. 
 
 
Inclusion and 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria will be fully 
assessed at the 
enrolment/ D1 Visit. 
Benefits 
verification, as 
needed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current Medical 
Conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments  
X 
Lab assessments, including HIV testing and STI clinical diagnoses (defined for this study as syphilis (any 
stage), gonorrhea, chlamydia, or trichomonas) at Screening and during PrEP should be performed using local 
laboratories and should be in accordance with the CDC PrEP clinical management guidelines and the USPI 
or per clinical local standard of care.  All lab reports must be stored in the participants source documentation 
at the clinical sites with only the protocol-specified test results to be reported in the eCRF*. 
 
For PSPs with incident HIV-1 infections, all available HIV-1 test results (viral load, genotype/phenotype, 
recency assay) conducted by the site as standard of care and, if applicable and available, the start date of 
ART and ART regimen (by category) used will be reported in the eCRF. 
X 
*All performed HIV 
test results 
(regardless of result, 
including positive, 
negative, or 
indeterminate) and 
HIV test type will be 
reported in the 
eCRF.  
Study Treatment:   Participants who are started on oral Cabotegravir PrEP as optional oral lead in will receive their first dose of oral CAB in M1.  Participants who are started on 
APRETUDE injections (direct to injection) will receive their first dose of APRETUDE injection in M1. 
 
All injections will be administered according to the CAB LA for PrEP USPI. 
CAB tablets for 
PrEP  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
CAB LA for 
PrEP IM 
Initiation 
injection 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
For PSPs receiving 
optional OLI, 1st 
injection occurs 
following completion 
of OLI and the final 
oral doses of OLI 
should be taken on 
the same day when 
injections with 
APRETUDE are 
started. 
 
CAB LA for 
PrEP IM 
Maintenance 
injections 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
IM dosing is 
expected to occur 
on the same date of 
the month as 
determined by Dose 
1 - Treatment Target 
Date.  Dosing 
window is (+ or -) a 
7-day window as per 
the USPI. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Concomitant 
medication 
review 
X 
======================================================→ 
X 
Contraindicated or 
concomitant 
medications with the 
potential for drug 
interactions 
according to the 
CAB PrEP USPI 
only must be 
recorded in the 
eCRF at each visit.   
Adverse Event 
(AE) Review 
 
X 
======================================================→ 
X 
Only drug related 
AEs and AEs 
leading to CAB Prep 
discontinuation will 
be collected in the 
eCRF. 
Serious AEs 
(SAEs) 
X 
 
=====================================================→ 
X 
All SAEs regardless 
of relatedness will 
be collected in the 
eCRF. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Pregnancy 
status 
X 
=====================================================→ 
X 
Ask person of 
childbearing 
potential at each 
visit if they are 
pregnant and ask for 
the date of their 
LMP. 
Questionnaires and Interviews: Questionnaires and Interviews should be completed before receiving APRETUDE IM injections 
Patient Study Participants 
PSP baseline questionnaires should be completed within two weeks prior to or on their D1 visit and before receiving the 1st CAB LA for PrEP injection. 
 
Participants interviews should be completed within two weeks prior to or two weeks following their D1 visit and within two weeks prior to or two weeks following the target dates for 
their D4 and D7 visits. Approximately 3 participants per site will be interviewed; sites with larger volume of participants might have more interviews. Participants will be purposely 
sampled for interviews based on demographic characteristics, such as race/ethnicity, prior PrEP use.  
 
All study visits, including those where questionnaires and/or interviews are administered at M7 and M13, will be anchored off of each participant’s D1 visit, regardless of what dose 
they are on and regardless of whether they have missed any injections and received oral PrEP. 
Participant 
Questionnaires  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
To be completed 
prior to injection. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Participant 
Interviews  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Interviews will be 
completed on a 
subset of PSPs (see 
Section 4.1.3.1). 
Window - within 2 
weeks before or 2 
weeks following the 
indicated study visit. 
 
Staff Study Participants: Month 1 questionnaires should be completed prior to the first participant is enrolled 
Baseline IS assessment is defined as the first assessment taken prior to administering the first IM injection to the first participant at each site. 
Baseline questionnaires should be completed by all SSPs within 1-2 weeks of their site initiation.  
For sites with both OLI and DTI participants, M4/M5 visit will be defined by the target date when at least 1 participant, at their respective site, has completed their M4(DTI)/M5(OLI) 
study visit (Dose 3 visit), respectively, whichever comes first.  M12/M13 visit will be defined by the target date when at least 1 participant, at their respective site, has completed their 
M12(DTI)/M13(OLI) study visit (Dose 7 visit), whichever comes first.  
If the site only has OLI participants, the visits will be defined at M5 and M13, respectively.   If a site has only OLI patients, the SSP assessment follows the OLI SOA in ANNEX 1. 
Interim and final SSPs questionnaires and/or interviews can be completed within 3 weeks prior to or three weeks after study visits. 
Implementation facilitation, implementation monitoring, and FRAME-IS can begin after baseline questionnaires have been completed by all SSPs. Sexual Health Assessment and 
aggregate clinic PrEP-related data collection can start prior to participant enrolment. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
SSP 
Questionnaires 
X  
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
At least 1 participant 
must include an 
SSP who prescribes 
APRETUDE. 
SSP Interviews  
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Implementation 
Facilitation Calls 
(DI Arm Only) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Group Quarterly: At 
least 1 consistent 
SSP knowledgeable 
of implementation. 
One-on-one - 
monthly: At least 1 
consistent SSP 
knowledgeable of 
implementation. 
Implementation 
Monitoring  
(RI Arm Only) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
At least 1 consistent 
SSP knowledgeable 
of implementation 
participate  
FRAME-IS 
Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
 
All SSPs in the RI 
and DI arms will be 
asked to complete. 

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Procedure1 
Screening/ 
Eligibility/ 
Enrollment2 
 
Treatment Period4  
Months (M) & Dose (D) 
E.D.5 
Notes 
 
 
M1  
(At least 
28 
days) 
M23 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
M13 
 
 
 
Up to 90 
days 
OLI 
 
D1 
visit 
D2 
visit 
 
D3 
visit 
 
D4 
visit 
 
D5 
visit 
 
D6 
visit 
 
D7 
visit 
 
 
Sexual Health 
Assessment (DI 
Arm Only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
 
 
Site level PrEP 
Information 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
 
Quarterly aggregate 
clinic PrEP-related 
data. 

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11.3. 
ANNEX 3. List of Stand-Alone Documents 
Study Reference Manual (SRM) 
 
 
 

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11.4. 
ANNEX 4. AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
11.4.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
• Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a PSP 
diary and that is communicated by a PSP/ PSP’s parent(s)/ LAR(s) who has signed 
the informed consent. Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The PSP/ PSP’s parent(s)/ LAR(s) will be instructed to contact the site as 
soon as possible to report medically attended event(s), as well as any events that, 
though not medically attended, are of PSP/ PSP’s parent(s)/ LAR(s) concern. 
Detailed information about reported unsolicited AEs will be collected by qualified 
SSPs and documented in the PSP’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
PSP/ PSP’s parent(s)/ LAR(s) will be collected during an interview with the PSP/ 
PSP’s parent(s)/ LAR(s) and by review of available medical records at the next 
visit. 
• Solicited AEs are predefined local [at the injection site] and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their diary.  
 

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Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the PrEP Provider (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
•  The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. "Lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 
 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
PrEP Provider to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 

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11.4.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
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) that may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the PrEP Provider in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 

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An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
abuse. 
 
11.4.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
PrEP Providers will be required to fill out the specific CV event page of the CRF for 
the following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 

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11.4.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the PrEP Provider to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The PrEP Provider will then record all relevant AE/SAE information. 
• It is not acceptable for the PrEP Provider to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the Sponsor required form. 
• 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 PrEP Provider will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The PrEP Provider will make an assessment of intensity for each AE and SAE reported 
during the study according to the DAIDS toxicity scales Version 2.1 July 2017. 
 
 
Assessment of Causality 
• The PrEP Provider is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. The PrEP Provider will use 
clinical judgment to determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The PrEP Provider will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the PrEP Provider must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the PrEP Provider has 
minimal information to include in the initial report to the Sponsor. However, it is 
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Assessment of Causality 
causality for every event before the initial transmission of the SAE data to the 
Sponsor. 
• The PrEP Provider may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The PrEP Provider is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the Sponsor to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the PrEP Provider will provide the Sponsor with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The PrEP Provider will submit any updated SAE data to the Sponsor within 24 
hours of receipt of the information. 
 
11.4.5. 
Reporting of SAE to the Sponsor 
SAE Reporting to the Sponsor via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to the Sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone. 

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SAE Reporting to the Sponsor via Electronic Data Collection Tool 
• If the site during the course of the study or poststudy becomes aware of any 
serious, nonserious AEs, pregnancy exposure, related to any GSK non-IMP they 
will report these events to GSK or to the concerned competent authority via the 
national spontaneous reporting system.  These will be classified as spontaneous 
ICSRs. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor and safety team. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the PrEP Provider to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for paper SAE reporting can be found in the SRM. 

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11.5. 
ANNEX 5:  Medical device reporting Definition of Medical 
Device AE and ADE 
11.5.1. 
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 inadequacy of the information supplied by 
the manufacturer. 
11.5.2. 
Reporting of Medical Device Deficiencies  
• 
Reporting to the Sponsor  
• Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com.  
 
• If the device incident is linked to an SAE, please email gsk-
rd.complaints@gsk.com, within 24 hours. The associated SAE form should also be 
reported to the CRO and Sponsor.  
 

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11.6. 
ANNEX 6:  COVID-19 Pandemic and Clinical Trial Continuity  
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.  
11.6.1. 
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 may be contacted, to provide guidance for safety 
monitoring.  
• When on-site visits are reduced, it is important that the PrEP Provider continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 
• There may be cases where the current PrEP Provider of a site is indisposed for a 
period and may need to delegate parts of his/her duties temporarily, e.g. to a sub-
PrEP Provider. Any such changes should be documented in the site’s source 
records. Any permanent changes in a PrEP Provider should be communicated to 
the sponsor. 
• There may also be circumstances where immediate actions are required by the 
sponsor and/or PrEP Provider, 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. 
 
11.6.2. 
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 
if written 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 
PrEP Provider, or the PrEP Provider contacting the participant by telephone or video call 
and obtaining verbal consent, supplemented with email confirmation.   
Any updated informed consent form or other participant-facing materials should be 
provided to participants before re-consent is obtained. Any consent obtained in an 
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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. 
 
11.6.3. 
COVID-19 Specific Data Capture 
11.6.3.1. 
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. 
 
11.6.3.2. 
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. 
PrEP Providers 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, PrEP Providers 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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WHO Case Definition - 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.  
Covid-19 Contact: 
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case:  
1. 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes;  
2. 
Direct physical contact with a probable or confirmed case;  
3. 
Direct care for a patient with probable or confirmed COVID-19 disease 
without using proper personal protective equipment; OR  
4. 
Other situations as indicated by local risk assessments.  
 

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

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11.7. 
ANNEX 7: Regulatory, Ethical and Study Oversight 
Considerations 
11.7.1. 
Financial Disclosure 
 PrEP Providers and sub-PrEP Providers 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. PrEP Providers are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. 
11.7.2. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, a PrEP Provider signatory 
will be identified for the approval of the clinical study report.  The PrEP Provider 
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 
Sponsor site or other mutually agreeable location. 
• The Sponsor will also provide all PrEP Providers who participated in the study 
with a summary of the study results and will tell the PrEP Providers what 
treatment their patients received.  The PrEP Provider(s) is/are encouraged to share 
the summary results with the study participants, as appropriate. 
• Under the framework of the SHARE initiative, The Sponsor intends to make 
anonymized participant-level clinical and implementation science data from this 
study 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 study participants are used to maximum effect 
in the creation of knowledge and understanding. Requests for access may be made 
through www.clinicalstudydatarequest.com. 
• 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 the Sponsor’s Policy. 
• The Sponsor intends to make anonymized patient-level data from this study 
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 study participants are used to maximum effect 
in the creation of knowledge and understanding 
• A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 

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11.7.3. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs or Electronic Data Capture System (EDC) unless transmitted to the sponsor 
or designee electronically (e.g., laboratory data). The PrEP Provider is responsible 
for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• Guidance on completion of CRFs and EDC will be provided in the PrEP Provider 
site file. 
• Quality tolerance limits (QTLs) will be pre-defined in a QTL Plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• The PrEP Provider must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the 
study Data Management Plan. 
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the PrEP Provider for 25 years from the issue of the 
final Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the sponsor.  
 

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11.7.4. 
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 
PrEP Provider’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 PrEP Provider may need to request previous medical 
records or transfer records, depending on the study. Also, current medical records 
must be available. 
• Definition of what constitutes source data and its origin can be found in the 
Source Data Acknowledgment. 
• The PrEP Provider must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
 
11.7.5. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first center initiated (first site open) and will be the 
study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of The Sponsor. 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 PrEP Provider 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 PrEP Provider may include 
but are not limited to: 
For study termination: 

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• Discontinuation of further study intervention development 
For site termination: 
• Failure of the PrEP Provider to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the PrEP Provider 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the PrEP Providers, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The PrEP 
Provider shall promptly inform the subject and should assure appropriate 
participant therapy and/or follow-up 
 
11.7.6. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the PrEP Provider 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 PrEP Provider will be designated 
by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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11.8. 
ANNEX 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. 
Amendment [1]: 18-FEB-2022 
This amendment was considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European. 
Overall Rationale for the Amendment: Information was updated to reflect the 
safety guidance in the FDA approved Apretude USPI Dec 2021 and to provide 
additional clarification in selected sections. 
Minor editorial changes for accuracy, clarity, formatting and consistency have been made 
throughout the document and are not included in the description(s) below 
Bold: Newly added text 
Section # and Name 
Description of Change 
Brief Rationale 
Abstract 
 
 
 
Used to read: 
CAB LA for PrEP will 
provide people who are at 
higher risk of HIV 
acquisition with a new 
prevention option. 
Now reads: 
CAB LA for PrEP 
(hereafter referred to as 
APRETUDE) will provide 
people who are at higher 
risk of HIV acquisition with 
a new prevention option. 
Update the terminology 
from CAB LA for PrEP to 
APRETUDE throughout 
the protocol. 
 
With the FDA approval of 
APRETUDE in Dec 2021, 
it is important that the 
terminology was aligned 
with what a participant 
would readily identify in 
the real world. 
ANNEX 1 and 2: 
Schedule of Activities – 
direct to injection/Oral 
Lead In (Section 11.1 and 
11.2) 
Updates to the schedules of 
activity (SoAs) to align with 
the USPI in Annex 1 and 
Annex 2 and changes in the 
protocol. 
Providers are advised to 
follow the APRETUDE 
USPI for the preparation 
and administration of the 
product. The SoAs were 
updated to align with the 
USPI to avoid any 
confusion with the study 
sites. 

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Section # and Name 
Description of Change 
Brief Rationale 
The SoAs were also 
updated to reflect the 
changes made throughout 
the protocol. 
Study Design Schematic 
(Section 3.1) 
Figure 1. Study Schema 
updated  
Schema updated to reflect 
updated screening and 
enrolment period of up to 
90 days and updated 
months (due to alignment 
with SoAs) 
Study Design (Section 3.1) Used to read: 
The period includes up to a 
21-day screening period and 
a  
Now reads: 
The study includes a 
screening period of up to a 
90 days to allow sufficient 
time for any benefit 
verification checks to be 
completed, as required. 
PSPs will be initiated on 
CAB PrEP as soon as their 
eligibility is confirmed.  
Updated to reflect changes 
in screening and 
enrollment period. 
Study Population (Section 
3.2) 
Used to read: 
And at least five SSPs per 
site will be included. 
Now reads: 
The number of SSPs will 
vary by site and 
approximately 5 per site 
will be included. 
Clarification on SSPs. 
Abstract/ Objectives and 
endpoints (Section 2) 
 
Changed terminology from 
PrEP Needs Assessment to 
Sexual Health Assessment 
and revised the endpoints 
Feedback from the 
community advised that 
the language ‘PrEP Needs 

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Section # and Name 
Description of Change 
Brief Rationale 
 
 
Secondary Analysis 
(Section 5.4) 
associated with the Sexual 
Health Assessment 
Added endpoint: 
SSPs and PSPs 
perceptions of Sexual 
Health Assessment over 
time 
Assessment’ might be 
stigmatizing.   
 
Secondary Analyses 
(Section 5.4) 
Added: 
Analyses of the 
implementation outcomes 
for SSPs and PSPs will use 
standardized measures, 
such as the FIM and AIM, 
as well as items from the 
ISQ that measure these 
outcomes using different 
terminology  
Added:  
Table 10 
A table and text was added 
to clearly outline the 
definitions of 
implementation outcomes 
and additional terminology 
use to measure them that 
are used in the 
implementation science 
questionnaires. 
Objectives and Endpoints 
(Section 2) 
 
 
Secondary Analysis 
(Section 5.4) 
To evaluate fidelity and 
reach of client Sexual 
Health Assessments for 
APRETUDE 
Two endpoints were added:  
1) Proportion of MSM & 
TGM who report having 
had sex in the last 6 
months through M13 on 
the Sexual Health 
Assessment by service 
delivery method;  
2) Proportion of MSM & 
TGM who expressed 
interest in PrEP or never 
heard of PrEP out of those 
who report having had sex 
in the last 6 months 
Endpoints added to reflect 
data will measure fidelity 
and reach.   
 
 
 
Clarifying text was added. 

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Section # and Name 
Description of Change 
Brief Rationale 
through M13 by service 
delivery method. 
Additional text added to 
endpoint: by clinic 
characteristics, patient 
subgroups, and service 
delivery method (e.g., 
telehealth vs. face-to-face 
in clinic) 
Objectives and Endpoints 
(Section 2) 
 
 
Secondary Analysis 
(Section 5.4) 
To evaluate fidelity to 
injection and dosing 
window 
One endpoint was added: 
Proportion of PSPs 
completing target number 
of injections through M13 
and by patient subgroups 
Endpoints added to reflect 
data that will measure 
fidelity. 
Objectives and Endpoints 
(Section 2/ Section 5.4) 
Timepoints updated 
throughout endpoints and 
throughout protocol: 
Used to read 
M4 
M12 
M6/M5 
M12/M11 
Now reads: 
M5 
M13 
M7(OLI)/M6(DTI) 
M13(OLI)/M12(DTI) 
Changes to timepoints to 
align with SoAs. 
 

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Section # and Name 
Description of Change 
Brief Rationale 
Objectives and Endpoints 
(Section 2) 
 
Other/tertiary Endpoints 
Section 5.5) 
To evaluate the PrEP 
continuum of care at site-
level 
Removed endpoints  
Added one endpoint:  
 
 
 
 
 
 
 
 
Endpoints adjusted based 
on the data that will be 
available during the trial. 
Objectives and Endpoints 
(Section 2) 
 
 
Other/tertiary Endpoints 
Section 5.5) 
To evaluate feasibility of 
implementation of 
APRETUDE 
Updated text to endpoint: 
 
 
 
 
 
 
 
Endpoints updated to 
reflect data that will 
measure feasibility. 
Objectives and Endpoints 
(Section 2) 
 
 
Other/tertiary Endpoints 
Section 5.5) 
Added a tertiary objective 
and endpoint focused on 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Objectives and Endpoints 
(Section 2) 
To evaluate perceptions, 
barriers and facilitators with 
SSPs and PSPs’  
Upon review of the 
implementation science 
questions, several key 
CCI
CCI
CCI
CCI
CCI

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Section # and Name 
Description of Change 
Brief Rationale 
 
Secondary Analysis 
Section 5.4)/Abstract 
Moved the endpoint from 
tertiary to secondary:  
SSIs, FRAME-IS and 
facilitation calls assessed 
qualitatively with SSPs and 
SSIs with PSPs over time  
questions are included 
under this endpoint. 
Objectives and Endpoints 
(Section 2) 
 
Secondary Analysis 
Section 5.4) 
To evaluate switch from 
oral PrEP to APRETUDE 
Edited endpoint: 
PSPs reasons for choosing 
APRETUDE, including 
switching, as assessed by 
SSIs and ISQ  
Clarification 
Objectives and Endpoints 
(Section 2) 
 
Secondary Analysis 
(Section 5.4) 
Added acronyms for 
implementation science 
questionnaire and 
implementation monitoring 
calls 
ISQ=implementation 
science questionnaire 
IMC= implementation 
monitoring calls 
Added the acronyms for 
clarity in noting the set of 
Implementation Science 
questionnaires being 
administered in the study. 
The ISQ and IMC 
themselves are not new 
questionnaires. 
Objectives and Endpoints 
(Section 2)/Secondary 
Analysis (Section 5.4) 
Added footnote: 
If the site has only DTI 
patients, endpoints will be 
a month prior for SSPs. 
Clarification of DTI 
schedule 
SSPs (Section 3.3.2) 
Added clarification on when 
baseline questions for SSPs 
will be completed: 
baseline questionnaires with 
SSPs should be completed 
prior to the enrollment of 
the first participant at 
their site, which might 
vary by site depending on 
whether the first PSP 
Clarification  

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Section # and Name 
Description of Change 
Brief Rationale 
started CAB PrEP with or 
without optional OLI. 
Added clarification of 
documentation in the eCRF: 
Additional PSP contacts 
should be documented in the 
medical records but will not 
need to be entered as a 
study visit in the eCRF, 
unless the contact results 
in any safety information 
that is required to be 
documented for the study 
(refer to Section 9).  
Implementation 
Assessments (4.1.3) 
Updates to Table 3 
Changes to nomenclatures 
for timepoints and updated 
acronyms  
Timepoints Definitions for 
Completion of 
Questionnaires and 
Interviews (4.1.3.1) 
Added: 
Approximately 3 PSPs per 
site will participate in 
SSIs; number of SSIs 
might vary by site. 
Participants will be 
purposely sampled for 
interviews based on 
demographic characteristics, 
such as race/ethnicity, prior 
PrEP use.  
Edited and added: 
For sites with both OLI 
and DTI participants, 
M4/M5 visit will be 
defined when at least 1 
participant, at their 
respective site, has 
completed their 
M4(DTI)/M5(OLI) study 
visit (Dose 3 visit), 
respectively, whichever 
comes first.  M12/M13 
 
Clarification 
 
 
 
 
 
Clarification 
 
 
 
 
 

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Section # and Name 
Description of Change 
Brief Rationale 
visit will be defined after 
at least 1 participant, at 
their respective site, has 
completed their 
M12(DTI)/M13(OLI) 
study visit (Dose 7 visit), 
whichever comes first.  
Questionnaires and/or 
interviews can be completed 
within 3 weeks of the 
respective study visits. 
For a site with only DTI 
patients, the visits will be 
defined at M4 and M12, 
respectively.  For a site 
with only OLI patients, 
the visits will be defined at 
M5 and M13, respectively. 
Removed: or OLI PSPs; 
Dose 1 (first oral dose), 
Dose 2 (first injection)  
Added text: at least 1 
consistent SSP will 
participate in group and 
1:1 facilitation 
 
 
 
 
 
Clarification 
 
 
 
 
 
 
 
Clarification 
Routine Implementation 
(4.1.1.) 
Added: 
All SSPs will be asked to 
complete the FRAME-IS 
in order to understand 
implementation from the 
perspective of the different 
roles. 
At least one consistent SSP 
from each site should 
participate in all 
implementation 
monitoring. This SSP 
should be aware of how 
implementation is going and 
be willing and able to report 
Clarified the roles 
participating in the 
implementation 
assessments and the 
approximate number of 
participants.  
 
Clarified the SSP roles 
who will complete 
implementation 
assessments and the PSPs 
who will be interviewed. 

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Section # and Name 
Description of Change 
Brief Rationale 
out on behalf of the clinic 
and communicate back to 
the team at the clinic.   
Dynamic Implementation 
Pathway (Section 4.1.2) 
Updated Figure 2: Dynamic 
Implementation Pathway 
 
Clarification of site staff 
training, sharing of data 
with Sponsor, and de-
identified data. 
Added: 
At least one consistent SSP 
from each site should 
participate in both one-on-
one and quarterly 
facilitation calls. This SSP 
should be aware of how 
implementation is going and 
be willing and able to report 
out on behalf of the clinic 
and communicate back to 
the team at the clinic.   
Added: 
All SSPs in the DI arm 
will be asked to complete 
the FRAME-IS in order to 
understand 
implementation from the 
perspective of the different 
roles. 
The figure was updated to 
change the language from 
PrEP Needs Assessment to 
Sexual Health Assessment 
 
Clarification 
 
Clarification on data 
collection 
 
 
 
 
 
 
Clarification on data 
collection 
Statistical Considerations 
(Section 5) 
Added: 
Baseline analyses will be 
completed when a 
sufficient number of staff 
study participants 
complete their baseline 
assessments. 
The protocol did not 
previously specify when 
baseline analyses will be 
completed 
 
 

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Section # and Name 
Description of Change 
Brief Rationale 
Month 5-time point for 
SSPs  
Month 7(OLI)/6(DTI) time 
point 
Time points are revised 
from M12 to M13 
 
Added and/or clarified 
timepoints based on 
updates made in SOAs. 
Exclusion Criteria for 
SSPs (3.2.1.4.) 
Used to read: 
Engaged or planned 
engagement in an 
implementation science 
study on long acting 
injectables at any time 
during the study. 
Now reads: 
Engaged or planned 
engagement in an 
implementation science 
study with similar 
strategies on long acting 
PrEP injectables at any 
time during the study. 
The intent of the previous 
criteria was not clear and 
could negatively impact a 
site’s engagement in 
research in other 
therapeutic areas. 
Therefore, additional 
clarity was added to the 
exclusion criteria.   
Pregnancy (Section 9.3.3) 
Use to read: 
If a pregnancy is reported, 
the site will record 
pregnancy information on 
the appropriate form and 
submit it to Syneos (CRO) 
within 24 hours of learning 
of the pregnancy and should 
follow the procedure 
outlined in SRM.   
Now reads:  
If a pregnancy is reported, 
the site will record 
pregnancy information on 
the appropriate form and 
submit it to the Sponsor 
Pregnancy reporting 
guidance was updated 
based on updated safety 
guidance in the FDA 
approved Apretude USPI 
Dec 2021. 

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Section # and Name 
Description of Change 
Brief Rationale 
within 24 hours of learning 
of the pregnancy. 
Pregnancies will also be 
directly reported to the 
Antiretroviral Pregnancy 
Registry (APR) by the 
PrEP provider. The 
procedure for reporting is 
outlined in the SRM. 
Clarification of text:   
Whilst pregnancies are not 
part of the study, they will 
be reported to the sponsor 
or designee within 24 
hours of awareness and 
documented in the eCRF 
Reporting of AEs and 
timelines (Section 9.3.2) 
Used to read: 
All SAEs need to be 
reported within 24 hours of 
documentation sent by an 
automated, electronic safety 
alert within the CRF, All 
AEs listed below will 
require reporting within 3 
days. 
Now reads: 
All SAEs will be recorded 
and reported immediately 
and under no 
circumstance should this 
exceed 24 hours., All AEs 
listed in Section 9.1.1 will 
require reporting within 3 
days 
Clarified the reporting of 
AEs. 
Liver Chemistry 
Monitoring (Section 9.2.2) 
Used to read: 
The decision whether to 
discontinue CAB PrEP in 
the presence of abnormal 
liver tests should be made 
Information was updated 
to reflect the safety 
guidance in the FDA 
approved Apretude USPI 
Dec 2021 

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Section # and Name 
Description of Change 
Brief Rationale 
by the PrEP provider in 
accordance with the PrEP 
CDC clinical management 
guidelines and the US 
prescribing information for 
CAB tablet for PrEP and 
CAB LA for PrEP Adverse 
Events (AEs), Pregnancy 
Exposure and Incident 
Reporting 
All PSP clinical safety data 
will be collected as outlined 
in the eCRF. No clinical 
safety data will be collected 
for SSPs. The definitions of 
adverse events (AE) or 
serious adverse events 
(SAEs) can be found in 
ANNEX 4. 
Now reads: 
The decision whether to 
discontinue CAB PrEP in 
the presence of abnormal 
liver tests should be made 
by the PrEP provider in 
accordance with the PrEP 
CDC clinical management 
guidelines and the US 
prescribing information for 
CAB tablet for PrEP and 
APRETUDE. 
In cases where the PrEP 
provider suspects a PSP 
has an event of 
hepatotoxicity, the liver 
eCRF forms will also need 
to be completed, in 
addition to any 
corresponding AE or SAE 
form. The additional 
forms will gather further 
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Section # and Name 
Description of Change 
Brief Rationale 
and should be completed 
in a timely manner. 
References (Section 10) 
Added reference for the 
CDC guidelines published 
in 2021 and linked the 
references accordingly 
where cited in the protocol. 
Added references for 
Weiner and Aarons and 
linked the references 
accordingly where cited in 
the protocol 
Added reference that was 
not available at the time of 
the original protocol.  
 
Added references to new 
content in the protocol 
Annex 1 (Section 11.1) 
 
Annex 1 (Section 11.2) 
Used to read: 
The screening period will be 
up to 21 days.  
Screening/enrollment can 
occur on the same date as 
the first Cabotegravir LA 
for PrEP injection as long as 
a negative HIV test is 
documented within the prior 
7 days and prior to initiation 
of CAB LA for PrEP. 
During 
screening/enrollment, the 
following will be completed 
for PSPs: 1) Informed 
consent form (ICF), 2) 
Confirm Inclusion and 
Exclusion criteria, 3) 
demography  4) Medical 
History, including history of 
HCV infection, and Current 
medical conditions 5) 
required labs per clinical 
local standard of care.  It 
will be completed and a 
negative HIV test needs to 
be documented for eligible 
PSPs within the prior 7 days 
Updated to reflect changes 
in screening and 
enrollment period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TMF-15754477 
CONFIDENTIAL 
 
 
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Amendment 2 
13 Apr 2023 
151 
 
Section # and Name 
Description of Change 
Brief Rationale 
to initiation of CAB LA for 
PrEP. 
Now reads: 
Benefits verification 
should be performed at 
the start of the screening 
period, which may be 
extended up to 90 days to 
allow for this 
confirmation. 
Screening/eligibility 
procedures (excluding 
informed consent) should 
not be performed prior to 
receiving this 
confirmation. 
Additionally, in line with 
the USPI, all patient 
participants require proof 
of a negative HIV test, 
dated within the 7 days 
prior to PrEP initiation, 
regardless of any prior 
negative test results. 
During 
screening/enrollment, the 
following will be 
completed for PSPs: 1) 
Informed consent form 
(ICF), 2) Benefits 
verification, as required, 
3) Confirm Inclusion and 
Exclusion criteria, 4) 
Demography 5) Medical 
History, including history 
of HCV infection, and 
current medical conditions 
6) required labs per 
clinical local standard of 
care. Screening/enrollment 
can occur on the same 
date as the first 
APRETUDE injection as 
long as a negative HIV test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TMF-15754477 
CONFIDENTIAL 
 
 
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Amendment 2 
13 Apr 2023 
152 
 
Section # and Name 
Description of Change 
Brief Rationale 
is documented within 
7 days prior to initiation of 
APRETUDE. Refer to 
Section 3.3.1 for details on 
re-screening for PSPs who 
fail screening. 
Added: 
Approximately 3 
participants per site will 
be interviewed; sites with 
larger volume of 
participants might have 
more interviews. 
Participants will be 
purposely sampled for 
interviews based on 
demographic characteristics, 
such as race/ethnicity, prior 
PrEP use.  
Added: 
Contraindicated or 
concomitant medications 
with the potential for drug 
interactions according to the 
CAB PrEP USPI only must 
be recorded in the eCRF at 
each visit.   
Added: 
To be completed prior to 
injection. 
Added: 
All SSPs in the RI and DI 
arms will be asked to 
complete. 
Added: 
At least 1 consistent SSP 
knowledgeable of 
 
 
 
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TMF-15754477 
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Amendment 2 
13 Apr 2023 
153 
 
Section # and Name 
Description of Change 
Brief Rationale 
implementation to 
participate. 
Added: 
Site level PrEP 
Information 
Questionnaire 
Added: 
Quarterly aggregate clinic 
PrEP-related 
Added: 
One-on-one - monthly: At 
least 1 consistent SSP 
knowledgeable of 
implementation. 
Added: 
Group - Quarterly: At 
least 1 consistent SSP 
knowledgeable of 
implementation.   
Added: 
At least 1 participant must 
include an SSP who 
prescribes APRETUDE. 
Added: 
For sites with both OLI 
and DTI participants, 
M4/M5 visit will be 
defined when at least 1 
participant, at their 
respective site, has 
completed their 
M4(DTI)/M5(OLI) study 
visit (Dose 3 visit), 
respectively, whichever 
comes first.  M12/M13 
 
Clarification 
 
 
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TMF-15754477 
CONFIDENTIAL 
 
 
217710 
 
 
Amendment 2 
13 Apr 2023 
154 
 
Section # and Name 
Description of Change 
Brief Rationale 
visit will be defined after 
at least 1 participant, at 
their respective site, has 
completed their 
M12(DTI)/M13(OLI) 
study visit (Dose 7 visit), 
whichever comes first.  
If the site only has DTI 
patients, the visits will be 
defined at M4 and M12, 
respectively.   
Added: 
Interviews will be 
completed on a subset of 
PSPs (see Section 4.1.3.1). 
Window within 2 weeks 
before or 2 weeks 
following study visit. 
Updated enrollment days 
and months 
Changed Day 1 to Month 1 
Added row for benefits 
verification 
 
 
 
 
 
 
Clarification 
 
 
 
Revisions based on new 
enrollment period 
Revisions based on USPI 
Revisions based on 
changes to enrollment 
List of Abbreviations 
DTI = direct to injection 
VHC = ViiV Healthcare 
Added explanation of 
acronym previously used 
in protocol to the list of 
abbreviations  
 

Signature Page for  217710 TMF-15754477 v1.0
Signature Page for TMF-15754477 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 13-Apr-2023 09:08:25 GMT+0000
PPD