Clinical trial NCT05549726
Conditions: HIV
Keywords: Cabotegravir Injectable Suspension PrEP HIV Treatment and Prevention Community Health
Sponsor: University of California, San Francisco
Start date: 2023-01-02; Completion date: 2025-01-30
Enrollment: 984 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall purpose of this SEARCH CAB-LA (Cabotegravir Injectable Suspension) randomized extension study is to determine if adding the option of CAB-LA as a prevention choice using a person-centered dynamic choice HIV (human immunodeficiency virus) prevention model, with option to switch products over time, compared to the standard of care: 1) increases prevention coverage; 2) reduces HIV incident infection; and 3) increases prevention coverage during periods of self-assessed risk of HIV infection, in three settings in rural Uganda and Kenya.

In addition, this study will describe implementation of a person-centered model for dynamic choice HIV prevention including CAB-LA, using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) evaluation framework among persons randomized to the intervention arm.

Detailed description:
The SEARCH CAB-LA (Cabotegravir Injectable Suspension) dynamic choice HIV prevention study is a randomized extension study of a person-centered Dynamic Choice HIV Prevention model for delivering existing evidence-based biomedical prevention interventions vs. standard of care (SOC). The study is conducted in 3 settings in rural Western Uganda and Kenya: antenatal (ANC) clinics, the outpatient department (primary care clinics), and in community settings. Participants previously randomized to Dynamic Choice HIV Prevention or SOC are re-consented and remain in their initial randomized arm. During the extension, the Dynamic Choice HIV Prevention intervention offers participants choices of biomedical prevention product (oral Pre-Exposure Prophylaxis (PrEP), oral post-exposure prophylaxis (PEP), or Cabotegravir Injectable Suspension (CAB-LA) on an ongoing basis with the option to switch products over time based on participant preference and perceived risk. The primary endpoint is proportion of time that is covered by a biomedical prevention product over 48 weeks; secondary endpoints are: i) incident HIV infection over 48 weeks; and, ii) proportion of time during which a participant reports risk of HIV infection that is covered by a biomedical prevention product over 48 weeks. Participants in the intervention arm only are reconsented at 48 weeks for implementation evaluation up to 96 weeks.

Arms: arm 1: The Dynamic Choice Delivery Model includes integrated PrEP and PEP services at outpatient clinics, antenatal clinics, and via VHT workers in community households. CAB-LA will be integrated into the dynamic choice delivery model as an additional biomedical prevention option in a patient-centered delivery model based on the precede framework. arm 2: The standard of care for PEP or PrEP differs according to each country's guidelines.
Interventions: intervention 1: Cabotegravir Injectable Suspension intervention 2: Dynamic Choice Delivery Model intervention 3: Standard of Care
Intervention descriptions: intervention 1: CAB-LA will be one of the options for the Dynamic Choice Delivery intervention arm. CAB-LA will be a choice for at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Single-dose vial containing 600 mg/3 mL (200 mg/mL) of cabotegravir is a white to light pink, free-flowing, extended-release injectable suspension. CAB-LA administration will occur at health facilities. intervention 2: The Dynamic Choice Delivery Model includes integrated PrEP (including CAB-LA) and PEP services at outpatient clinics, antenatal clinics, and via VHT workers in community households. The procedures for each trial include PrEP/PEP counseling and services, choice of service location, HIV testing options, option for longer PrEP refills, provision of a clinical officer's or nurse's mobile telephone number for immediate PEP starts any day of the week, assessment of PrEP/PEP barriers and personalized actions, psychologic supports for traumatic experiences, and offer of concurrent, additional health or prevention related services. intervention 3: The standard of care differs according to country but does not routinely offer PEP or PrEP to clients seeking services, does not offer choice of service location, HIV testing option or access to medical provider mobile phone number.

Protocol documents:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document: 
Informed Consent Form 
 
Official Study Title: 
SEARCH CAB LA Dynamic Choice HIV Prevention Study Extension 
NCT05549726 
 
Document Date: 
September 19, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
INFECTIOUS DISEASES RESEARCH COLLABORATION 
 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Study Title: Extension of SEARCH SAPPHIRE Dynamic Choice Prevention Study 
 
Extension of SEARCH SAPPHIRE Dynamic Choice Prevention Study – Informed Consent Form 
 
Site Principal Investigator: 
Moses R. Kamya, MBChB, MMed, PhD  
Co-Chair, Makerere University  
Address: Department of Medicine, P.O. Box 7072, Kampala, Uganda   
Phone Number: +256-414-533200  
Email: mkamya@infocom.co.ug  
Sites of Research: 
Mbarara District, Uganda; Nyanza Province, Kenya 
Principal Investigators: 
Diane Havlir, MD; Moses Kamya, MBChB, MMed, MPH, PhD; Elizabeth 
Bukusi, MBChB, MMed, MPH, PhD, Maya Petersen, MD, PhD 
UCSF-CHR Number: 
20-32144  
SOM-REC Number: 
2022-434 
UNCST Number: 
HS2447ES 
Version Date: 
19-Sept-2022 
 
 
This is a clinical research study. The Principal Investigator, who is the person in charge of this study, or one of 
the other members of the study team from the Extension study will explain the study to you. 
 
STUDY SUMMARY 
 
The objective of the DCP Long-Acting Cabotegravir (CAB-LA) Extension study is to reduce HIV incidence and 
to improve community health with multi-sector, scalable interventions. This Extension will examine if enhanced 
HIV prevention options, including CAB-LA, is superior to the current standard of care.  
 
CAB-LA is an injectable HIV-prevention method, taken in clinic every 4 weeks for two times, and then every 8 
weeks thereafter. CAB-LA is very effective to prevent HIV if taken accordingly. 
 
Introduction: We are asking you to consider taking part in a research study being done by researchers from 
Makerere University (MU), the Infectious Diseases Research Collaboration (IDRC), the University of 
California, Berkeley (UCB), and the University of California, San Francisco (UCSF). The U.S. National 
Institutes of Health (NIH) pays for this study.  
 
The first part of this consent form gives you a summary of this study. We will give you more details about the 
study later in this form. The study team will also explain the study to you and answer any questions you have. 
 
Research studies include only people who choose to take part. It is your choice whether or not you want to take 
part in this study. Please take your time to make a decision about participating. You can discuss your decision 
with your family, friends and health care team.  
 
Purpose of the study: 
 


 
 
The researchers want to study ways to improve HIV prevention programs in your community. This study will 
compare the effects, good and/or bad, of enhanced dynamic choice prevention choices, including CAB-LA, 
versus standard of care to find out which is better. In this study, you will either continue receiving the enhanced 
dynamic choice options, with the addition of CAB-LA, or standard of care. You will not get both. 
 
Study Procedures:  
 
If you choose to continue in this study, you will remain assigned to the randomization arm, either intervention or 
control, you are currently in. If you are in the intervention arm, we will offer you the choice of CAB-LA as one 
of your DCP selections; if you are in the control arm, you will remain being treated per MoH standard-of-care 
guidelines. Regardless of which group you are in, (Pre-Exposure Prophylaxis) PrEP and (post-exposure 
prophylaxis) PEP medications will be available to you according to standard practices in the community. PrEP 
is a daily pill you can take to prevent HIV (year-round) and PEP is a daily pill you can take after an HIV-
exposure for a 28-day course. This extension will cover the time period between after the current 48 week study 
ends and 48 weeks beyond when the intervention arm has access to CAB-LA.   
 
Possible Risks and/or discomforts: There are risks to taking part in a research study. Some of the most likely 
risks of participation in this study include: 
• 
Breach of confidentiality 
• 
Sensitive Discussions 
• 
Pain or discomfort from Hair Sample or Blood Collection (when applicable) 
 
There are rare but serious risks of participation if you are in the intervention arm and decide to take CAB-LA, 
like:  
• 
Pain, tenderness, hardened mass or lump, swelling, bruising, redness, itching, warmth, abscess, 
discoloration, or loss of sensation at the injection site 
• 
Stomach pain 
• 
Vomiting 
 
We’ll tell you about the other risks later in this consent form. 
 
Possible Benefits: 
 
There will be no direct benefit to you from participating in this study. The enhanced measures to improve PrEP 
and PEP delivery, if you are assigned to the group that receives it, may help you stay on medications, receive 
care, or reduce the likelihood of acquiring HIV infection,  but this cannot be guaranteed. Your participation in 
the study may benefit the community, scientists and doctors who work on providing HIV care in health centers 
such as yours. 
 
Your other options: 
 
You do not have to participate in this study. Your other choices may include: 
• 
You can be put on to the national standard of care for HIV prevention. Your access to PrEP and PEP 
through the clinic will not be affected if you decide to stop participating in the study. 
 
Please talk to your doctor about your choices before agreeing to participate in this study. 
 
Following is a more complete description of this study. Please read this description carefully. You can ask any 
questions you want to help you decide whether to join the study. If you join this study, we will give you a signed 
copy of this form to keep for future reference. 


 
 
 
DETAILED STUDY INFORMATION 
 
This part of the consent form gives you more detailed information about what the study involves. 
 
Why is this study being done? 
 
Providing successful HIV prevention methods can be difficult for doctors, nurses, hospitals and local 
governments. When you first consented to this study, there were two ways HIV could be prevented: by taking 
PrEP or PEP. PrEP is a prevention method that involves HIV negative people taking antiviral drugs to try to 
prevent infection for as long as they are at risk. PEP medications are taken immediately after a suspected 
exposure to HIV through sexual contact or other ways, and is normally taken for a month. Now, there are three 
ways to prevent HIV: PrEP, PEP, and Long-acting Cabotegravir (CAB-LA), which is an injectable prevention 
method, taken in clinic every 4 weeks for two times, and then every 8 weeks thereafter. CAB-LA is approved 
for use for HIV prevention in the United States for adolescents 12 years and older and weighing at least 35 
kilograms. CAB-LA is not approved for HIV prevention in Kenya and Uganda but is under review. You will be 
able to take this drug on an investigational basis in this clinical trial. This extension study will continue 
delivering these options as before, that seek to improve existing PrEP and PEP services, with the new addition 
of CAB-LA. This study will continue to include convenient access to clinicians for changes to your HIV 
prevention methods, the offer of other health services to make visits more efficient, options for PrEP and PEP 
delivery (if not on Long-Acting CAB-LA), and discussions with the clinician on ways to overcome any barriers 
to receiving these services. 
 
What is the usual care for my condition? The usual care for HIV prevention is standard of care per country 
MoH guidelines 
 
How many people will take part in this study? 
 
Approximately 600 participants will take part in this study 
 
What will happen if I take part in this study? 
 
Before you begin the main part of the study… 
 
You will need to re-enroll, as described below. 
 
Enrollment in the Extension 
 
Enrollment will take place at a health facility or in a community location. Study staff will review your clinic 
record and talk to you about the study to confirm you are eligible to participate. If you are eligible and agree, 
you will be asked to review and sign this consent form to take part. The consent discussion and brief questions 
will take 30 minutes to an hour. 
 
During the main part of the study…. 
 
Study Procedures for Participants Assigned to Receive Standard Care 
• 
If you are in the standard-of-care group, per your first randomization, you will continue to be 
seen by staff in the HIV clinic or other service location, like a drop-in centre, according to 
standard care guidelines recommended by the country’s Ministry of Health and may choose to 
seek PrEP and PEP at a local health facility. There will be no change to your care. 


 
 
• 
Data from your clinic records will be collected by study staff related to PrEP, PrEP, and other 
standard prevention methods, including when you were on PrEP/PEP, any HIV or sexually 
transmitted infections, and other details related to care or HIV prevention.  
• 
You will also be seen for a study visit at the mid-point and end of the extension study (every 24 
weeks) for HIV testing, including rapid and RNA tests, and a survey on what prevention 
method(s) you have been using. If you are currently using medications such as PrEP or PEP, 
you may be asked to provide hair, urine, or blood samples in order to measure the level of HIV 
prevention medications in your body. The results from tests measuring medication levels will 
not be shared, as this testing is for research only and will be performed in the future. The most 
blood drawn at a study visit will be about 1 tablespoon. 
 
For SOC participants, Skip to the “Testing HIV-Positive” Section and Continue Consenting 
 
 
Study Procedures for Participants Assigned to Continue to Receive Enhanced Services 
• 
If you were assigned to receive the enhanced PrEP or PEP services, you will still receive these 
treatments according to standard care guidelines, but will also receive the services and 
procedures described below: 
i. 
Staff will discuss with you the integrated services offered in this study, described 
below. All your options will be discussed and questions answered. You will be 
provided a phone number of a study clinician that you can call any day of the week to 
start PEP immediately if you have had a recent exposure, or discuss any other urgent 
issue. 
ii. 
Study Visits: DCP Intervention Participants 
a. If you do not choose CAB-LA, you will return to clinic every 3-months for 
study visits and offered the DCP Package, as before.  
b. PrEP or PEP: you will take PrEP or PEP medications according to standard 
care guidelines recommended by the Ministry of Health, or have the option of 
HIV-testing only if you are not ready to start PrEP.  
c. You may switch between PrEP, PEP, CAB-LA, and frequent HIV-testing only 
at any time, according to your needs and the advice of your provider. At each 
visit, the HIV prevention method that is best for you will be discussed, with 
your options and preferences part of this continuing conversation. If new 
methods, such as the dapivirine vaginal ring, become available, these will also 
be offered as options. You may also have the option for a longer supply of PrEP 
medication or to use HIV self-testing. 
d. You will be asked questions on your attitudes on your choices of prevention 
and challenges at the start of the study extension and at the end of the study 
extension 
iii. 
Study Visits: CAB-LA Participants 
a. Once you choose to begin CAB-LA, you will be seen in clinic once a month for 
the first two months after the initial injection, then every 2-months for 
injections and your clinic study visits.  
 
b. SAPPHIRE staff will assist in scheduling and remembering these appointments 
 
c. If you are on CAB-LA, you can choose to stop at any time and switch to PEP, 
PrEP, or frequent HIV-testing only. Study staff will assist in the transition, so 
there are no gaps in prevention coverage 
 


 
 
d. If you stop and would like to restart the injections, the study staff will assist in 
the timing of the injection restart, so there are no gaps in prevention coverage 
 
e. You must come to clinic for the CAB-LA injection within +/- 7 days of your 
scheduled appointment: administration is not permitted off-site 
 
f. If you cannot make it to clinic within the window for your next injection 
appointment, contact the SAPPHIRE study staff immediately to reschedule or 
to make arrangements for other prevention coverage 
 
iv. 
All participants will come to clinic for the midpoint and closeout visits.  
v. 
Staff will review with you any symptoms you may be having and refer you to other 
clinic services as needed. If staff think you have signs of recent HIV infection, a test 
will be ordered to rapidly measure any virus in your blood as an alternative way of 
testing for HIV. 
vi. 
If there are challenges for you to access your oral medications, staff may deliver your 
PrEP or PEP medications and provide follow-up care at home or another location 
outside of the clinic that works for you. You may opt to change the location of the visit 
at any time during the study, including having phone visits. For any visits that take 
place at your home or other offsite location, staff will work with you to find a space that 
is private and where others cannot overhear the discussion or observe study procedures. 
vii. 
Staff will also be available at any time to provide support if you have had any traumatic 
experiences or abuse at home or elsewhere, and will be trained to provide specialized 
counseling to help you manage these problems and help you find additional resources. 
viii. 
Data from your clinic records will be collected by study staff related to PrEP, PrEP, 
CAB-LA, and other standard prevention methods, including when you were on 
PrEP/PEP/CAB-LA, any HIV or sexually transmitted infections, and other details 
related to care or HIV prevention. 
ix. 
You will be seen for a study visit at the mid-point and end of the study for HIV testing, 
including rapid and RNA tests,  and a survey on what prevention method(s) you have 
been using (every 24 Weeks). If you are currently using medications such as PrEP, 
CAB-LA, or PEP, you may be asked to provide hair, urine, or blood samples in order to 
measure the level of HIV prevention medications in your body. The results from tests 
measuring medication levels will not be shared, as this testing is for research only and 
will be performed in the future. The most blood drawn at a study visit will be about 1 
tablespoon. Visits will take about the same amount of time as a regular clinic visit for 
people on PrEP or PEP.  If you have discussions about your options or need additional 
testing, your visit may be an extra 30 or 45 minutes, as needed. 
x. 
If you miss a visit, study staff may call you or visit you at your home.  If you would not 
like to be visited at home or have a preference on the best way to be contacted, please 
tell the study staff. 
 
Long-Acting CAB General Overview 
 
1. If you choose the Long-Acting CAB option, you will continue having study visits similar to the 
quarterly visits in the DCP intervention. These will align with your CAB-LA injection visits.  
• 
If you choose to stop the CAB-LA injections, you will resume the DCP intervention as before, 
returning to clinic every three months for study visits and offered the original DCP Package.  
2. At baseline, you will have a rapid HIV test and will proceed with the injection if negative. You will also 
have HIV-RNA testing, but will not have to wait for these results to receive the injection 


 
 
3. At follow-up visits, you must have a negative HIV rapid test to proceed with the injection 
4. You will have a health provider administer all injections. You will need injections every month for the 
first two months, and then every two months thereafter 
• 
You may choose to stop injections at any time 
• 
You may switch to PrEP, PEP, or HIV testing at anytime 
• 
Your study doctor will draw safety blood samples, such as ALT (Alanine transaminase) to test 
your liver health or check for Hepatitis B at the study start and during the study course at 
designated timepoints or per provider discretion 
o Participants found to have an Hepatitis B diagnosis will be discontinued from study 
 
Reasons you may have to stop taking the Long-Acting CAB injections 
 
There are some reasons you may have to stop taking CAB-LA: 
• 
You experience a side-effect and it is no longer safe for you to take it 
• 
The investigator determines that it is not safe for you to take it 
• 
You get an HIV infection, which is explained further below 
 
Risks and/or discomforts:  
 
Most Common Side Effects: 
• Pain, tenderness, hardened mass or lump, swelling, bruising, redness, itching, warmth, abscess, 
discoloration, or loss of sensation at the injection site 
• stomach pain 
• vomiting 
• diarrhea 
 
• muscle pain 
• headache 
• rash 
• fever 
• loss of appetite 
• tiredness 
• drowsiness 
• sleep problems 
• back pain 
• nausea 
• upper respiratory infection 
 
Other side effects of cabotegravir may include:    
a. Allergic reactions: 
• 
generally ill feeling 
• 
blisters 
• 
tiredness  
• 
muscle or joint aches 
 
• 
trouble breathing 
• 
fever 
• 
blisters or sores in the mouth 
• 
redness or swelling of eves 
• 
swelling of the mouth, face lips or tongues 
b. Small increases in liver inflammation  
c. Depression or Mood Changes 


 
 
d. Hypersensitivity to Cabotegravir 
 
If you experience any side effects, including those not mentioned above, contact your doctor immediately.  
 
The shots you receive in this study are long acting, meaning they stay in your body for a long time – as long as a 
year or more. If you develop a side effect to CAB-LA after the shot, there will be no way to remove it from your 
body. If you get infected with HIV while on CAB-LA, it is possible that other HIV drugs that are like it may not 
work to fight the virus. The amount of CAB-LA in your body will decrease overtime and will eventually 
disappear.  
 
Pregnancy and Breastfeeding: 
 
Risks and Benefits 
 
We have very little information on the safety of CAB-LA during pregnancy and breastfeeding You will need to 
weigh the risks to your pregnancy and infant to the benefits of your HIV prevention based on the information we 
have summarized below.  
 
If you become pregnant during the study and choose to take CAB-LA during pregnancy, we will ask you to sign 
a separate consent form with more information, since pregnant women are excluded from enrolling in this study 
and we want you to make an informed decision about whether to continue.   
 
If you are breastfeeding when you start this study or you breastfeed after becoming pregnant on the study and 
choose to begin CAB-LA, we want you to understand we have limited information on the safety of this drug 
during breastfeeding. We do know that in studies of another drug, called dolutegravir, which is very similar to 
CAB LA, no nursing babies had any problems. These babies were breastfed by mothers who had HIV and who 
were taking dolutegravir as treatment.  Small amounts of dolutegravir were found in the breastmilk. It is 
possible some CAB LA may pass to a baby through breastmilk. 
 
CAB LA has been detected in the blood circulation for up to 12 months or longer after an injection and the 
consequences of this level of exposure to the infant are currently unknown. Consideration should be given to the 
potential for infant exposure during pregnancy, even after the injections have been stopped.  
 
• 
The safety of exposure of CAB- LA to infants through breastfeeding has not been established.   
• 
Due to the nature of CAB-LA injections, CAB-LA may be present in breastmilk for up to, or beyond, a 
year after the final injection.   
• 
The clinical consequences of exposure of the infant to CAB-LA are unknown. 
 
While not required, to prevent any risk to the participant’s pregnancy or to the infant, it is recommended that 
participants of child-bearing potential taking CAB-LA should use an effective contraceptive method, such as 
birth control (pills, intrauterine device, or implant) during the study, which can be obtained through standard 
care at the MoH.  It is advised to continue using contraceptives through any additional extension phase and for 
52 weeks (one year) after the last injection if stopping CAB-LA, to avoid pregnancy.   
 
Storage and Shipment of Samples: 
The hair, blood, and/or urine samples we may ask to collect from you to measure medication levels, confirm 
HIV infection, or test for resistance to HIV medicines will be stored at IDRC study facilities. Samples may be 
shipped to laboratories in the United States headed by researchers involved in the study: Dr. Monica Gandhi at 
UCSF in San Francisco or Dr. Urvi Parikh at the University of Pittsburgh. The samples will be stored for no 


 
 
more than 5 years after the conclusion of the study and will only include study ID numbers as identifiers and 
will not include your name. 
 
If these samples are requested, do you agree to have your samples collected and shipped to the laboratory in the 
United States for testing?  If you decline this collection and shipment, you may still participate in other parts of 
the study. 
 
 
Hair samples: 
 
□  Yes   __________________            □  No   __________________  
          Participant’s initials or thumbprint and date in space next to answer 
 
Urine samples: 
 
□  Yes   __________________            □  No   __________________  
                       Participant’s initials or thumbprint and date in space next to answer 
 
Blood samples: 
 
□  Yes   __________________            □  No   __________________  
                       Participant’s initials or thumbprint and date in space next to answer 
 
 
 
When you are finished with the study (Week 48: Final Study Visit), ... 
For intervention participants, your study doctor will assist with a transition plan to refer you to standard of care, 
ensuring no lapse in prevention coverage. For control participants, you will remain offered standard of care. 
 
• 
Study Locations: This part of the study will take place in health centers and communities in 
Western Uganda and  Western Kenya.  
 
 
How long will I be in the study? 
 
The program described in this consent form may last up to three years. 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to 
stop. They will tell you how to stop your participation safely.  
 
Intervention participants: It is important to tell the study doctor if you are thinking about stopping so any risks 
from the PrEP/PEP/CAB-LA can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
All participants: If you withdraw from the study, any data or specimens we have already collected from you will 
remain part of the study records. After you withdraw, the researchers may still get information from your 
medical records if it is relevant to the study (e.g., laboratory results, treatment courses, health outcomes). You 


 
 
must tell the study team you do not want this information to be collected when you withdraw, otherwise it will 
be collected.  
 
The study doctor may stop you from taking part in this study at any time if they believe it is in your best interest, 
if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study? 
 
Sensitive Discussions: 
Some of the discussion about HIV and recent exposures may make you feel uncomfortable.  If you feel 
uncomfortable with the topic under discussion, tell the study staff.  If the discussion brings up instances of 
violence against you, including by a partner, family member or stranger, we will refer you to available resources 
for support or for reporting the event to the police.  This is voluntary; it is up to you if you want to utilize such 
resources. 
 
Confidentiality: 
We will do our best to protect the information we collect from you, but confidentiality cannot be guaranteed and 
there is a small chance your information may be revealed.  We will replace your name and all other identifying 
information with a unique code number on all study documents except those kept for contact information. There 
is a chance visits conducted at your home or other offsite location could be noticed by others, but we will work 
with you to find a private space in which to conduct the visit. Study-specific information will be stored in locked 
files, and only a small number of study staff will have access to it. You will not be identified in any report from 
this study. All information will be handled in compliance with Uganda and United States law for private 
information. 
 
Hair Collection and Blood Drawing Risks: 
If you are taking HIV prevention medicines like PrEP, CAB-LA, or PEP, a small hair sample may be collected 
(about 50-100 strands – the amount naturally lost each day). The hair sample will be collected from the back of 
the scalp using a clean pair of scissors in a process that takes 90 seconds. There is a potential but low risk of 
cutting the skin with the scissors. If you are suspected to have recently been exposed to HIV, a blood sample 
may be drawn by study staff to detect any HIV virus that may be in the blood. Taking blood may cause brief 
discomfort and bruising.  Infection or fainting can happen but are rare. 
 
Risks from taking CAB-LA: 
 
Risks and/or discomforts:  
 
Most Common Side Effects: 
• Pain, tenderness, hardened mass or lump, swelling, bruising, redness, itching, warmth, abscess, 
discoloration, or loss of sensation at the injection site 
• stomach pain 
• vomiting 
• diarrhea 
 
• muscle pain 
• headache 
• rash 
• fever 
• loss of appetite 
• tiredness 
• drowsiness 


 
 
• sleep problems 
• back pain 
• nausea 
• upper respiratory infection 
 
Other side effects of cabotegravir may include:    
e. Allergic reactions: 
• 
generally ill feeling 
• 
blisters 
• 
tiredness  
• 
muscle or joint aches 
 
• 
trouble breathing 
• 
fever 
• 
blisters or sores in the mouth 
• 
redness or swelling of eves 
• 
swelling of the mouth, face lips or tongues 
f. Small increases in liver inflammation 
g. Depression or Mood Changes 
h. Hypersensitivity to Cabotegravir 
 
Are there benefits to taking part in this study? 
 
There will be no direct benefit to you from participating in this study. The enhanced measures to improve PrEP 
and PEP delivery, if you are assigned to the group that receives it, may help you stay on medications, receive 
care, or reduce the likelihood of acquiring HIV infection,  but this cannot be guaranteed. Your participation in 
the study may benefit the community, scientists and doctors who work on providing HIV care in health centers 
such as yours. 
 
What other choices do I have if I do not take part in this study? 
 
You do not have to participate in this study. Your other choices may include: 
• 
You can be put on to the national standard of care for HIV prevention. Your access to PrEP and PEP 
through the clinic will not be affected if you decide to stop participating in the study. 
 
Are there any costs to me for taking part in this study? 
 
 
No. The sponsor has agreed to pay for all items associated with this research study; you or your insurer will not 
be billed. 
Will I be reimbursed for taking part in this study? 
In return for your time and effort, you will be receiving a reimbursement of 20,000 Uganda shillings to offset 
the cost of travel and time for participating at Weeks 0, 24, and 48.  
 
Will I be compensated for taking part in this study? 
 
You will not be compensated for taking part in this study. 
 
How will my information be used? 
 


 
 
Researchers will use information to conduct this study. Once the study is done using your information, we may 
share them with other researchers so they can use them for other studies in the future. We will not share your 
name or any other personal information that would let the researchers know who you are. We will not ask you 
for additional permission to share this de-identified information. 
 
How will information about me be kept confidential? 
 
Care will be taken to protect your privacy. Study participants will be identified only by their unique code 
number on all study documents except those kept for contact information. All information will be handled in 
compliance with Uganda and U.S. law for confidential information. The Makerere School of Medicine Research 
Ethics Committee (SOMREC) and Uganda National Council for Science and Technology (UNCST), which are 
institutions that oversee human research, may have access to study information that may have your name. In 
addition, authorized representatives from the National Institutes of Health and University of California may 
review your research data for the purpose of monitoring or managing the conduct of the study. Besides these 
institutions, the universities and research organizations running this study are not allowed to let others know the 
identity of the people in the study. 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If 
you decide to take part in this study, you may leave the study at any time. No matter what decision you make, 
there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not 
affect your medical care. You can still get your medical care from our institution.  
 
We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form. 
 
What happens if I am injured taking part in this study? 
 
It is important that you tell the study doctor, Dr. Moses Kamya, at 075-2-900012, if you feel that you have been 
injured because of taking part in this study. 
 
Who can answer my questions about the study? 
 
If you have any questions about this study, including those about research-related harm, please contact the lead 
investigator in Uganda, Dr. Moses Kamya, at 075-2-900012. You may also contact Assoc. Prof Ponsiano 
Ocama, the chair of the Makerere University School of Medicine - Research and Ethics Committee in Uganda at 
077-2-421190, which approved this study, for questions about participants’ rights and research-related harm. 
 
In addition, a description of this study will be available on http://www.ClinicalTrials.gov.  This website will not 
include information that can identify you.  After the study is over, this website will include a summary of its 
results


 
 
CONSENT:  WHAT YOUR SIGNATURE OR THUMBPRINT MEANS 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You have the right to decline to participate or to 
withdraw from participation at any point in this study without penalty or loss of benefits to which you are 
otherwise entitled. A copy of this consent form will be given to you. Your signature or thumbprint below 
means that you have had this study explained to you.  Your signature or thumbprint below means you 
have had the opportunity to ask questions and get answers. If you wish to participate in this study, you 
should sign or place your thumbprint below.   
 
 
Name of Participant (printed) 
 
 
 
Signature or Fingerprint* of Participant  
  
 
 
 
Date 
 
 
 
 
 
Name of Study Staff Administering Consent (printed) 
 
 
 
Position/Title 
 
 
 
Signature of Study Staff Administering Consent  
 
 
 
Date 
 
 
 
Name of Translator (if necessary) 
 
 
 
Signature of Translator  
 
 
 
 
 
 
Date 
 
*If the participant is unable to read and/or write, an impartial witness must be present during the consent 
discussion. After the written informed consent form is read and explained to the participant, and after he 
or she has orally consented participate in this study, and has either signed the consent form or provided 
his or her fingerprint, the witness must sign and personally date the consent form.  By signing the consent 
form, the witness attests that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the participant, and that consent was freely given. 
 
 
 
Name of Person Witnessing Consent (printed) 
 
 
 
 
 
 
Signature of Person Witnessing Consent  
 
 
Date 
 

Prot_000.pdf: 
1 
 
 
 
 
 
 
 
 
Document: 
Study Protocol 
 
Official Study Title: 
SEARCH CAB LA Dynamic Choice HIV Prevention Study Extension 
NCT05549726 
 
Document Date: 
26-July-2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
 
 
 
 
 
 
 
Extension of SEARCH SAPPHIRE Dynamic Choice Prevention Study  
 
 
Sustainable East Africa Research in Community Health (SEARCH) Consortium 
 
Clinical Trial Phase:  IV 
 
 
Funded by:  National Institutes of Health 
 
 
Protocol Chair:  Diane Havlir, MD 
 
Protocol Co-Chairs:  Moses Kamya, MBChB, MPH, PhD 
                                    Maya Petersen, MD, PhD 
 
Protocol Vice-Chair:  Gabriel Chamie, MD, MPH 
 
Version Number: 3.0 
 
Version Date: 26-July-2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1. KEY ROLES ............................................................................................................................... 6 
2. LIST OF ABBREVIATIONS ................................................................................................... 10 
3. PROTOCOL SUMMARY ........................................................................................................ 12 
4. INTRODUCTION .................................................................................................................... 14 
4.1 Background ......................................................................................................................... 14 
5. POPULATION ......................................................................................................................... 16 
5.1 Recruitment ......................................................................................................................... 16 
5.2 Inclusion and Exclusion Criteria ......................................................................................... 16 
6. HYPOTHESES AND OBJECTIVES ....................................................................................... 18 
6.1 Hypotheses .......................................................................................................................... 18 
6.2 Objectives ........................................................................................................................... 18 
7. INTERVENTION ..................................................................................................................... 18 
7.1 Study Design and Schema .................................................................................................. 18 
7.2 Dynamic Choice Delivery Model ....................................................................................... 19 
7.3 Measurement ....................................................................................................................... 20 
7.3.1 Behavioral Measures .................................................................................................... 20 
7.3.2 Costing Evaluations ..................................................................................................... 21 
8. STUDY PROCEDURES .......................................................................................................... 22 
8.1 Schedule of Evaluations ...................................................................................................... 23 
9. INFORMED CONSENT .......................................................................................................... 28 
9.1 Informed Consent Process .................................................................................................. 28 
9.2 Assent Process .................................................................................................................... 28 
9.3. Documentation of Informed Consent................................................................................. 28 
9.4 Waiver of Informed Consent ............................................... Error! Bookmark not defined. 
9.5 Stored Samples and Associated Data Considerations ......................................................... 29 
10. SAFETY ASSESMENT OVERVIEW ................................................................................... 29 
10.1 Cabotegravir (GSK1265744A) Injectable Suspension- for intramuscular use: Product 
information ............................................................................................................................... 29 


4 
 
10.2 Administration Overview.................................................................................................. 29 
10.3 Pharmacy........................................................................................................................... 30 
10.4 Injection Dosing ................................................................................................................ 30 
10.5 Missed Doses .................................................................................................................... 30 
10.6 Contraindications. CAB-LA is contraindicated in individuals: ........................................ 31 
10.7 Drug Interactions ............................................................................................................ 32 
10.8 Drug Overdosage .............................................................................................................. 33 
11. HUMAN SUBJECTS PROTECTIONS ................................................................................. 33 
11.1 Vulnerable Participants ..................................................................................................... 33 
11.1.1 Pregnant Women and Fetuses .................................................................................... 33 
11.1.2 Children...................................................................................................................... 34 
11.1.3. Illiterate Participants ................................................................................................. 34 
12. RISKS ..................................................................................................................................... 34 
13. SOCIAL IMPACT EVENTS .................................................................................................. 37 
14. BENEFITS .............................................................................................................................. 37 
15. COMPENSATION ................................................................................................................. 37 
16. PARTICIPANT PRIVACY AND CONFIDENTIALITY ..................................................... 37 
17. STUDY DISCONTINUATION ............................................................................................. 38 
18. Community Advisory Board, Stakeholders and Communication of Results ......................... 38 
19.ADMINISTRATIVE PROCEDURES .................................................................................... 39 
19.1 Regulatory Oversight ........................................................................................................ 39 
19.2 Clinical Site Monitoring ................................................................................................... 41 
19.3 Study Implementation ....................................................................................................... 41 
19.4. ClinicalTrials.gov............................................................................................................. 41 
19.5 Adverse Event Procedures and Reporting Requirements ................................................. 41 
20.TOXICITY MANAGEMENT ................................................................................................. 42 
20.1 Participant Discontinuation ............................................................................................... 42 
20.2 Guidance on Toxicity Management for Specified Toxicities: .......................................... 43 
21.Analyses ................................................................................................................................... 49 
21.1 Overview ........................................................................................................................... 49 
21.2 Pharmacokinetic analyses: ................................................................................................ 50 
21.3 Analyses of In-Depth Interviews.................................................................................... 51 
21.4 Costing ........................................................................................................................... 51 
21.5 Power and Sample size considerations ............................................................................. 51 


5 
 
22. 
DATA HANDLING AND RECORD KEEPING ............................................................. 52 
22.1 . Data Management Responsibilities................................................................................. 52 
22.2. Essential/Source Documents and Access to Source Data/Documents ............................ 53 
22.3. Quality Control and Quality Assurance ........................................................................... 53 
23. 
PUBLICATION POLICY ................................................................................................. 54 
24. 
REFERENCES .................................................................................................................. 54


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1. KEY ROLES 
List of Investigators 
 
Diane Havlir, MD 
Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 424 
Email:  diane.havlir@ucsf.edu 
 
Moses R. Kamya, MBChB, MMed, PhD  
Co-Chair, Makerere University 
Address: Department of Medicine, P.O. Box 7072, Kampala, Uganda   
Phone Number: +256-414-533200 
Email: mkamya@infocom.co.ug 
 
Maya L. Petersen, MD, PhD 
Co-Chair, University of California, Berkeley 
Address: School of Public Health, 5402 Berkeley Way West, Berkeley, CA 94720-7358, 
U.S.A. 
Phone Number:  +1-510-642-0563 
 
Gabriel Chamie, MD, MPH 
Vice-Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 445 
Email:  gabriel.chamie@ucsf.edu 
 
Laura Balzer, PhD 
Investigator and Protocol Statistician, University of California, Berkeley 
Address:  School of Public Health, 5317 Berkeley Way West, Berkeley, CA 94720-7358, 
U.S.A. 
Phone Number:  +1-203-558-3804 
Email:  laura.balzer@berkeley.edu 
 
Andrew Phillips, MSc, PhD 
Investigator, Modeling, University College London, London 
Address: Institute for Global Health, Glower Street, WC1 6BT, U.K. 
Phone Number:  +20-7830-2886 
Email: andrew.phillips@ucl.ac.uk  
 
Florence Mwangwa, MBChB, MPH 
Investigator, Adult and Adolescents Studies, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Phone Number: +256-779-386616 


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Email:  fmwangwa@idrc-uganda.org  
 
Jane Kabami, MPH 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 7475, Kampala, Uganda 
Phone Number: +256-706-315810 
Email: jkabami@idrc-uganda.org  
 
Elijah Kakande, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Phone Number: +256-779-386616 
Email:  rkakande@idrc-uganda.org   
 
Asiphas Owaraganise, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Email:  asiphas@gmail.com 
 
Elizabeth Bukusi, MBChB, M.Med, MPH, PhD 
Investigator, Youth and Integration of HIV and Reproductive Health Services, Kenya Medical 
Research Institute 
Address:  Box 54840, Nairobi, Kenya 
Phone Number: +254-733-617503 
Email:  ebukusi@rctp.or.ke 
 
James Ayieko, MBChB, MPH, PhD 
Investigator, Adult and Adolescent Studies, Kenya Medical Research Institute 
Address: P.O. Box 517-20107, Njoro, Kenya 
Phone Number: +254-720-925262 
Email: jimayieko@gmail.com  
 
Norton Sang, MA 
Investigator, Kenya Medical Research Institute 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: nortonsang@gmail.com  
 
Marilyn Nyabuti, MBChB 
Investigator, Kenya Medical Research Institute and the University of Washington, Seattle 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: mnyanduko@gmail.com  
 
Judith Hahn, PhD, MA 
Investigator, Alcohol Use Studies, University of California, San Francisco 


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Address:  UCSF Box 1224, San Francisco, CA 94158 
Phone:  +1-415-476-5815 
Email:  judy.hahn@ucsf.edu  
 
Carol Camlin, PhD, MPH 
Investigator, Social Sciences/Qualitative Studies, University of California, San Francisco 
Address:  Center for AIDS Prevention Studies, San Francisco, CA 94143, U.S.A. 
Phone Number:  +1-415-597-4998 
Email:  carol.camlin@ucsf.edu 
 
Starley Shade, PhD 
Investigator, Cost Effectiveness, University of California, San Francisco 
Address:  Box 0886, San Francisco, CA 94143-0886, U.S.A. 
Phone Number:  +1-415-476-6362 
Email:  starley.shade@ucsf.edu 
 
Harsha Thirumurthy, PhD 
Investigator, Behavioral Economics Studies, University of Pennsylvania 
Address:  Department of Medical Ethics and Health Policy, Philadelphia, PA 19104 
Phone Number:  +1-215-746-0410 
Email:  hthirumu@upenn.edu 
 
Edwin Charlebois, PhD, MPH 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A 
Phone Number:  +1-415-476-6241 
Email:  edwin.charlebois@ucsf.edu 
 
Priscilla Hsue 
Investigator, Cardiovascular Studies, University of California, San Francisco 
Address:  UCSF Box 0846, San Francisco, CA 94110 
Phone:  +1+415-206-8257 
Email:  Priscilla.hsue@ucsf.edu  
 
Theodore Ruel, MD 
Investigator, HIV Adolescent and Young Adult Studies, University of California, San Francisco 
Address:  UCSF Box 0434, San Francisco, CA 94143-0136, U.S.A. 
Phone Number:  +1-415-476-9197 
Email:  theodore.ruel@ucsf.edu 
 
Craig Cohen, MD, MPH 
Investigator, University of California, San Francisco 
Address:  Reproductive Sciences, Box 1224., San Francisco, CA 94158 - youth and 
integration of HIV and reproductive health services 
Phone Number:  +1-415-476-5874 
Email:  craig.cohen@ucsf.edu  


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Eric Goosby, MD 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-5483 
Email:  eric.goosby@ucsf.edu  
 
Catherine Koss, MD 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 
Email: catherine.koss@ucsf.edu   
 
Urvi M Parikh, PhD 
Virologist, University of Pittsburgh, Pittsburgh 
     Address: S830 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261 
     Phone Number: 412-648-3103 
     Email: ump3@pitt.edu 
 
Bishop Opira, Bpharm, MPH 
Pharmacist, Infectious Diseases Research Collaboration, Kampala, Uganda 
    Address: Plot 2C Nakasero Hill Road,P.O. Box 7475 Kampala, Uganda 
    Phone: +256 (0)312 281 479 
    Email: opibish@idrc-uganda.org 
 
Greshon Rota, Bpharm 
Pharmacist, Kenya Medical Research Institute 
   Address:P.O. Box 54840 00200 Off Raila Odinga Way. Nairobi, Kenya. 
   Phone: +254 722205901 
   Email: director@kemri.go.ke 
 
 
 
 
 
 
 
 
 
 
 


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2. LIST OF ABBREVIATIONS  
 
AIDS: Acquired immunodeficiency syndrome 
ART: Antiretroviral therapy 
CAB-LA: Long-Acting Cabotegravir 
CE: Cost-effectiveness 
CHR: Committee on Human Research 
CHV: Community health volunteer 
CRF: Case report form 
CVD: Cardiovascular disease 
DALYs: Disability-adjusted life years 
DM: Diabetes mellitus 
DSMB: Date Safety Monitoring Board 
ELA: Empowerment and Livelihood for Adolescents 
FTE: Full-time equivalent 
FGD: Focus group discussion 
GPS: Global positioning system 
HIV: Human immunodeficiency virus 
HSV: Herpes simplex virus 
HTN: Hypertension 
IDI: In-depth interview 
IPV: Intimate partner violence 
IRB: Institutional Review Board 
KEMRI: Kenya Medical Research Institute 
MoH: Ministry of Health 
MTCT: Mother-to-child HIV Transmission 
NASCOP: National AIDS and STI Control Programme 
PEP: Post-exposure prophylaxis 
PEth: Phosphatidylethanol 
PRECEDE: Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and 
Evaluation 
PrEP: Pre-exposure prophylaxis 
SAP: Statistical analysis plan 
RE-AIM: Reach, Effectiveness, Adoption, Implementation and Maintenance 
SEARCH: Sustainable East Africa Research in Community Health 
SOMREC: Makerere University School of Medicine - Research and Ethics Committee 
SOPs: Standard Operating Procedures 
SSA: Sub-Saharan Africa 
STI: Sexually-transmitted infections 
TB: Tuberculosis 
TDF/FTC: Tenofovir disoproxil fumarate/Emtricitabine 


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TMLE: Targeted maximum likelihood estimation 
TFV: Tenofovir analyte 
UCSF: University of California, San Francisco  
UNCST: Uganda National Council for Science and Technology 
VMMC: Voluntary medical male circumcision 
VHT: Village health team. This term (Uganda) used in protocol refers to equivalent CHV 
(community health volunteer)  
 
 


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3. PROTOCOL SUMMARY  
Title: Extension of SEARCH SAPPHIRE Dynamic Choice Prevention Study 
The Extension of SEARCH SAPPHIRE Dynamic Choice Prevention Study is a continuation of 
the 3 ongoing SEARCH SAPPHIRE Dynamic Choice Prevention randomized trials. The parent 
SEARCH SAPPHIRE Dynamic Prevention intervention studies were initiated in 2021, and were 
testing the hypothesis that a patient centered HIV Dynamic choice intervention would increase 
HIV biomedical prevention time in persons at risk for HIV infection.  
The trial is being conducted in 3 settings; outpatient clinics, antenatal/family planning clinics, 
and via VHT workers in community households. The dynamic choice intervention includes 
counseling on and services of PrEP/PEP, choice of service location (e.g. clinic, household, 
community, phone), HIV testing options (including rapid or self-test provision), option for 
longer (e.g. 3 month) supply of PrEP, provision of a clinical officer’s or nurse’s mobile 
telephone number for immediate PEP starts any day of the week, routine assessment of barriers 
to initiation or adherence to PrEP/PEP, including the offer of personalized potential solutions 
such as choice of in-clinic or offsite service delivery, psychologic supports for traumatic 
experiences, and offer of concurrent, additional health or prevention related services. These 
services are integrated into Uganda and Kenya Ministry of Health (MoH) guidelines driven 
services for PrEP/PEP, augmenting local standard care procedures for the prevention of HIV. In 
both arms, participants have access to standard prevention offerings and will have study visits 
every 24 weeks for up to 3 years for HIV testing and outcomes measurement (including 
PrEP/PEP adherence assessment via small hair sample).  
This extension protocol is a continuation of the 3 Dynamic Prevention Randomized studies for a 
48 week follow up period following re-consent, with the addition of  Cabotegravir (CAB-LA) as 
one of the dynamic choice biomedical options for intervention participants. CAB-LA is a new 
prevention intervention that requires injections every 8-weeks, rather than daily pill 
intake.  CAB-LA offers an option for HIV prevention that does not require daily pills. In two 
head-to-head comparison studies that randomized persons to either CAB-LA or Tenofovir daily, 
HIV infections were reduced by over 50% in the CAB-LA arm. CAB-LA was approved in the 
United States in December 2021; while it is not yet approved in Uganda or Kenya, applications 
have been submitted and approval is expected in the coming year.  
In this DCP CAB-LA Extension, persons who are currently enrolled in the DCP trials and were 
randomized to the intervention arm will be eligible to receive CAB-LA as one of the options in 
the “Dynamic prevention” model.  Persons in the control arm will be eligible to receive CAB-LA 
if and when it is rolled out through in-country programs. Upon study approval, all participants 
will be offered re-consenting to continue on this study. 
If CAB-LA is not available in country at the 48-week endpoint, all participants in the 
intervention arm will have the opportunity to continue in the study until Week 96, and 
participants who are currently on CAB-LA may continue through the extension. The study will 
end at Week 96, and by that time participants will be transitioned to in country prevention care. 
At 96 weeks, persons on CAB-LA will be transitioned to in country CAB-LA or to other 
prevention options if CAB-LA is not available. Prior to this transition, available in country 


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options will be assessed by the study team.  HIV prevention options will be discussed with each 
study participant by their Week 88 visit, with a plan established for the transition to the 
participant’s preferred prevention method in coordination with local health facilities to avoid 
interruption after their 96 weeks of study participation is completed. 
Participants in the control arm can access biomedical  HIV prevention interventions (oral PrEP, 
PEP)  through the local health clinics. They will have access to CAB LA when it becomes 
available through the Ministry of Health.  Participants in the intervention arm with have access to 
PrEP, PEP + CAB LA with the additional structured dynamic choice support described above. 
Intervention participants that choose not to use CAB-LA will continue on a quarterly study visit 
schedule, per the standard DCP Intervention study schedule. Intervention participants that choose 
CAB-LA will be seen once every 4 weeks for the first two injections, then every 8-weeks for 
injections and study visits. Should participants stop CAB-LA, they will revert to the quarterly 
DCP visit schedule. All participants will be seen for mid-point and end-point visits every 24 
weeks.   
A subset of participants that use CAB-LA (up to 40) will be asked to complete an in-depth-
interview and all participants will take a survey at Weeks 0, 24, and 48 (or at CAB-LA 
discontinuation) for researchers to better understand participant’s experience with CAB-LA and 
to improve delivery as it becomes more widely available. A subset of 10 providers will also be 
asked to complete an in-depth interview and all providers will complete surveys at their Weeks 
0, 24, and 48 of administering CAB-LA. These interviews and surveys will help researchers 
understand better ways to deliver CAB-LA, as it becomes more widely available. Participants 
that seroconvert (acquire HIV during the trial) will also be asked to participate in an in-depth 
interview, as it will help researchers understand transmission and ways to improve DCP delivery 
in future implementation. 
 
There is limited safety information available about CAB-LA use during pregnancy or 
breastfeeding. In the HPTN 084 trial (Phase 3 safety and efficacy trial of injectable cabotegravir 
compared with TDF-FTC for HIV prevention in HIV-uninfected women), the 63 women who 
became pregnant while taking CAB-LA had no birth defects. Given this precedent, participants 
will not be allowed to begin CAB-LA while pregnant, but may continue CAB-LA if they become 
pregnant or are breastfeeding. Participants will be explained the risks and benefits of CAB-LA 
during pregnancy or breastfeeding prior to enrolling in the study. Participants that become 
pregnant will be provided detailed information on the risks and benefits of continuing CAB LA 
and asked to sign a separate consent form, asking that the study team follow her, for 
informational purposes only, for up to 8 weeks post-partum to ascertain the outcome of the 
pregnancy The pregnancy follow-up is for health monitoring of the mother and infant, as well as 
contributing to the global knowledge base of pregnancy and CAB-LA use.  
 
The overall purpose of this extension is to 1) Determine if adding the option of CAB-LA as a 
prevention choice using a patient-centered HIV prevention delivery model increases prevention 
coverage (i.e. proportion of time that is covered by a biomedical prevention option, such as PrEP 
or PEP) compared to the standard-of-care in 3 ongoing randomized trials of Dynamic Choice 
Prevention in rural Uganda and Kenya; and, 2) Conduct a hybrid implementation study (Primary 
Objective Clinical and Secondary Objective Implementation) focusing on initial implementation 


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of a patient-centered model for CAB-LA using the RE-AIM evaluation framework among 
persons randomized to the intervention arm 
4. INTRODUCTION 
4.1 Background 
 
SEARCH SAPPHIRE is an ongoing, NIH-funded study that is testing multi-disease and multi-
sector interventions aimed at reducing HIV burden and improving health in rural Uganda and 
Kenya. Phase A is a portfolio of randomized prevention and treatment implementation studies 
that will inform a population-level study in Phase B.  
 
HIV incidence in Sub-Saharan Africa (SSA) remains well above global elimination targets.1 
Despite an increasingly large, evidence-based toolkit to prevent HIV transmission, there were 
over 1 million new HIV infections in SSA in 2018.1 We know from SEARCH2 and three other 
recent SSA population-level studies3-5 that reaching (and exceeding) the UNAIDS 2020 
population-level viral suppression target of 73%6 is insufficient to achieve epidemic control 
(Table 1). We also know that key sub-populations, in particular youth,4, 7-10 men,2, 4, 10-12 mobile 
populations,13-15 and persons with heavy alcohol use16, 17 continue to fall short of viral 
suppression targets, putting them at higher risk for HIV complications, mortality, and onward 
HIV transmission. Finally, pre-exposure prophylaxis (PrEP), an intervention that has reduced 
incidence in affected populations in some areas where high rates of viral suppression were 
already present,18, 19 has not been effectively deployed in high risk populations (such as young 
women) in SSA.20, 21 To achieve control of the HIV epidemic and mitigate its consequences, we 
need new and scalable interventions to improve delivery of prevention and treatment to vital 
segments of the population that contribute to persistence of new infections.  We describe 
below why previous approaches that were effective for the majority of people in the ART roll-
out do not work for subsets of these “persistent-driver” populations, our proposed solutions, and 
how a multi-component intervention trial can effectively inform stakeholders on programming 
and resource allocation to accelerate reductions in HIV incidence. 
 
HIV prevention services that offer choice of delivery options (PrEP, CAB-LA, & PEP) and 
flexibility in their use and location of delivery over time allow for a dynamic, patient-centered 
model of prevention. This approach is responsive to the reality of an individual’s changing 
needs, thereby facilitating continued engagement. In SEARCH, PrEP use declined over time in 
spite of initial enthusiasm and uptake by early adopters22. In multiple settings, poor adherence to 
PrEP remains its Achilles’ heel.23,24 Rather than presenting PrEP in a similar framework to ART 
(i.e. lifelong use with 100% adherence for efficacy with delivery at HIV clinic), approaches that 
incorporate flexibility in choice and delivery location, akin to contraception options for women 
in developed countries, may prove more successful. Indeed, over the past four decades, increased 
choice in contraception and flexibility in access have been directly associated with increased 
use.25,26 Framing prevention in the context of healthy choices, rather than an assessment of risk, 
may also reduce the association of PrEP with “risky” behavior or promiscuity. Offering PEP – an 
event-driven option that does not require accurate prediction of risk before a potential HIV 
exposure (akin to a “morning after” pill), and which additionally provides protection for those 
with less sexual agency – is a critical innovation in flexible access to prevention services. PEP 
can also act as a “gateway” to PrEP or CAB-LA and other prevention modalities, providing 


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infrastructure to add new prevention options as they become available (e.g. the PrEP vaginal 
ring27,28).  
 
In the HPTN 084 superiority trial there was an 88% reduction in HIV infections in the CAB-LA 
arm compared to TDF/FTC, with a study population (3,224 participants) of cisgender women, 
aged 18-45, in Sub-Saharan Africa, including Uganda. Amongst participants that became 
pregnant, no congenital abnormalities were reported, with more data on pregnancy and infant 
outcomes expected from the HPTN 084 open-label study.  
 
This extension describes a 48-week extension of 3 ongoing randomized trials in SEARCH Phase 
A studying a patient-centered “Dynamic Choice Prevention” (DCP) implementation strategy for 
delivering existing evidence-based biomedical prevention interventions vs. standard of care 
(SOC). The Dynamic prevention model offers participants choices on prevention modality on an 
ongoing basis: oral PrEP, or oral PEP, and the option to switch between products. The trials are 
being conducted in 3 settings: antenatal (ANC) clinics, the outpatient department (primary care 
clinics), and in rural community settings in Western Uganda and Kenya. All clinic and village 
health team staff (i.e., Clinical Officers, nurses, coordinators, health workers) are trained and 
equipped for HIV prevention care in the clinical setting, appropriate to their role.  
 
In this extension study, participants in the intervention and control arms are reconsented and 
remain in their initial randomized arm. Persons in the intervention arms who remain HIV 
negative will be offered CAB-LA as an additional biomedical prevention option, if eligible.  
CAB-LA will be delivered at health clinics. The primary 48-week endpoint for this extension is 
proportion of time covered by a biomedical prevention product.  As of May 9, 2022, a total of 
1213 HIV-negative persons aged 15 years and older and at risk for HIV acquisition were 
enrolled in the studies. (Table 1). New participants are currently being enrolled in the original 
SEARCH SAPPHIRE DCP trials to replace those participants who have moved or have been 
unable to continue in the DCP study. The total number of participants in the study eligible for 
CAB-LA will not exceed the 593 listed in Table 1. 
 
 
Table 1. Enrollment in 3 SEARCH Sapphire Dynamic Prevention Trials as of May 9, 2022  
Dynamic Prevention 
Study  
Intervention 
and Control, 
(N) Uganda  
Intervention  
(N) Uganda  
Intervention 
and Control, 
(N) Kenya 
Intervention (N) 
Kenya  
Total Enrolled 
(N), 
Intervention 
and Control   
Total 
Enrolled 
Intervention 
(N) 
Antenatal/SRH 
Clinic  
200 
100 
201 
103 
401 
203 
Outpatient 
Department 
Clinics  
201 
100 
201 
97 
402 
197 
Household 
Study 
Community 
Village Health 
Team (VHT)  
200 
83 
210 
110 
410 
193 
All Trials 
Together  
601 
283 
612 
310 
1213 
593 


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5. POPULATION 
5.1 Recruitment 
 
The persons eligible for participation in the extension are those who were enrolled in the 3 
ongoing DCP trials. Persons for the ANC study are recruited and enrolled through offering study 
participation at ANC clinics at government sponsored health facilities. Persons for the Outpatient 
department are recruited and enrolled through offering study participation at Outpatient 
department clinics at government sponsored health facilities. Persons for the community study 
are recruited via home visits by village health teams/community health workers. 
 
5.2 Inclusion and Exclusion Criteria 
 
Inclusion criteria for the Extension include:  
1) Enrollment in a SEARCH Sapphire Dynamic Choice Prevention study 
2) HIV negative at start of extension 
3) Residing in study region 
 
Additional inclusion criteria to access CAB-LA as a prevention option  
1) Not pregnant at time of initial CAB-LA injection 
2) Participant weighs at least 35kg 
 
Additional Exclusion Criteria to access CAB-LA as a prevention option 
1) Participant has Hepatitis B or chronic Hepatitis C Diagnosis  
2) Participant has ALT >=5x ULN 
3) Participant has clinical history of liver cirrhosis or current clinical evidence of cirrhosis 
or severe liver disease 
4) Previous hypersensitivity reaction to cabotegravir  
5) Receiving the following co-administered drugs for which significant decreases in 
cabotegravir plasma concentrations may occur due to uridine diphosphate 
glucuronosyltransferase: 
i. Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin 
ii. Antimycobacterials: Rifampin, rifapentine 
6) Participants with a current or anticipated need for chronic systemic anticoagulation or a 
history of known or suspected bleeding disorder, including a history of prolonged 
bleeding, except for the use of anticoagulation for deep vein thrombosis (DVT) 
prophylaxis (e.g., postoperative DVT prophylaxis) or the use of low dose acetylsalicylic 
acid (≤325 mg). 
 
Study Intervention Clinic Locations:  
 
All participating ANC and OPD clinics in the DCP trial will offer CAB-LA. For VHT/CHV 
communities, the nearest health facility will offer CAB-LA for all participants 
1) In Uganda, the sites for each of the trials: 


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a. OPD: Itojo Hospital, Kitagata Hospital 
b. ANC: Bwizibwera HCIV, Bushenyi HCIV 
c. VHT: Ndeija Health Center III 
2) In Kenya, the sites for each of the trials: 
a. OPD: Magunga Level IV Hospital, Oyani Hospital 
b. ANC: Oyani Hospital, Sena Health Centre 
c. CHV: Sibouche Health Centre, Ogongo Sub-District Hospital 
 
The demographic characteristics of the persons enrolled in the intervention arm of the DCP 
Trials as of May 9, 2022 currently who will be eligible for CAB-LA patient-centered 
intervention are shown in Table 2. 
 
Table 2. Demographics of persons in intervention arm eligible for CAB-LA in extension 
phase of trial as of May 9, 2022.  
ANC Clinic  
Outpatient 
Department  
Community   
Total Enrolled  
203  
197  
193  
Female Participants   
203 (100%)  
119 (60.4%)  
111 (57.2%)  
Age years number 
and %  
   
   
   
   15-25 years   
120 (56.9%)  
90 (44.1%)  
75 (38.9%)  
   26- 30  
47 (22.3%)  
33 (25.0%)  
29 (25.4%)  
   31-40  
35 (16.6%)  
51 (16.2%)  
49 (18.7%)  
   41-60   
9 (4.3%)  
26 (12.7%)  
36 (15.0%)  
   61+  
0 (0%)  
4 (2.0%)  
4 (2.1%) 
  
Rationale: HIV prevention services that offer choice of prevention products (PrEP & PEP) and 
flexibility in their use and location of delivery over time allow for a dynamic, patient-centered 
model of prevention. This approach is responsive to the reality of an individual’s changing 
needs, thereby facilitating continued engagement. CAB-LA is highly efficacious for HIV 
prevention that was recently approved by the US FDA based on two large, randomized trials 
HPTN 083 and HPTN 084. As CAB-LA is rolled out across rural sub-Saharan Africa, it is 
important to determine how the addition of this option impacts prevention coverage in real-
world settings for women and men at risk for HIV. In addition, it is critical to design, evaluate, 
and improve patient-centered CAB-LA delivery strategies that maximize uptake and impact of 
this new product.    
 
Ethical Considerations: The HPTN 084 study that showed efficacy of CAB LA for prevention 
included sites in both Uganda and Kenya. Applications for approval of CAB LA are under 
review in each of these countries. Thus,  the information generated in this study on evaluating a 
dynamic prevention implementation strategy will be directly applicable.  During this proposed 
study extension, CAB LA is expected to become publicly available through Ministry of Health 
(“MoH”) sponsored programs in both Kenya and Uganda. UCSF is developing an additional 
extension to 96 weeks, which will examine longer-term safety and implementation data of CAB-
LA. Should there be delay in rollout of the MoH programs, participants could continue in this 
additional extension phase. After the endpoint of the 96-week extension is reached, participants 


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will be transitioned to a standard of care regimen, via local healthcare system, based on the 
investigator’s clinical judgment and local country guidelines. 
 
6. HYPOTHESES AND OBJECTIVES  
 
6.1 Hypotheses 
 
A dynamic choice prevention model that includes a patient-entered CAB-LA delivery option will 
have higher levels of biomedical prevention coverage (assessed over 48 weeks following re-
consent for the CAB-LA extension study) compared to the standard of care.   
 
This hypothesis will be tested by comparing covered time between the intervention and 
control arms in the 3 ongoing randomized trials during the extension phase.  
 
The secondary hypothesis:  Addition of patient-centered CAB-LA into an ongoing dynamic 
choice prevention will improve biomedical prevention coverage (compared to dynamic choice 
prevention without CAB-LA).  
 
These hypotheses will be tested by comparing covered time during the extension with the 
CAB-LA option to covered time prior to the extension among intervention arm participants.  
 
We expect that incorporating the option of CAB-LA with patient-centered delivery for persons 
who self-identify at risk for HIV living in rural Uganda and Kenya will increase overall 
biomedical covered prevention time compared to the standard of care. In a population that has 
been offered -- and some of whom have taken up -- oral PrEP and PEP, we also expect to learn 
characteristics of who is most interested in CAB-LA, how our patient-centered CAB-LA 
delivery models work in different settings, and the cost of the delivery models in different 
settings.  
 
6.2 Objectives 
 
Primary Objective: To compare biomedical prevention coverage achieved using a Dynamic 
prevention model that includes a patient-centered CAB-LA delivery intervention to biomedical 
prevention coverage under the standard of care over 48 weeks.  
 
Secondary Objectives: To determine the reach, effectiveness, adoption, implementation and 
maintenance of a patient-centered CAB-LA program embedded in 3 ongoing trials in the setting 
of antenatal clinic, outpatient clinic, and community.  
 
Tertiary Objectives: To evaluate change in knowledge, awareness and acceptability/satisfaction 
at the staff and provider level with CAB-LA before and after provider and staff training and 
education in CAB-LA with patient-centered delivery model. 
 
7. INTERVENTION 
7.1 Study Design and Schema 
 


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Study Design: This proposal is an extension of 3 ongoing randomized trials comparing a 
patient-centered “Dynamic Choice” implementation strategy for delivering biomedical 
prevention options compared to standard of care (Figure 1). Each trial is enrolling persons 15 
years of age and older who are HIV uninfected and at risk of acquiring HIV. The Dynamic 
Choice Prevention intervention allows choice of PEP/PrEP, refill schedule, service delivery 
location (e.g. clinic, community, home), and HIV testing (self or staff). Persons can move from 
PEP to PrEP as they prefer.  
 
Figure 1. Dynamic Choice Implementation Strategy.  
 
Intervention: In the extension phase, participants will remain in their initial randomization arm. 
For persons in the intervention arm, CAB-LA will be integrated into the dynamic choice delivery 
model as an additional biomedical prevention option in a patient-centered delivery model based 
on the precede framework. 
 
7.2 Dynamic Choice Delivery Model  
 
 
 
The Dynamic Choice Delivery Model includes integrated PrEP and PEP services at outpatient 
clinics, antenatal clinics, and via VHT workers in community households. The procedures for 
each trial include PrEP/PEP counseling and services, choice of service location, HIV testing 
options, option for longer PrEP refills, provision of a clinical officer’s or nurse’s mobile 
telephone number for immediate PEP starts any day of the week, assessment of PrEP/PEP 
barriers and personalized actions, psychologic supports for traumatic experiences, and offer of 
concurrent, additional health or prevention related services. For participants that chose CAB-LA 
as the biomedical prevention option, the patient-centered delivery model (Table 3) will be 
implemented.  The standard of care differs according to country but does not routinely offer PEP 
or PrEP to clients seeking services, does not offer choice of service location, HIV testing option 
or access to medical provider mobile phone number. Clients are required to return after one 
month for a refill for PrEP, whereas in our model, there is an option from the start for 3 month 
medication supply. 
 


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Table 3. Patient-Centered Delivery Model. 
Intervention  
Population and frequency 
Purpose 
Education, case studies and discussion on concept of  dynamic 
prevention and on the profile of each prevention option product  
Health center leadership and staff, provider, 
participants;  initial and ongoing  
Predisposing  
Integration into antenatal, OPD clinics, IPV/GBV support services, 
travel packs, 24 hour hotline for participants   
For oral PrEP/PEP only- HIV testing choice (self or staff) and home or 
clinic delivery 
Participants;  ongoing  
Enabling 
Provider text/check-in to participant one week after starting new 
option, data on biomedical prevention covered time (reinforcing)  
Participants and staff; ongoing data feedback  
Reinforcing 
 
7.3 Measurement 
 
Outcomes: The primary outcome for the extension is the proportion of time covered by a 
biomedical prevention option during the 48 week follow-up period of the CAB-LA Extension; 
follow-up time will be censored at HIV diagnosis, death, or withdrawal. Biomedical covered 
time is defined as the proportion of follow-up time that each participant is covered by either 
PrEP (TDF/3TC or CAB-LA) or PEP. For TDF/3TC, covered time is defined using self-reported 
use; in a subset of participants who report PrEP use we will measure tenofovir drug levels using 
small hair samples to allow for calibration of self-reported measures. For CAB-LA, coverage 
begins 3 days after initial injection continues 2 months + 7 days after last injection. For PEP, 
covered time is defined using self-reported use; in a subset of participants who report PEP use 
we will measure drug levels using hair samples to allow for calibration of self-reported 
measures. A secondary outcome for the extension is “at-risk covered time”, defined as the 
proportion of time that a participant reports being at risk of HIV infection during which they are 
covered by a biomedical prevention option. Incident HIV infections, defined by a prespecified 
testing algorithm, will be an additional secondary outcome. 
 
Secondary outcomes of reach, effectiveness, adoption, implementation and maintenance will be 
evaluated using a mixed methods approach that includes surveys of participants, and health 
center providers and staff.  Tertiary outcomes of knowledge, awareness and 
acceptability/satisfaction at the staff and provider level will be measured by surveys at the 
baseline, midpoint and end of the study.  Measurement details are delineated in Table 4 . 
 
7.3.1 Behavioral Measures 
 
In addition to these surveys, trained staff will conduct in depth interviews (IDI) to provide 
insights into the intervention implementation and attitudes of participants and staff. These 
qualitative in-depth interviews will be conducted among purposively-selected samples of study 
participants and providers, to ascertain the perceptions of and experiences with CAB-LA use and 
delivery. Participants who are clients will be asked about 1) Experiences with counseling, 
method/service preferences and decision-making to go on CAB-LA; 2) Method/services 
satisfaction, barriers and facilitators to uptake and maintenance, and social networks and support 
as a facilitator or hindrance; and 3) Recommendations to improve CAB-LA Delivery. Health 


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care providers engaged in  CAB-LA service delivery will be asked about their 1) Professional 
identity and motivation, as a potential factor influencing implementation; 2) First impressions 
and knowledge of CAB-LA; 3) Clinical training experiences relevant to CAB-LA provision; 4) 
Experiences with and acceptability of individual elements of CAB-LA; and 5) Recommendations 
for improving CAB-LA delivery.  
 
For all research activities related to qualitative evaluation of SEARCH SAPPHIRE, written 
informed consent will be obtained from all selected for recruitment to the study. 
 
Qualitative IDIs for CAB-LA will be conducted between 2-6 months from enrolment. The 
specific data collection activities to be conducted during the phase are listed below. For 
Seroconverts, IDIs are will continue until the maximum number of participants is reached or the 
study intervention ends, whichever comes first. 
i. CAB-LA Patient IDI cohort: We will systematically select ~n=30 patients per each 
region (South West Uganda and Kenya) (total 40 < ~n < 72), with samples within 
region to be balanced by original trials (Out- patient, ANC/PNC, VHT); further balance 
to be observed by gender and community, proportional to overall intervention 
enrolment. 
ii. CAB-LA Provider IDI cohort: We will select a sample of care providers who 
administer CAB-LA from the CAB-LA trial health facilities or who inform the 
community about that option (VHTs / CHVs per each region. I.e. n=2-3 OPD 
providers, n=2-3 ANC/PNC providers, n-1-2 VHTs per region (total 8 < ~n < 12 
providers per region).  
iii. Seroconverts Patient IDI cohort: We aim to interview all participants in the intervention 
arm who received a diagnosis of HIV during the course of the DCP study and who are 
willing to be interviewed, up to a total of 36 per country. 
 
For this study, IDIs will be recorded using the TASCAM DR-05 digital recorder. This digital 
recording device was selected for use in this study because it has a high quality microphone that 
captures high quality sound even in settings with a lot of ambient background noise. 
 
For this study, the interviews will be conducted in the participant’s preferred language. The  
Qualitative study team will then transcribe and translate the audio recorded data into English for 
analysis within 14 days of the interview. Staff will use either Express Scribe or VideoLAN Client 
(VLC) software for this process. QRCs/QRAs will share responsibility for coding all transcriptions 
of recorded IDIs. Coding will be conducted in Dedoose using a codebook developed iteratively by 
the team. Analysis will follow a modified framework analysis of key code excerpts exported from 
Dedoose after coding. 
 
 
7.3.2 Costing Evaluations 
Costing of CAB-LA implementation will be conducted in each region and location type 
(Antenatal Clinic, Outpatient Department, Community) at Baseline/Screening and at two 
injection visits during follow-up.  Costing exercises will employ an activity-based approach and 
include site visits and employ rigorous costing methods using standardized micro-costing tools. 


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We will also conduct time-and-motion activities using self-administered tools with on-site staff 
to estimate the amount of time spent implementing CAB-LA.  We will interview study staff to 
identify resources used to implement the intervention and estimate time spent providing 
oversight and management of implementation activities. 
 
Implementation Research Design: The secondary objective of the extension is an 
implementation evaluation of the intervention focused on the initial implementation of patient-
centered CAB-LA using the RE-AIM framework. The domains of interest and key outcomes are 
summarized in the table below. Throughout, study weeks are used to refer to weeks in CAB-LA 
extension (eg, “week 0” is date of re-consent for the CAB-LA extension, “week 48” is 48 weeks 
after re-consent for the CAB-LA extension). 
 
Table 4. RE-AIM Evaluation Framework. 
 
As a tertiary objective, we will also assess provider and staff Knowledge, Acceptability and 
Awareness via provider and staff surveys (Likert scales) and IDI at weeks 0, 24, and 48.  
8. STUDY PROCEDURES 
Domain /Outcome 
Definition  
Measurement  
Timing  
Reach 
(Participant level)  
Proportion of eligible participants who 
initiate CAB-LA weeks 0-48. 
Characteristics (including prior PrEP and 
PEP use) and attitudes (knowledge, 
acceptability and feasibility) of participants 
using CAB-LA 
Demographics, CAB-LA 
dispensing logs 
Knowledge, Acceptability and 
Feasibility (Survey and IDI). 
Evaluation includes focus on 
equitable access by gender, 
education and SES.  
CAB LA dispensing 
throughout follow-up 
Surveys and IDI: Week 0, 
24 and week 48  
Effectiveness 
(Participant level) 
Impact of adding CAB-LA to Dynamic 
choice prevention on biomedical covered 
time (comparison of follow-up during the 
CAB-LA extension vs. follow-up time in 
Phase A trials prior to CAB-LA extension). 
CAB-LA dispensing logs, 
PrEP and PEP use as defined 
for primary endpoint in 
extension. 
Throughout follow-up  
Adoption  
(Provider and staff 
level in different 
settings) 
% of staff and providers invited that 
participate in the interventions, where 
participation is defined as  
i) participation in CAB-LA trainings; and ii) 
offering CAB-LA to participants. We will 
further assess the characteristics of 
participant vs. non-participant staff.   
Training attendance rosters; 
CAB-LA dispensing logs  
Throughout follow-up 
Implementation 
(Provider and 
systems level)  
Fidelity: Proportion of providers offering 
CAB-LA on appropriate schedule, 
appropriate provision of oral bridging   
Costing: Incremental cost of adding CAB-LA 
to dynamic choice prevention  
Adaptations: Type, timing and reasons they 
were made 
CAB-LA and oral bridging 
dispensing logs 
Time in motion and program 
costing 
Adaptation logs  
Throughout follow-up 
Maintenance 
(adapted from 
standard RE-AIM to 
accommodate shorter 
follow-up) 
(Participant level)  
Persistence on CAB-LA among participants 
who initiate CAB-LA 
Reasons for discontinuation of biomedical 
prevention or switching to other biomedical 
prevention option 
CAB-LA dispensing logs 
Participant survey on reasons 
for discontinuation and 
switching  
Throughout follow up 


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8.1 Schedule of Evaluations 
 
For all participants, from the time of reconsenting at the start of study CAB-LA availability 
(Week 0), there will be study visits every 24 weeks for the duration of their participation.  
 
At the time of writing of this protocol version, the standard of care for both Kenya and Uganda is 
to offer biomedical prevention as part of the HIV prevention package that includes provision of 
PrEP for persons at risk of HIV acquisition, such as persons with partners living with HIV or of 
unknown HIV status, or those with a history of exchange/transactional sex, recent STIs, or 
recurrent use of PEP (more than 3 times a year). PEP is offered primarily after occupational 
exposures or in cases of sexual assault.  For participants consenting in the extension, in the 
control arm, they will continue to be seen by government staff in the HIV clinic or other service 
location, like a drop-in centre, and receive prevention interventions according to standard of care 
guidelines recommended by the country’s Ministry of Health.  There will be no change to their 
HIV prevention healthcare. 
  
Control participants will be seen for a study visit every 24 weeks for HIV testing (RNA and 
rapid), weight, and a survey on which prevention method(s) they have been using and self-
reported risk. If control participants report using medications such as PrEP or PEP at the interim 
visits, they will be asked to provide hair, blood, or urine samples in order to measure HIV 
prevention medication levels. 
 
For intervention participants who do not choose CAB-LA, there will be study visits every 12 
weeks; however, they can decide to begin CAB-LA at any time during the initial 48-week 
extension. Participants will not be able to initiate or restart CAB-LA in the additional extension 
period between Week 48 and Week 96; only those who are taking CAB-LA at the time of the 
Week 48 visit may continue. Intervention participants that choose CAB-LA will have study visits 
that align with their injection visits (every 4 weeks for the first two months and then every 8 
weeks thereafter), but can return to an alternate DCP intervention if they decide to stop CAB-
LA. 
 
For participants that select CAB-LA, the extension visits will also include (Table 6): 
• A separate qualitative interview (At time of CAB-LA start, Week 24 and Week 48)  
• Safety Labs: 
o HBsAg at baseline 
o ALT at Weeks 0 and 24; optionally at Weeks 8 and 48 
• Pregnancy tests  
• In addition to the Week 24 and 48 extension visits, injection visits will occur in clinic 
every 4 weeks for the first two months and then every 8 weeks thereafter 
• HIV-RNA Cepheid test at baseline, Week 24, Week 48, Week 72, Week 96 
• Plasma will be stored at each visit for future use to evaluate use of alternate HIV 
assays and cabotegravir PK. Small hair samples will be stored at visit weeks 8, 24, 
32, and 48 to assess cabotegravir PK.    
• Participants that stop CAB LA prior to the end of the extension time period will 
continue to be followed in the study but not be actively followed beyond the 96 week 
followup time of the study.  


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o Oral PrEP (TDF/3TC) will be recommended to cover tail 
o Participants will switch back to Q12 week follow-up


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Table 5. Schedule of Evaluations Dynamic Choice Prevention Extension – Baseline to Week 48 
 
Screening/ 
Baseline 
Week 12 
Week 24 
Week 36 
Week 484 
DCP Intervention (For persons not receiving CAB-
LA)1 
 
 
 
 
 
Study visit 
X 
X 
X 
X 
X 
DCP intervention, including: 
X 
X 
X 
X 
X 
- Offer PrEP, PEP, prevention options2 
X 
X 
X 
X 
 
- HIV testing options 
X 
X 
X 
X 
X 
- Visit location choice 
X 
X 
X 
X 
X 
- Structured assessment of barriers 
X 
X 
X 
X 
X 
- GBV screening 
X 
 
X 
 
X 
HIV self-test (alternative to rapid) 
 
X 
X 
X 
 
Rapid (blood-based) HIV test 
X 
X 
X 
X 
X 
STI symptom screen 
X 
X 
X 
X 
X 
Pregnancy testing (optional) 
X 
X 
X 
X 
X 
DCP (including those persons on CAB-LA) and SOC 
 
 
 
 
 
Measure height (baseline only) and weight 
X 
 
X 
 
X 
Assess self-reported PrEP/PEP use and HIV risk over 
prior 6 months 
X 
 
X 
 
X 
Complete Week 24 or 48 Visit eCRF 
 
 
X 
 
X 
Hair sample collection if any PrEP or PEP doses taken 
in last 30 days 
 
 
X 
 
X 
HIV RNA 
 
 
X 
 
X 
SOC Only 
 
 
 
 
 
Study Visit 
X 
 
X 
 
X 
Referral to standard prevention options 
X 
 
X 
 
X 
Rapid (blood-based) HIV test 
X 
 
X 
 
X 
Suspected seroconversion3 
1Late visits for routine assessments will not be considered Protocol Violations, allowing flexibility during the COVID-19 pandemic 
2 This assessment will be done on all intervention participants at baseline 
3 See Figure 2 
4 Week 48 visits may occur between 40 and 56 weeks after Baseline 
 


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If CAB-LA is not available in country at the 48-week endpoint, all participants in the intervention arm will have the opportunity to 
conitinue on the study until week 96 or until CAB-LA is available in country, whichever occurs first, according to the schedules of 
evaluation described in Tables 5a and 6.  Participants who are currently on CAB-LA at the Week 48 visit may continue on CAB-LA 
through Week 96.  CAB-LA may not be initiated or restarted during the additional 48-week extension to Week 96.  Prior to conducting 
procedures for visits after Week 48, participants in the intervention arm will be reconsented to extend their participation up to Week 
96. 
Table 5a. Schedule of Evaluations for Extension of Intervention Arm – Week 60 to Week 96 
 
Week 60 
Week 72 
Week 84 
Week 963 
DCP Intervention (For persons not receiving CAB-
LA)1 
 
 
 
 
Study visit 
X 
X 
X 
X 
DCP intervention, including: 
X 
X 
X 
X 
- Offer PrEP, PEP, prevention options2,* 
X 
X 
X 
X 
- HIV testing options 
X 
X 
X 
X 
- Visit location choice 
X 
X 
X 
X 
- Structured assessment of barriers 
X 
X 
X 
X 
- GBV screening 
 
X 
 
X 
HIV self-test (alternative to rapid) 
X 
X 
X 
 
Rapid (blood-based) HIV test 
X 
X 
X 
X 
STI symptom screen 
X 
X 
X 
X 
Pregnancy testing (optional) 
X 
X 
X 
X 
Measure weight 
 
X 
 
X 
Assess self-reported PrEP/PEP use and HIV risk over 
prior 6 months 
 
X 
 
X 
Complete Week 72 or 96 Visit eCRF 
 
X 
 
X 
HIV RNA 
 
X 
 
X 
Suspected seroconversion2 
 
1Late visits for routine assessments will not be considered Protocol Violations, allowing flexibility during the COVID-19 pandemic or for other outbreaks. 
2 See Figure 2 
3 Week 96 visits may occur between 88 and 104 weeks after Baseline 
*Participants will not be given the option to initiate or restart CAB-LA after the Week 48 visit; only other prevention options will be available. 
 
 
 


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Table 6. Schedule of Evaluations for CAB-LA users (weeks indexed by date of initial CAB LA injection) – Baseline 
to Week 96  
 
CAB 
Screening/ 
Baseline 
CAB 
Week  
4 
CAB 
Week 8 
CAB 
Week 
16 
CAB 
Week 
24 
CAB 
Week 
32 
CAB 
Week 40 
CAB 
Week 
487 
CAB 
Week  
56 
CAB 
Week 
64 
CAB 
Week 
72 
CAB 
Week  
80 
CAB 
Week 
88 
CAB 
Week  
967 
Measure weight 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CAB LA injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
STI Symptom Screen 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
Suspected 
Seroconversion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Rapid test (Country 
std. algorithm) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-HIV RNA6 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
-Stored plasma (2cc) 
for future HIV testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CAB PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Hair sample (if CAB-
LA received in last 
120 days) 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
   -Stored plasma (from 
2 cc sample above) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Safety Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Pregnancy testing1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-ALT Monitoring4, 5 
X 
 
X* 
 
X 
 
 
X* 
 
 
X* 
 
 
X* 
Adverse Event 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GBV Screening 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Survey and IDI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Participant CAB-LA 
Survey and IDI2 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
-Provider and Clinic 
Staff DCP-LA Survey 
and IDI 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Costing3 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
For participants who stop CAB LA before end of extension study 
 
 
 
 
 
 
   -For 48 weeks from last injection: Recommend oral PrEP (TDF/3TC) to cover tail  
 
 
 
 
 
 
  -Switch back to Q12 week visits - HIV RNA and pregnancy testing Q12 weeks 
 
 
 
 
 
 
1For women who become pregnant, repeat pregnancy tests are not needed. Women who become pregnant during the study will be followed to delivery for assessment of mother and infant status  
2 Participant survey/IDI will be conducted at start of CAB-LA and Weeks 24 and 48 from time of CAB-LA start or discontinuation.  
3Costing will occur between weeks 24-48. 
4ALT Monitoring will occur at baseline, Week 24 for all participants. *Per provider discretion, ALT monitoring will occur at Weeks 8, 48, 72 and 96. 
5Bilirubin and additional labs indicated will be tested in the case of ALT increase. 
6HIV RNA will be drawn at CAB-LA reinduction, as described in Table 6. 
7 Week 48 visits may occur between 40 and 56 weeks after Baseline; Week 96 visits may occur between 88 and 104 weeks after Baseline; only participants on CAB-LA at the Week 48 visit may take CAB-LA between weeks 48 and 96. 


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9. INFORMED CONSENT 
9.1 Informed Consent Process 
 
All participants in the DCP trials will be offered participation in the CAB-LA Extension. 
Consent forms will be translated from the original English to the language(s) spoken in the 
community. The consent form will be read to participants in their local language. Participants 
who agree to take part and sign the consent form will continue in the study. In this consent, 
women will be informed about the risks and benefits of CAB-LA during pregnancy and 
breastfeeding.  In the case that participants become pregnant while using CAB-LA, they will be 
asked for an additional re-consent to follow-up for ascertainment of pregnancy and infant 
outcomes.  
 
Participants will remain in the randomization arm they were assigned to at their initial DCP visit 
in Phase A. Participants in the SOC arm will consent to return for two additional follow-up visits 
at weeks 24 and 48 following re-consent for the CAB-LA extension. Intervention participants 
that do not choose CAB-LA will consent to continue the quarterly study visits and Intervention 
participants that choose CAB-LA will have study visits that align with their injection visits 
(every 4 weeks for the first two months and then every 8-weeks thereafter). Intervention 
participants will have flexibility to switch between PrEP, PEP, and CAB-LA. Unlimited switches 
between biomedical prevention options, including between CAB-LA and oral, will continue to 
be permitted during the extension, both to reflect participant choice and to bridge planned missed 
doses of CAB-LA. Clients and providers will discuss options for prevention and risk during 
regular visits and interim visits, in addition to continuous provider trainings on offering choice 
and refreshers for clients. Changes in prevention choices will be documented in study eCRF 
forms, which will include the CAB-LA option. DCP intervention participants that choose the 
CAB-LA option will be informed about the visit schedule, side effects, and risks and benefits, 
before consenting. If CAB-LA becomes available via the Ministry of Health during the trial, 
persons in the control arm will be eligible as per standard of care.  
 
 
9.2 Assent Process 
 
Participants aged 15-17 years old who meet the definition of ‘mature or emancipated minors’ as 
set by the Uganda National Council for Science and Technology and Kenya MoH can participate 
in these studies and will be consented on the adult participant consent forms. Participants aged 
15-17 that do not meet the definition of ‘mature or emancipated minors’ may participate with 
parental co-signature. All participants will be asked to re-consent for the CAB-LA extension. 
 
9.3. Documentation of Informed Consent  
Documentation of written informed consent and verbal consent will be recorded on informed 
consent logs for all study activities.  The logs will contain the participant’s study ID, clinic ID, 
initials, name, language of consent used, and whether the individual signed the document or 
provided a fingerprint in the case of written consents, or verbally affirmed their consent in the 
case of verbal consents. 
 


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9.4 Stored Samples and Associated Data Considerations  
 
Plasma samples will be collected and stored for retrospective HIV testing and PK.  
 
Hair samples collected from participants on PrEP, CAB-LA or PEP in the extension will be 
collected and stored for later measurements of HIV-prevention drug levels, which will be 
conducted at the UCSF Hair Analytical Lab in the United States.   
 
Blood samples from persons who acquire HIV in Phase A prevention trials will be stored for 
additional testing for HIV diagnostics (if indicated) and HIV drug resistance. Testing will be 
performed in-country when available (e.g. standard genotyping for HIV drug resistance). 
Specialized research assays for diagnostic and resistance testing (e.g. next-generation 
sequencing) will be performed at the University of Pittsburgh Parikh Lab in the United States. 
Blood and urine samples will be stored for testing CAB-LA/PrEP/PEP drug levels performed at 
the UCSF Hair Analytical Lab in the United States.   
 
Specimens may be held up to five years in order to complete HIV diagnostics, resistance, or PK 
tests as outlined in this protocol. The study may hold specimens to test in batches at later time 
since these tests are being performed solely for research, not for clinical care, or for a biobank 
for future use. Specimens will be destroyed after tests are performed.  
 
All other biological samples collected during the study will be tested shortly after collection and 
any remaining specimen discarded. 
 
10. SAFETY ASSESMENT OVERVIEW 
 
10.1 Cabotegravir (GSK1265744A) Injectable Suspension- for intramuscular use: Product 
information  
 
a. CAB-LA will be supplied by the ViiV Healthcare Limited Pharmaceutical Company 
b. Indications and Usage. CAB-LA is indicated in at-risk adults and adolescents 
weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of 
sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior 
to initiating CAB-LA. CAB-LA will not be used as a supplement for PEP. 
 
10.2 Administration Overview.  
a. CAB-LA will be offered as direct to inject only (no oral lead-in) 
b. Injection: Single-dose vial containing 600 mg/3 mL (200 mg/mL) of cabotegravir 
is a white to light pink, free-flowing, extended-release injectable suspension 
c. CAB-LA will be administered by trained healthcare staff by gluteal intramuscular 
injection only. Body Mass Index will be considered to ensure appropriate needle 


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length is sufficient to reach the gluteal muscle.  
d. Study participants will be tested for HIV infection prior to initiating CAB-LA, 
and with each subsequent injection of CAB-LA, including HIV RNA testing 
(Cepheid).   
e. Prior to starting CAB-LA, healthcare staff will counsel study participants about 
the importance of adherence to scheduled dosing visits to help reduce the risk of 
acquiring HIV infection and development of resistance. 
10.3 Pharmacy 
a. The study sponsor, UCSF, will receive CAB-LA directly from ViiV Healthcare 
and distribute to the country pharmacies per country study drug shipping 
procedures 
b. In-country pharmacists will receive and log the CAB-LA per country procedure 
and detailed in the CAB-LA Pharmacy SOPs  
c. As described in 6c below, CAB-LA will stored at 2°C to 30°C (36°F to 86F) at 
clinic sites; proper storage and handling will be monitored by in-country 
pharmacy teams and validated by accountability logs and other source documents 
d. Details on these procedures are outlined in the Standard Operating Procedures.  
i. CABPHARM-01 Study Drug Ordering and Acquisition 
ii. CABPHARM-02 Study Drug Accountability 
iii. CABPHARM-03 Study Drug Storage 
iv. CABPHARM-04 Dispensing and Administration of Study Drug 
v. CABPHARM-05 Disposition and Destruction of Study Drug 
vi. CABPHARM-06 Communication and Dissemination of Information to the 
Study Pharmacist 
10.4 Injection Dosing 
a. The initial injection dose of CAB-LA is a single 600-mg (3-mL) intramuscular 
injection of CAB-LA given 4-weeks apart for 2 consecutive times  
b. After the 2 initiation injection doses given consecutively 4-weeks apart, the 
continuation injection dose of CAB-LA will be a single 600-mg (3-mL) intramuscular 
injection of CAB-LA, every 8-weeks.  
c. There is a +/- 7 day window for before or after the date the participant is scheduled to 
receive their next injection 
10.5 Missed Doses 
Study staff will provide adherence support to CAB-LA participants. When doses are missed, 
study staff will follow the applicable guidelines. Providers will work pro-actively and 
prospectively identify periods during which participants are likely to miss doses (eg travel).  
Participants will be provided with oral bridging prevention medication (TDF-FTC) to cover these 
periods. Upon return to clinic for planned or unplanned missed doses, CAB-LA dosing will be as 
per protocol below.  
a. If a scheduled injection visit is missed or delayed by more than 7 days, the study 


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clinician will determine when resumption is appropriate.  
b. Recommended Dosing after a missed visit is detailed in Table 7. 
 
Table 7. Missed Dosage Recommendations  
Time since Last Injection 
Recommendation 
If second injection is missed and 
time since first injection is: 
Less than or equal to 8-weeks 
Administer 600-mg (3-mL) gluteal intramuscular injection 
of CAB-LA as soon as possible, then continue to follow 
the every 8-weeks injection dosing schedule. 
Greater than 8-weeks 
Restart with 600-mg (3-mL) gluteal intramuscular 
injection of CAB-LA, followed by a second 600-mg (3-
mL) initiation injection 4-weeks later. Then continue to 
follow the every 8-weeks injection dosing 
schedule thereafter. 
If third or subsequent injection 
is missed and time since prior 
injection is: 
Less than or equal to 12 weeks 
Administer 600-mg (3-mL) intramuscular injection of 
CAB-LA as soon as possible, then continue with the 
every 8-weeks injection dosing schedule. 
Greater than 12-weeks 
Restart with 600-mg (3-mL) gluteal intramuscular 
injection of CAB-LA, followed by the second 600-mg (3-
mL) initiation injection dose 4-weeks later. Then continue 
with the every 8-weeks injection dosing schedule 
thereafter. 
  
10.6 Contraindications. CAB-LA is contraindicated in individuals: 
a. With unknown or positive HIV-1 status  
b. With previous hypersensitivity reaction to cabotegravir  
c. Receiving the following co-administered drugs for which significant decreases in 
cabotegravir plasma concentrations may occur due to uridine diphosphate 
glucuronosyltransferase: 
vii. Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin 
viii. Antimycobacterials: Rifampin, rifapentine 
 


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10.7 Drug Interactions 
 
a. 
Use of Other Antiretroviral Drugs after Discontinuation of CAB-LA. Residual 
concentrations of cabotegravir may remain in the systemic circulation of individuals for 
prolonged periods (up to 12 months or longer). These residual concentrations are not 
expected to affect the exposures of antiretroviral drugs that are initiated after 
discontinuation of CAB-LA  
b. 
Potential for Other Drugs to Affect CAB-LA. Cabotegravir is primarily metabolized 
by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of 
UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations; therefore, 
coadministration of CAB-LA with these drugs is contraindicated  
c. 
Established and Other Potentially Significant Drug Interactions. Information 
regarding potential drug interactions with cabotegravir is provided in Table 8 below.  
 
 
Table 8. Drug Interactions with CAB-LA 
 
Concomitant Drug Class: 
Drug Name 
Effect on 
Concentration 
Clinical Comment 
Anticonvulsants: 
Carbamazepine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Cabotegravir 
Coadministration is contraindicated with 
CAB-LA due to potential for significant 
decreases in plasma concentration of CAB-
LA. 
Antimycobacterials: 
Rifampin 
Rifapentine 
Cabotegravir 
Antimycobacterial: 
Rifabutin 
Cabotegravir 
When rifabutin is started before or 
concomitantly with the first initiation 
injection of CAB-LA, the recommended 
dosing of CAB-LA is one 600-mg 
(3-mL) injection, followed 2 weeks later by a 
second 600-mg (3-mL) initiation injection 
and monthly thereafter while on rifabutin. 
When rifabutin is started at the time of the 
second initiation injection or later, the 
recommended dosing schedule of CAB-LA 
is 600 mg (3 mL) monthly while on 
rifabutin. After stopping rifabutin, the 
recommended dosing schedule of CAB-LA 
is 600 mg (3 mL) every 8 weeks. 


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d. 
Drugs without Clinically Significant Interactions with Cabotegravir. The following 
drugs can be co-administered with cabotegravir (non-antiretrovirals) or given after 
discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose 
adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and 
ethinyl estradiol, and rilpivirine. 
 
10.8 Drug Overdosage 
 
There is no known specific treatment for overdose with CAB-LA. If overdose occurs, the 
participant will be treated appropriately, and further CAB-LA continuation determined by the 
Investigator.  
 
 
11. HUMAN SUBJECTS PROTECTIONS 
 
11.1 
Vulnerable Participants 
 
11.1.1 Pregnant Women and Fetuses 
 
a. 
CAB-LA will be used during pregnancy if the expected benefit justifies the potential risk 
to the fetus. Factors to consider include the long acting nature of CAB-LA, the actual 
gestational age, adherence, the risk of seroconversion and available data around the safety 
of study drugs and alternative PrEP regimens in pregnancy and breastfeeding. 
b. 
In the HPTN 084 trial evaluating cabotegravir long-acting (LA) for pre-exposure 
prophylaxis (PrEP) in women in sub–Saharan Africa, no birth defects were reported of 
the 63 women that became pregnant while taking CAB-LA. Given the need for more data 
on pregnancy and breastfeeding while taking CAB-LA, participants will be monitored 
closely for side effects during pregnancy and breastfeeding during the study and up to 8 
weeks post-partum.  
c. 
Pregnant participants will sign a consent to be monitored for up to 8-weeks postpartum to 
ascertain the pregnancy and infant outcomes 
d. 
Participants will be registered in the Antiretroviral Pregnancy Registry to contribute to 
the global scientific community’s understanding of CAB-LA use in pregnancy and 
breastfeeding  
e. 
It is recommended that participants of child bearing potential taking CAB LA should use 
an effective contraceptive method during the study, through any additional extension 
phase and for 52 weeks after the last injection if transitioning off CAB-LA, to avoid 
pregnancy.  Participants that are currently on a contraceptive method at CAB-LA start 
will be informed of the risks and benefits of CAB-LA during pregnancy, if they chose to 
stop using contraceptives. Participants not on a contraceptive method when starting CAB-
LA will be informed about the risks and benefits to CAB-LA during pregnancy if they 
become pregnant. CAB-LA will not be given to women who are pregnant at time of 
initial injection; women who become pregnant after starting CAB-LA will be allowed to 


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remain on CAB-LA during pregnancy, as deemed appropriate by their provider, and will 
be re-consented for additional follow-up of pregnancy and infant outcomes. 
f. 
It is not known if cabotegravir is present in human breast milk, affects human milk 
production, or has effects on the breastfed infant. Participants who are currently 
breastfeeding will be informed of the risks and benefits in the consenting process, and 
unknown effects on infants of exposure to CAB-LA through breastmilk.   
g. 
No dosage adjustment of CAB-LA is necessary for participants with mild (creatinine 
clearance 60 to <90 mL/min) or moderate renal impairment (creatinine clearance 30 to 
<60 mL/min). In participants with severe renal impairment (creatinine clearance 15 to 
<30 mL/min) or end-stage renal disease (creatinine clearance<15 mL/min), increased 
monitoring for adverse effects will be provided 
h. 
No dosage adjustment of CAB-LA is necessary for participants with mild or moderate 
hepatic impairment 
 
11.1.2 Children 
 
Youth aged 15 years and up are among the populations most in need of improved HIV outcomes 
and are a group targeted for participation this study.  The Uganda National Council for Science 
and Technology (UNCST) has determined that individuals aged ≥14 years are able to provide 
independent consent for research if they have a sexually transmitted infection.  In Uganda and 
Kenya, children of the age represented in this study can obtain HIV testing services and HIV 
care without parental consent if considered independent or an emancipated minor. 
Participants aged 15-17 taking part in HIV prevention procedures (CAB-LA Extension) and 
those taking part in the surveys who are not considered mature or independent minors will be 
required to sign an assent form, with separate parental consent.  Information discussed in study 
visits and test results, including for HIV or STI testing, will not be disclosed to parent/guardians. 
As with adults, participants <18 years will be given sufficient time to read or be read the consent 
form in their language and to ask any questions.  None of the diagnostic tests or procedures 
provided in the study are more harmful to youth as compared to other groups. 
 
11.1.3. Illiterate Participants  
They study will enroll participants who may be economically or educationally disadvantaged.  
Participants in rural populations and those who are educationally disadvantaged are among those 
most at risk in their country for poor HIV care outcomes, and it is important to provide 
opportunities to participate in research to all people independent of their literacy. If a potential 
study participant is unable to read or write, his or her fingerprint will substitute for a signature, 
and a signature from a witness to the informed consent procedures will be obtained. Participants 
taking part in activities for which a verbal consent is required will have the consent text read to 
them in their language. As with other groups, illiterate participants will be provided sufficient 
time to be read the consent form or ask questions in order to understand study procedures. 
 
12. RISKS 


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Privacy: The primary risk to study participation is breach of privacy.  Care will be taken to 
protect the privacy of participants and parents/guardians. However, there is a risk that others may 
inadvertently see patients’ medical information, and thus their privacy may be compromised.   
 
Psychological Discomfort: There is the possibility of some psychological discomfort that may 
arise from questions and sensitive issues assessed in the stigma, sexual behavior, and youth life-
skills and behaviors surveys and the in-depth qualitative interviews.  We will train all study staff 
involved with surveys and qualitative interviews to recognize signs and symptoms of 
psychological discomfort and in the use of strategies to minimize such discomfort.  This will 
include reminders that an individual may always choose to not answer any specific question that 
makes them uncomfortable or to stop surveys and interviews at any time.  Referral resources for 
significant issues will also be made available to study staff should subject referrals to care be 
desired. 
 
Venipuncture and fingerprick sample collection: Study sampling during testing activities will be 
done by venipuncture or fingerprick, depending on the assay. The total volume of blood taken 
per participant, including blood taken for standard health facility evaluations, is too small to for 
participants to experience any serious side-effects, although a mild and transient feeling of 
discomfort or bruising may occur at the site of sampling and bruising. 
 
Ensuring Necessary Medical or Professional Intervention in the Event of Adverse Effects: 
Procedures will be put in place for the referral and care, free of charge, for necessary medical or 
professional intervention in the event of the unlikely occurrence of severe adverse effects.  Care 
will be provided at local Ministry of Health care clinics or nearby referral hospitals as necessary. 
 
Potential Side Effects of CAB-LA 
 
 
Most Common Side Effects: 
• 
Pain, tenderness, hardened mass or lump, swelling, bruising, redness, itching, warmth, 
abscess, discoloration, or loss of sensation at the injection site 
• 
stomach pain 
• 
vomiting 
• 
diarrhea 
 
• 
muscle pain 
• 
headache 
• 
rash 
• 
fever 
• 
loss of appetite 
• 
tiredness 
• 
drowsiness 
• 
sleep problems 
• 
back pain 
• 
nausea 
• 
upper respiratory infection 


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Other side effects of cabotegravir may include:    
a. Allergic reactions: 
• 
generally ill feeling 
• 
blisters 
• 
tiredness  
• 
muscle or joint aches 
 
• 
trouble breathing 
• 
fever 
• 
blisters or sores in the mouth 
• 
redness or swelling of eves 
• 
swelling of the mouth, face lips or tongues 
b. Liver Changes  
c. Depression or Mood Changes 
d. Hypersensitivity to Cabotegravir 
 
Potential Risks associated with Pregnancy and Breastfeeding on CAB-LA: 
 
There is very little information on the safety of CAB-LA during pregnancy and breastfeeding 
Participants will need to weigh the risks to their pregnancy and infant to the benefits of their HIV 
prevention based on the information provided below.  
 
If participants become pregnant during the study and choose to take CAB-LA during pregnancy, 
staff will help participants understand that we have limited information on the safety of this drug 
during pregnancy. Of the 63 women who became pregnant while taking CAB-LA in Sub-
Saharan African trials, there were no birth defects. However, it is always possible there is some 
side effect we are unaware of as we learn more about CAB-LA in pregnancy. To ensure CAB-
LA is as safe as possible for the mother and baby, we will monitor participants closely during 
pregnancy and post-partum. Participants will also be required to sign an informed consent that 
agrees to 8-weeks of monitoring after delivery as part of the safety assessment.   
 
If participants are breastfeeding when they start this study or breastfeed after becoming pregnant 
on the study and choose to begin CAB-LA, staff will explain that we have limited information on 
the safety of this drug during breastfeeding. In studies of another drug, called dolutegravir, which 
is very similar to CAB LA no nursing babies had any problems. These babies were breastfed by 
mothers who had HIV and who were taking dolutegravir as treatment.  Small amounts of 
dolutegravir were found in the breastmilk. It is possible some CAB-LA may pass to a baby 
through breastmilk. 
 
CAB LA has been detected in the systemic circulation for up to 12 months or longer after an 
injection and the consequences of this level of exposure to the fetus are currently unknown. 
Consideration should be given to the potential for fetal exposure during pregnancy, even after the 
injections have been stopped.  
 
• The safety of exposure of CAB- LA to infants through breastfeeding has not been 
established.   


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• Due to the nature of CAB-LA injections, CAB-LA may be present in breastmilk for up 
to, or beyond, a year after the final injection.   
• The clinical consequences of exposure of the infant to CAB-LA are unknown. 
 
 
While not required, to prevent any risk to the participant’s pregnancy or to the infant, it is 
recommended that participants of child-bearing potential taking CAB-LA should use an effective 
contraceptive method during the study through any additional extension phase and for 52 weeks 
after the last injection if transitioning off CAB-LA, to avoid pregnancy.   
 
13. SOCIAL IMPACT EVENTS 
Individuals enrolled in this study may experience personal problems resulting from the study 
participation. Such problems are termed social impact events. Although study sites will make 
every effort to protect participant privacy and confidentiality, it is possible that participants' 
involvement in the study could become known to others, and that participants may experience 
stigmatization, discrimination or, in rare cases, intimate partner violence as a result of being 
perceived as being HIV-infected or at risk for HIV infection. For example, participants could be 
treated unfairly, could have problems being accepted by their families and/or communities, or 
could experience abuse by their partner. Problems may also occur in circumstances in which 
study participation is not disclosed, such as impact on employment related to time taken for 
study visits.  
 
In the event that a participant reports a social impact event, every effort will be made by study 
staff to provide appropriate assistance, and/or referrals to appropriate resources. Social impact 
events that are judged by the investigators to be serious, unexpected, or more severe or frequent 
than anticipated, will be reported to the relevant IRBs.  
 
14. BENEFITS 
There will be no direct benefit to participants from participating in this study. The enhanced 
measures to improve oral PrEP, CAB-LA and PEP delivery, if assigned to the group that 
receives it, may help participants stay on medications, receive care, or reduce the likelihood of 
acquiring HIV infection,  but this cannot be guaranteed. Participation in the study may benefit 
the community, scientists and doctors who work on providing HIV care in health centers such as 
in this study. 
 
15. COMPENSATION 
Participants will not receive compensation or payment in this study for taking part in research 
activities, except those participating in in-depth interviews. 
 
16. PARTICIPANT PRIVACY AND CONFIDENTIALITY  
Care will be taken to protect the privacy of participants and parents/guardians. Study participants 
will be identified only by their unique identification number on study documents except those 
maintained for contact information or consent documents.  Participant study documents will be 


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kept in individual files in secure filing cabinets in the study facilities. Testing results and sample 
and results transport documentation will be maintained in the local labs but will likewise not 
contain participant identifiers and will be accessed by study personnel only. After the study is 
over, all files containing personal identifiers such as participants’ names, names of parents, 
guardians or relatives, and phone numbers and home locations will be destroyed. 
 
In order to ensure data security and integrity, the following measures will be implemented: 
• All members of the study team will be educated in the study protocol prior to the onset of 
the study.  
• Detailed Standard Operating Procedures (SOPs) will be written for all project activities 
and be provided to relevant team members.  
• Team members will be thoroughly trained on the SOP’s.  
• Where applicable, team members will receive additional training on the use of tablet 
computers.  
• All data transcribed from paper will be double data entered or verified.  
• All electronic data will be backed up regularly.  
• All data will be transferred to the main Data Center in Kampala to the secure server. This 
sever is backed up on a daily basis and a monthly backup is stored off-site.  
• All computers, including the tablets, will be password protected.  
• All computers, including tablets, will be locked in a secure room each night.  
• Log books and CRF’s will be locked in a secure room each night. 
 
17. STUDY DISCONTINUATION  
The study may be discontinued at any time by the IRB, NIAID, or other government entities as 
part of their duties to ensure that research participants are protected.  
 
18. Community Advisory Board, Stakeholders and Communication of Results 
We will utilize a multilayered set of boards. These include: a) stakeholder advisory board 
consisting of representatives from the Uganda and Kenya Ministries of Health, IDRC and 
KEMRI research organizations, and PEPFAR implementing partners at the national and regional 
level, who will meet after Phase A is complete and prior to initiation of Phase B, and again at the 
conclusion of Phase B; b) formal external scientific advisory board meeting annually that 
includes experts in HIV prevention and treatment; experts in PrEP and youth in Uganda and 
Kenya; and experts in economics/development in East Africa; and c) in-country advisory board 
meeting annually with representation of MoH leads from HIV, non-communicable disease, the 
World Bank, PEPFAR implementing partners and HIV+ persons.  Finally, local community 
advisory boards will provide invaluable input and communication with biannual meetings.  We 
will have ongoing communication with the Kenya and Uganda National AIDS program, and with 
the PEPFAR implementing partners.  Results of this study will be shared with the community, 
stakeholders, and at scientific meetings, with subsequent submission to publication.  
 


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19.ADMINISTRATIVE PROCEDURES 
19.1 Regulatory Oversight 
 
The proposed extension will be reviewed and approved by the IRBs of all the participating 
institutions in the U.S., Uganda and Kenya. This includes the UCSF Committee on Human 
Research (CHR), the Makerere University School of Medicine - Research and Ethics Committee 
(SOMREC), the Uganda National Council of Science and Technology (UNCST), the Kenya 
Medical Research Institute (KEMRI).  As described in Section 18.0, this study will employ four 
levels of data and participant safety monitoring including Study Steering Committee oversight, 
US and host country Institutional Review Board (IRB) review, Data Safety Monitoring Board 
(DSMB) Review, and External Clinical Site Monitoring. Table 9 describes event reporting 
guidelines to individual IRBs overseeing this study. 
 
CAB-LA was very well tolerated in the registration studies. For this extension, SAEs will be 
captured in the intervention arm and Grade 3 and 4 AEs and non-serious ADRs leading to 
withdrawal will be captured for participants on CAB-LA. Grade 3 and 4 AEs will be graded and 
recorded using the NIAID Adverse Event Grading of Severity scale 
(https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables). Clinical 
Adverse Events not identified elsewhere are described in Table 10. The Clinical Management 
Team (CMT) will be notified of SAEs as soon as possible and will be reported per regulatory 
guidelines as stated in Table 9 below.  
 
 
Table 9. Reporting Guidelines 
 
Institution 
 
Contact information 
Type of Event 
  Reporting 
Timeframe 
Reporting 
Method 
UCSF IRB 
UCSF Committee for 
Human Research 
3333 California Street, 
Suite 315 
University of California 
San Francisco, CA 94118  
Campus Mailbox: 0962  
Facsimile: (415) 502-134 
SAEs/ Grade 3 or higher 
AEs that change the study 
risks or benefits, OR 
necessitates modification 
to the IRB-approved 
consent document(s), 
and/or the IRB-approved 
application/protocol 
Within 10-working 
days of awareness 
 
Via online 
reporting system 
NIAID 
Melanie Bacon, Program 
Officer, NIH 
SAEs or Harm determined 
to be possibly, probably or 
definitely related to study 
intervention 
 
Participants administered 
CAB-LA: 
 
All pregnancies  
 
At the time of 
reporting to IRBs 
 
 
 
One-week of 
awareness 
(Pregnancies) 
 
Email 
ViiV 
 
GSK Medical Information, 
Safety Services & Vendor 
Management Group 
Participants administered 
CAB-LA: 
 
Within 72 hours of 
awareness (SAEs 
and Significant 
Safety Issues) 
 All SAEs and 
Significant 
Safety Issues: 
Email 


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oax37649@gsk.com 
All SAEs and Significant 
Safety Issues  
 
All pregnancies  
 
All Liver Events Grade 3 
and higher 
 
One-week of 
awareness 
(Pregnancies and 
Liver Events) 
notification with 
SEARCH 
SAPPHIRE AE 
CRF, Country-
specific SAE 
Reporting Forms, 
and attachment 
with 
supplemental 
information 
 
Pregnancies: 
Email 
notification with 
Pregnancy 
Reporting CRF  
 
Liver Events 
(Grade 3+): 
Email 
notification with 
Liver Reporting 
CRF  
  
KEMRI-SERU 
The Scientific and Ethics 
Review Unit 
Through The Deputy 
Director CMR  at 
seru@kemri.org. 
All reportable SAEs, 
SUSARs, and Harm 
Notify/ report to 
SERU secretariat 
within 48 hours 
upon learning of 
the event and 
submit the full 
report within 5 
working days of 
awareness 
Via online 
reporting system 
to SERU 
secretariat  
PPB 
Pharmacy and Poisons 
Board 
  
All reportable Grade 3 or 
higher SAEs, SUSARs, 
and Harm 
Report to PPB 
within 7 working 
days of awareness 
Via online 
reporting system 
to PPB ECCT 
(Expert 
Committee on 
Clinical Trials) 
MU-SOMREC 
Executive Secretary 
Faculty of Medicine, 
Research and Ethics 
Committee 
P.O. Box 7072 
Kampala 
 
 
All serious and 
unexpected events 
irrespective of 
relationship 
Fatal and life 
threatening events 
within 3 working 
days of awareness 
and all other SAEs 
within 7 calendar  
days  
Via Regulatory 
Manager 
NDA 
National Drug Authority 
All serious and 
unexpected events 
irrespective of 
relationship 
Within 7 days of 
awareness 
Via online 
reporting 
 
 
 


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19.2 Clinical Site Monitoring  
 
Site monitors under contract to the University of California, San Francisco will visit participating 
clinical research sites to review participants records, including consent forms, CRFs, and 
laboratory records to ensure protection of study participants, compliance with IRB approved 
protocol/amendments, and accuracy and completeness of records. The monitors will inspect 
sites’ regulatory files to ensure that local regulatory requirements, in addition to U.S. Federal 
regulations, are being followed. 
 
19.3 Study Implementation 
No study activities will commence prior to approval of US and host country IRBs and all other 
required local and international institutions. This study is funded and supported by the National 
Institutes of Health. 
 
19.4. ClinicalTrials.gov  
This protocol will be registered in ClinicalTrials.gov. 
 
 
19.5 Adverse Event Procedures and Reporting Requirements  
 
For persons receiving CAB-LA, Grade 3 and 4 AEs will be monitored in addition to SAEs.  
 
Grade 3  
Any grade 3 or higher clinical or laboratory AE observed prior to their first injection of active 
CAB will prompt consultation with the clinical officer (CO) prior to any injectable dosing.   
 
At any time, participants who develop a Grade 3 AE or toxicity that is not specifically addressed 
in the Table below and is judged to be related to CAB-LA by the Investigator, CAB-LA use will 
be temporarily discontinued. In general, the investigator will re-evaluate the participant until 
resolution of the toxicity. For Grade 3 AEs deemed related to CAB-LA, will be permanently 
discontinued if improvement to severity ≤Grade 2 cannot be documented within 4 weeks of 
awareness. If CAB-LA is resumed after holding for a Grade 3 AE and the same Grade 3 AE 
recurs without alternative explanation, CAB-LA will be permanently discontinued. For Grade 3 
AEs deemed unrelated to CAB-LA, the participant may continue with appropriate clinical 
management by the site, per local standards of care.    
 
Grade 4  
Any grade 4 or higher clinical or laboratory AE observed prior to first injection will prompt 
evaluation and may requiring holding of dosage, as determined by the CO and CMT. Participants 
who develop a Grade 4 AE or toxicity that is not specifically addressed in Table 11 (regardless 
of relationship to CAB-LA) will have the CAB-LA injections temporarily discontinued. CAB-
LA  use will not be resumed if the Grade 4 AE is considered by the Investigator to be related to 
the injections. If CAB-LA use is resumed and the same Grade 4 AE recurs at Grade 4 level at 
any time, CAB-LA will be permanently discontinued, unless an alternative explanation for the 
recurrence is clearly documented.  


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Pregnancy 
 
Any pregnancy that occurs during in participants taking CAB-LA must be reported using the 
Pregnancy Reporting Case Report form to NIAID and ViiV Healthcare within one week of 
learning of its occurrence. Pregnancies that are associated with SAEs will be reported within 72 
hours using the Adverse Event CRF, Country-specific SAE Reporting form, and supplemental 
information attached.   
   
The pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and child(ren), which must also be reported to NIAID and ViiV Healthcare 
using the Pregnancy Outcomes case report form. The pregnancy outcome should also be reported 
to ViiV Healthcare in accordance with the terms of the contract.  
 
Pregnancy complications and elective terminations for medical reasons must be reported as an 
adverse event or serious adverse event.  Spontaneous abortions must be reported as a serious 
adverse event in accordance with SAE reporting timelines. 
 
Any serious adverse event occurring in association with a pregnancy brought to the 
investigator’s attention after the participant has completed the study and considered by the 
investigator as possibly related to the investigational product, must be promptly reported to 
NIAID and ViiV Healthcare. 
 
 
 
Table 10. DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
 
20.TOXICITY MANAGEMENT 
 
20.1 Participant Discontinuation  
 
General Criteria for Discontinuation of CAB-LA 
 
Participants may voluntarily discontinue CAB-LA for any reason at any time. Investigators will 
permanently discontinue participants from CAB-LA per protocol for any of the specific criteria 


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below. Investigators also may permanently discontinue participants for reasons not shown here 
(e.g., to protect participants’ safety and/or if participants are unable or unwilling to comply with 
CAB-LA use procedures).  
 
 
The criteria for permanent discontinuation of CAB-LA use for an individual participant are:  
• 
CAB-LA -related toxicity requiring permanent discontinuation per the guidelines above 
and below  
• 
Request by participant to permanently terminate use of CAB-LA  
• 
Clinical reasons determined by the Investigator 
• 
Acquires HIV infection   
 
CAB-LA will be temporarily withheld from a participant for any of the following reasons:  
• 
Report of use of prohibited concomitant medications. CAB-LA injections may 
resume when the participant reports that he/she is no longer taking the prohibited 
medication, provided other reasons for temporary hold/permanent discontinuation do 
not apply.   
• 
The participant is unable or unwilling to comply with required study procedures such 
as HIV testing and routine laboratory assessments, or otherwise might be put at undue 
risk to their safety and well-being by continuing CAB-LA use, according to the 
judgment of the Investigator.   
• 
The participant has one or more reactive HIV test results or expresses a concern about 
having acute HIV infection.  
 
20.2 Guidance on Toxicity Management for Specified Toxicities:  
 
Table 11: Nausea, Vomiting, and Diarrhea 
CONDITION AND 
SEVERITY  
IMMEDIATE 
ACTION  
FOLLOW-UP AND MANAGEMENT  
 
Nausea, Vomiting, and Diarrhea  
Grade 1 and 2  
Continue CAB-LA 
Will be treated symptomatically with hydration, 
oral antiemetic therapies or antiemetic 
suppositories at the discretion of the Investigator. 
The Investigator will order any clinically relevant 
laboratory analyses (per judgment of the 
Investigator).  


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Grade ≥ 3   
Discontinue CAB-
LA temporarily  
Participants with Grade 3 nausea, vomiting, or 
diarrhea, for which an alternative etiology is not 
established, will discontinue CAB-LA 
temporarily until Grade 2 or lower and be treated 
symptomatically. Should condition(s) not improve 
to Grade ≤ 2 within 7 days, the Investigator will 
consider temporary discontinuation or progressing 
to permanent discontinuation of CAB-LA.  
 
 
 
 
Liver chemistry monitoring 
 
Liver chemistry monitoring is at the discretion of the provider and will occur at baseline and 
Week 24. Additional ALT measurements will be taken and Weeks 8 and 48 per provider 
discretion.  Cabotegravir will be stopped if certain protocol specified liver event stopping criteria 
are met, or hepatotoxicity is suspected. 
 
Liver Event Stopping Criteria 
 
CAB must be stopped if any of the following Liver Event Stopping Criteria are met, or if the 
Investigator believes that it is in the best interests of the participant: 
• 
ALT >= 3xULN AND bilirubin >= 2xULN  
• 
ALT >=5xULN for more than 2 weeks 
• 
ALT >=8xULN 
• 
ALT >=3xULN (or >=3x baseline ALT) with symptoms of worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash or eosinophilia 
Consideration should also be given to stopping CAB in any participant with aminotransferase 
elevations > 3x ULN who cannot be monitored every 1-2 weeks. 
 
When a Liver Event Stopping Criterion is met, the treating physician must do the 
following: 
 
•     Immediately stop CAB-LA 
• 
If ALT >= 3xULN and bilirubin >=2xULN, report as a serious adverse event (SAE) within 
72 hours using the SAE case report form. 
• 
For all events meeting Liver Event Stopping Criteria, perform repeat liver chemistries and 
liver event follow up assessments (ideally within 24 hours of knowledge of the liver 
chemistry elevations) as described in the Follow-Up Assessment below and report to 


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UCSF, NIAID, and ViiV Healthcare using the Liver Event Case Report form within one 
week of first becoming aware of the event.  
• 
A specialist or hepatology consultation is recommended if available. 
• 
Monitor participants 2 times a week until liver chemistries resolve, stabilise or return to 
within baseline values. 
 
Follow up Assessment following ANY Liver Stopping Event 
 
Make every attempt to carry out liver event follow-up assessments as described below for the 
laboratory tests that are available locally.  
 
• 
Viral hepatitis serology, including: 
• 
Hepatitis A immunoglobulin M (IgM) antibody; 
• 
HBsAg and hepatitis B core antibody; 
• 
Hepatitis C RNA; 
• 
Hepatitis E IgM antibody. 
• 
Cytomegalovirus IgM antibody. 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing). 
• 
Syphilis screening. 
• 
Drugs of abuse screen, including alcohol. Record alcohol use on the liver event case report 
form if using.  
• 
Serum acetaminophen/paracetamol levels  
• 
Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin >=1.5xULN. 
• 
Obtain complete blood count with differential to assess eosinophilia. 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (or gamma globulins). 
• 
Gamma glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), and serum 
albumin 
• 
International normalised ratio (INR) 
• 
Liver imaging (ultrasound, magnetic resonance, or computerised tomography) and /or liver 
biopsy to evaluate liver disease. [A Liver Imaging and/or Liver Biopsy Case Report Form 
is available if required]. 
• 
Obtain history and record the appearance or worsening of clinical symptoms of liver 
injury, or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever rash as relevant on the AE/SAE report form. 


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• 
Obtain history and record use of concomitant medications including acetaminophen, herbal 
remedies, other over the counter medications or putative hepatotoxins. 
 
Liver-Safety- CAB-LA Restart 
 
“Drug restart” refers to resuming study treatment in which there is a clear cause other than Drug 
Induced Liver Injury (DILI). For long acting agents, a restart may actually be a continuation of 
therapy rather than a true restart due to the timeframe between dose administration relative to 
decision making on allowing a restart. 
 
Participants who meet Liver Event Stopping Criteria should NOT restart CAB-LA unless there is 
a compelling alternative cause for the liver chemistry abnormalities.  
 
“Drug restart” with CAB-LA in a participant who has a Liver Stopping Event may be permitted 
when liver chemistries improve to within 1.5x baseline and ALT < 3 xULN, provided the criteria 
set out in the Liver Safety Restart Guidelines are met. This should take into account when the 
next scheduled injection of CAB LA is due. If the restart criteria are not met by the time window 
for the next injection, consideration should be made to transitioning participants onto an 
alternative regimen. 
 
If restart is not allowed or not granted by the Study’s Governing Body or Principal 
Investigator, permanently discontinue study treatment. Participants may continue participation in 
the study for any protocol specified follow up assessments. 
 
Liver Safety Restart Guidelines 
 
If a causal relationship between the liver event and CAB-LA cannot be ruled out, then CAB-LA 
must be permanently discontinued and the participant not restarted.  
 
Note: Any decision regarding potential restart should take into account when the next scheduled 
injection of CAB LA is due. If the restart criteria below are not met by the time window for the 
next injection(s), consideration should be made to transitioning participants onto an alternative 
regimen. 
 
CAB-LA Restart Following Transient Resolving Liver Events Not Related to CAB-LA 
 
Restart can be considered when liver chemistries improve to within 1.5x baseline and 
ALT<3xULN where: 
• 
Liver chemistries have a clear underlying cause other than drug-induced liver injury (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis).  Furthermore, 
there should be no evidence of alcoholic hepatitis or hypersensitivity, and the drug is not 
associated with HLA markers of liver injury. 
• 
The participant is receiving compelling benefit and the benefit of drug restart exceeds risk. 
The long acting nature of CAB LA should be taken into consideration. 


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• 
Approval from the Principal Investigator and Ethics Committee or Institutional Review 
Board for the drug restart has been obtained. 
• 
The participant has been provided with a clear description of the possible benefits and risks 
of drug restart, including the possibility of recurrent, more severe liver injury or death and 
the long acting nature of CAB injections. 
• 
The participant has also provided signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study file. 
• 
Following drug restart, the participant will return to the clinic once a week for liver 
chemistry tests for one month or for as long as clinically indicated and then laboratory 
monitoring may resume as per protocol.  If protocol defined stopping criteria for liver 
chemistry elevations are met, study drug must be permanently stopped.  
 
Hypersensitivity 
 
Hypersensitivity reactions have been reported in association with other integrase inhibitors and 
were characterized by rash, constitutional findings and sometimes organ dysfunction, including 
liver injury. Administration of CAB oral lead-in was used in clinical studies to help identify 
patients who may be at risk of a hypersensitivity reaction. While there have been no confirmed 
occurrence of a severe hypersensitivity reactions attributable to cabotegravir in clinical trials to 
date, investigators should remain vigilant regarding their occurrence and should discontinue 
CAB-LA and other suspect agents immediately if signs or symptoms of hypersensitivity 
reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, 
general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial 
oedema, hepatitis, eosinophilia or angioedema. Clinical status, including laboratory parameters 
with liver transaminases, should be monitored and appropriate therapy initiated. 
 
All rash and suspected hypersensitivity events should be assessed with special attention to 
systemic symptoms, laboratory abnormalities, or mucosal involvement.  Close clinical follow-
up, including follow-up of laboratory abnormalities, and appropriate medical intervention, 
including referral to dermatologist as appropriate, should be instituted for these events. The 
prolonged release characteristics of CAB LA should be taken into consideration when these 
products are discontinued. 
 
Participants should be instructed to contact the Investigator as soon as possible if they develop 
a rash or allergic symptoms on study. 
 
Suicidal Ideation 
 
There have been reports of depression and suicidal ideation and behaviours (particularly in 
patients with a pre-existing history of depression or psychiatric illness) in some people living 
with HIV being treated with integrase inhibitors. Depression has also been reported in 
individuals receiving cabotegravir for PrEP. 
 
Participants should be monitored appropriately for any unusual changes in behaviour, before 


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and during the course of the study. Participants with depressive symptoms or suicidal ideation 
and behaviours on CAB-LA should be promptly evaluated.  It is recommended that the 
investigator consider mental health consultation or referral for participants who experience 
signs of suicidal ideation or behaviour. 
 
 
Confirmation of suspected HIV infection   
In cases of suspected HIV-infection, clinic staff are trained and use a seroconversion SOP for 
reference to proceed as depicted in Figure 2. For all cases, the clinical management team is 
notified immediately, as simultaneous confirmatory testing, additional sample collection 
(including stored samples for further HIV testing and PK), counseling, and linkage to ART care 
are initiated.) 
 
 
Figure 2. HIV Seroconversion Algorithm and Sample Collection 
 
 
 
 
For persons receiving CAB-LA, the following approach will be used for guidance on testing and 
administration of CAB-LA injections (Figure 3). 
 
 
 
 
 
 
 
 


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Figure 3. Algorithm for participants receiving CAB-LA Injections 
 
 
 
21.Analyses 
21.1 Overview 
 
This section provides an overview of the statistical consideration. 
 
The primary study endpoint in this extension will be biomedical covered time defined as the 
proportion of follow-up time that the participant is protected from HIV infection by any PEP or 
PrEP (inclusive of CAB-LA). Follow-up will be over the 48 weeks following re-consent for the 
CAB-LA extension. At risk covered time will be a secondary outcome, defined as the proportion 
of at-risk follow-up time that the participant is protected from HIV infection by any PEP or PrEP 
(inclusive of CAB-LA). We will also conduct sensitivity analyses, varying the definitions of 
coverage and risk. For example, we will also examine covered time from CAB-LA only (i.e., 
exclusive of oral PrEP or PEP), and we will conduct a sensitivity analysis in which we treat time 
after loss to follow-up among persons not known to have moved out of the study region and time 
after study withdrawal as presumed to be non-covered.  
 
For our primary objective in this extension, we will compare covered time during the 48 week 
CAB-LA extension between the intervention and control arms. For improved efficiency, 
Targeted Maximum Likelihood Estimation (TMLE) will be used to adjust for differences in 
baseline participant characteristics between the two trial arms, accounting for the stratified 
randomization design. In secondary analyses, we will further use TMLE to i) adjust for measured 
differences between arms at time of start of the CAB-LA extension period; and, ii) adjust for 
baseline and time-varying factors that are predictive of the outcome and that differ between 
persons that do vs. do not have their follow-up time censored.  The primary analysis will pool 
over the trials, accounting for clustering inherent in the community trial; secondary analyses will 
stratify by trial site. We will test the null hypothesis that covered time is the same between arms 
with a two-sided test at the 5% significance level. 


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Our secondary objective to evaluate implementation will follow the RE-AIM framework and 
corresponding measures (defined in Table 4). Analyses assessing the primary measures of Reach, 
Adoption, Implementation and Maintenance will be based on standard descriptive statistics. 
Analyses to evaluate Effectiveness will compare covered time over the 48 week CAB-LA 
extension period to covered time prior to the CAB-LA extension among intervention 
participants. We will adjust for measured changes in participant characteristics between these 
two follow-up periods, using a TMLE designed for serial measures. Measures of control 
participants will also be used to adjust for temporal trends. We will test the null hypothesis that 
coverage of the DCP model with CAB-LA is the same as coverage of the DCP model without 
CAB-LA. We will again use a two-sided test at the 5% significance level. Primary analyses will 
again pool over trials, while secondary analyses will be stratified by trial. In addition, we will 
evaluate marginal and adjusted predictors of CAB-LA uptake and persistence. Our tertiary 
objective to evaluate changes in knowledge, awareness, and acceptability/satisfaction will be 
based on applying TMLE to survey data, accounting for repeated measures.  
 
Additional descriptive analyses will include HIV incidence and safety. HIV seroconversions will 
be measured in each arm and incidence rates will be calculated using person time at risk. Safety 
Grade 3 and Higher AEs and SAEs will be measured for participants using CAB-LA and 
incidence rates will be calculated during person time exposed. These analyses will be 
complemented with costing evaluations as well as participant and provider qualitative data from 
IDI. 
 
All analyses of the community-based trial will account for clustering.  
 
21.2 Pharmacokinetic analyses: 
 
We will perform pharmacokinetic (PK) analyses of cabotegravir concentrations in plasma and 
small hair samples with two objectives. 1) To examine hair levels of CAB as predictors of 
effectiveness; 2) To examine factors associated with CAB PK variability and study correlations 
between CAB hair and plasma levels at the end of dosing intervals and during the PK tail. In the 
phase 3 trials of CAB LA, plasma concentrations of CAB did not fully explain CAB 
breakthrough infections (especially since failures occurred despite on-time injections) and 
therefore PK metrics, such as hair, that reflect longer-term exposure, may provide important 
insights regarding CAB exposure in addition to plasma. Drug concentrations of cabotegravir will 
be analyzed via liquid chromatography tandem mass spectrometry (LS-MS/MS) at the Hair 
Analytical Laboratory at UCSF. Plasma samples will be collected prior to each injection, while 
hair samples will be collected at weeks 8, 24, 32, and 48 after CAB LA start.  
 
First, we will analyze hair concentrations of cabotegravir in plasma and small hair samples as 
predictors of effectiveness. We will take the proximal 2 cm of hair from the scalp and segment 
the hair into two 1.0 cm segments (reflecting the prior two months of drug exposure in 1 month 
intervals), analyzing CAB levels in each segment. We will analyze hair levels from each 
collection visit from all participants who acquire HIV infection after starting CAB LA and three 
randomly selected controls who did not acquire HIV to compare exposure metrics from those for 
with and without HIV acquisition. We use sampling fraction weights to properly combine data 


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from participants who acquire HIV (sampled with certainty) and controls in order to obtain 
accurate estimates for the entire study population.  
 
Second, to examine factors associated with PK variability, we will perform univariate linear 
mixed effects regression using hair levels of CAB assessed as continuous outcomes with 
candidate predictor variables that may influence exposure, such as age, sex and body mass index 
(BMI), as well as plasma levels, and delays in injection visits. We will then build multivariate 
models to assess how associations with hair levels change when controlled for other factors. We 
will examine scatterplots and Spearman correlation coefficients between hair and plasma 
concentrations of CAB, including at the end of the dosing interval (using the hair concentration 
in the proximal 0.5 cm of hair since hair is collected before injections) and during the PK tail for 
participants who elect to stop CAB LA or who acquire HIV and start an oral ART regimen.  
 
21.3 Analyses of In-Depth Interviews  
 
Qualitative in-depth interviews will be conducted among purposively-selected samples of study 
participants and providers, to ascertain the perceptions of and experiences with CAB-LA use and 
delivery. Data will analyzed using a framework analysis approach, wherein transcribed and 
translated data are inductively coded by a cross-regional team of trained qualitative researchers, 
the initial sets of findings are consolidated and grouped into conceptual categories, and a 
framework matrix is used to further condense findings tied most salient to the research questions.  
 
21.4 Costing  
 
Costs will be estimated as the sum of the product of resources (e.g. staff minutes) times unit 
costs (e.g. compensation levels). “Economic” costs (the true value of resources consumed or 
“opportunity costs”) will be assessed by identifying the value of subsidized or donated resources 
with information from databases (e.g. wage rates) and donors. We will use prices prevailing at 
the time of study onset and will convert any locally incurred costs using the Uganda/Kenya 
Shilling / US dollar exchange rate at that time. Costs of CAB-LA implementation will be 
compared to the costs of oral PrEP implementation estimated during the primary trial to estimate 
the incremental cost of CAB-LA implementation.  
 
21.5 Power and Sample size considerations 
 
For each ongoing trial, we assume 90% of participants consent to the extension (reflecting the 
high retention in the ongoing trials seen to date). Of those, we assume 90% are retained through 
the extension. In the individually randomized ANC and OPD trials, we anticipate >80% power to 
detect a 11% or greater absolute increase in prevention coverage between arms with 162 
participants/arm (assuming 𝜎=0.35). In the cluster-randomized community-based trial, we 
anticipate >80% power to detect a 15% or greater absolute increase in prevention coverage 
between arms with ~20 participants in each of the 16 clusters (assuming mean prevention 
coverage in the standard of care arm of 10%, 𝜎=0.35, and a matched-pair coefficient of 
variation km=0.25). These calculations are expected to be conservative given the ongoing 
enrollment and primary approach to conduct a pooled analysis as well as the increased precision 
from stratified randomization and through covariate adjustment with TMLE. Minimum 


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detectable effect sizes varying these assumptions (including allowing for lower retention in either 
the ongoing or extension studies) are shown in Figure 4.  
 
 
Figure 4. Minimum detectable effect sizes for the primary hypothesis  
 
 
 
 
22. DATA HANDLING AND RECORD KEEPING 
This is an implementation study; the primary risks for a client would be any loss of 
confidentiality, or risk from blood draw in measurement of the HIV outcome.  For risk 
mitigation, all participants undergo informed consent in their native language, staff are fully 
trained on confidentiality. The SEARCH Sapphire team has SOPs and procedures for data 
collection and security. Because CAB-LA is not yet approved in Uganda or Kenya, we will be 
recording Grade 3 and 4 AEs and reporting to these as required to regulatory authorities.  
 
22.1 . Data Management Responsibilities  
Data management for this study will be overseen by the Infectious Diseases Research 
Collaboration (IDRC) Data Management Center located in the main IDRC research complex in 
Nakasero, Kampala, Uganda.  The Data Management Center (DMC) is also responsible for 
providing IT support to all staff members. 
 
Data Management System 
For any study components using paper data collection, IDRC has designed and developed a 
custom Data Management System that is used to manage the data, using Microsoft SQL Server 
as the backend for all data storage.  MS Access is used for double data entry and SAS programs 
are used for comparing 1st and 2nd entry and generating discrepancy reports.  In addition, the 
DMC has developed custom Visual Basic programming for direct survey and data entry of data 
in the field. Data Transformation Services/ SQL Server Integration Services (DTS/SSIS) 
packages are used to automatically import/export any new data and stored procedures written in 
T-SQL are used to automatically generate new data queries on a daily basis.  There is a web 


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interface to the whole system written in ASP.NET to allow users to view the data, view reports, 
and even modify the data they are authorized to access.  With regular backups and a full audit 
trail, the whole system is regulatory compliant (21 CFR Part 11). 
 
22.2. Essential/Source Documents and Access to Source Data/Documents  
 
Data is collected as a mixture of paper Case Report Forms (CRFs) and logs and electronic data 
capture from health facility databases and field data tablets.  Data is entered locally and uploaded 
to the DMC after quality assurance measures have taken place.  Only study investigators and 
staff affiliated with the study will have access to source data. 
 
External data sharing will be made through a data request proposal procedure coordinated by the 
PIs and the IDRC Data Department.  A standardized data request sheet will be completed by 
outside investigators and reviewed by the senior management and/or the Principal Investigator.  
Data and associated documentation will be available to users under a data-sharing agreement that 
provides for: (1) a commitment to using the data only for research purposes and not to identify 
any individual participant; (2) a commitment to securing the data using appropriate computer 
technology; and (3) a commitment to destroying or returning the data after analyses are 
completed.  User registration is required to access or download files. As part of the registration 
process, users must agree to the conditions of use governing access to the public release data, 
including restrictions against attempting to identify study participants, destruction of the data 
after analyses are completed, reporting responsibilities, restrictions on redistribution of the data 
to third parties, and proper acknowledgement of the data resource. 
 
22.3. Quality Control and Quality Assurance 
 
The data management system is designed to collect, transfer and store data for Data Management 
Center studies. Data from any paper records will be 100% double entered into the system via 
Microsoft Access Databases or Web-based data entry screens. Locally collected data is 
compressed, password-protected, and then securely uploaded to a cloud based server (Network 
Solutions, Inc.) using secure-FTP via the FileZilla application.   Cloud-based uploads are 
downloaded daily to the Kampala DMC.  After the data has been input into the Data 
Management Center server, it is electronically verified and is then written to the SQL database. 
Edit checks or queries are run nightly and the results are posted to a secure clinical trials website 
so that the sites can electronically address problems with the data the next day. The site corrects 
data via the website and the database is updated automatically. 
 
In order to ensure data security and integrity, the following measures will be implemented: 
• All members of the study team will be educated in the study protocol prior to the onset of 
the study.  
• Detailed Standard Operating Procedures (SOPs) will be written for all project activities 
and be provided to relevant team members.  
• Team members will be thoroughly trained on the SOP’s.  
• Where applicable, team members will receive additional training on the use of tablet 
computers.  
• All data transcribed from paper will be double data entered or verified.  


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• All electronic data will be backed up regularly.  
• All data will be transferred to the main Data Center in Kampala to the secure server. This 
sever is backed up on a daily basis and a monthly backup is stored off-site.  
• All computers, including the tablets, will be password protected.  
• All computers, including tablets, will be locked in a secure room each night.  
• Any Log Books and CRF’s will be locked in a secure room each night. 
 
23. PUBLICATION POLICY  
The findings from this study may be published in a medical journal. No individual identities will 
be used in any reports or publications resulting from the study. The researchers will publish 
results of the study in accordance with NIH, UCSF, UNCST, KEMRI, and Makerere University 
guidelines. 
 
 
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30. Landovitz RJ, Li S, Eron JJ Jr, Grinsztejn B, Dawood H, Liu AY, Magnus M, Hosseinipour 
MC, Panchia R, Cottle L, Chau G, Richardson P, Marzinke MA, Eshleman SH, Kofron R, 
Adeyeye A, Burns D, Rinehart AR, Margolis D, Cohen MS, McCauley M, Hendrix CW. 
Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable 


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cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial. 
Lancet HIV. 2020 Jul;7(7):e472-e481. doi: 10.1016/S2352-3018(20)30106-5. Epub 2020 
Jun 1. PMID: 32497491. 
31. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, Cabello R, 
Chariyalertsak S, Dunne EF, Frank I, Gallardo-Cartagena JA, Gaur AH, Gonzales P, Tran 
HV, Hinojosa JC, Kallas EG, Kelley CF, Losso MH, Madruga JV, Middelkoop K, 
Phanuphak N, Santos B, Sued O, Valencia Huamaní J, Overton ET, Swaminathan S, Del 
Rio C, Gulick RM, Richardson P, Sullivan P, Piwowar-Manning E, Marzinke M, Hendrix 
C, Li M, Wang Z, Marrazzo J, Daar E, Asmelash A, Brown TT, Anderson P, Eshleman SH, 
Bryan M, Blanchette C, Lucas J, Psaros C, Safren S, Sugarman J, Scott H, Eron JJ, Fields 
SD, Sista ND, Gomez-Feliciano K, Jennings A, Kofron RM, Holtz TH, Shin K, Rooney JF, 
Smith KY, Spreen W, Margolis D, Rinehart A, Adeyeye A, Cohen MS, McCauley M, 
Grinsztejn B; HPTN 083 Study Team. Cabotegravir for HIV Prevention in Cisgender 
Men and Transgender Women. N Engl J Med. 2021 Aug 12;385(7):595-608. PMID: 
34379922. 
32. Eshleman SH, Fogel JM, Piwowar-Manning E, Chau G, Cummings V, Agyei Y, 
Richardson P, Sullivan P, Haines CD, Bushman LR, Petropoulos C, Persaud D, Kofron R, 
Hendrix CW, Anderson PL, Farrior J, Mellors J, Adeyeye A, Rinehart A, St Clair M, Ford 
S, Rooney JF, Mathew CA, Hunidzarira P, Spooner E, Mpendo J, Nair G, Cohen MS, 
Hughes JP, Hosseinipour M, Hanscom B, Delany-Moretlwe S, Marzinke MA. 
Characterization of Human Immunodeficiency Virus (HIV) Infections in Women 
Who Received Injectable Cabotegravir or Tenofovir Disoproxil 
Fumarate/Emtricitabine for HIV Prevention: HPTN 084. J Infect Dis. 2022 Mar 
18:jiab576. Epub ahead of print. PMID: 35301540. 
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Characterization of HIV infection in cisgender men and transgender women who 
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Rinehart AR, Margolis D, McCauley M, Hendrix CW, Landovitz RJ; HPTN 077 Study 


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Team. Brief Report: Hormonal Contraception Use and Cabotegravir 
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Manning E, Beigel-Orme S, Hosek S, Adeyeye A, Rooney J, Rinehart A, Hanscom B, 
Cohen MS, Hosseinipour MC. Long Acting Injectable Cabotegravir: Updated Efficacy and 
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Document: 
Statistical Analysis Plan 
 
Official Study Title: 
 SEARCH CAB LA Dynamic Choice HIV Prevention Study Extension 
NCT05549726 
 
Document Date: 
December 15, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
  
Sustainable East Africa Research in Community Health   
(SEARCH) Collaboration  
  
Statistical Analysis Plan for the  
SEARCH “Dynamic Choice HIV Prevention” Extension Study including the Option of Long Acting Cabotegravir  
Injectable Suspension (CAB-LA) in rural Kenya and Uganda  
   
Laura B. Balzer, PhD, Study Statistician1   
Diane V. Havlir, MD, co-Principal Investigator2 Moses R. Kamya, MD, PhD co-Principal Investigator 3-4  Maya L. 
Petersen, MD, PhD co-Principal Investigator1 for the SEARCH Collaboration5   
  
This document provides the statistical analytic plan (SAP) for the evaluation of the effect of the SEARCH Dynamic 
Choice HIV Prevention intervention, including the option of CAB-LA, on biomedical prevention coverage (primary 
outcome) as well as HIV incidence and biomedical prevention coverage during periods of self-reported HIV risk 
(secondary outcomes) in a randomized trial extension study in rural Kenya and Uganda (Clinicaltrials.gov: 
NCT05549726). The SAP was locked prior to unblinding and effect estimation.  
  
December 15, 2023   
v1.1  
   
Division of Biostatistics, University of California Berkeley, Berkeley, USA  
Division of HIV, Infectious Diseases, and Global Medicine, University of California San Francisco, San Francisco,  
USA  
Infectious Diseases Research Collaboration, Kampala, Uganda  
Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda  
www.searchendaids.com  
1. OVERVIEW OF TTHE SEARCH CAB-LA EXTENSION STUDY  
This study is testing the hypothesis that a “Dynamic Choice HIV Prevention” intervention that offers participants CAB-
LA, oral Pre-Exposure Prophylaxis (PrEP), or post-exposure prophylaxis (PEP) and the ability to switch between products 
over time using a patient-centered delivery approach will achieve higher prevention coverage for males and females ≥15 
years of age and at risk for HIV infection acquisition, as compared to the country standardof-care (SoC). The current SoC 
for biomedical HIV prevention includes oral PrEP and PEP. This study is being conducted in rural western Uganda and 
rural western Kenya. The follow-up is over 48 weeks. Additional details of the study design, arms, and procedures can be 
found in the Study Protocol.   
The primary objective is to evaluate the effect of the Dynamic Choice HIV Prevention intervention versus the  
SoC on biomedical HIV prevention coverage, defined as the proportion of follow-up time covered by either PrEP (oral 
PrEP or CAB-LA) or PEP. Secondary, pre-specified endpoints compared between arms and included in this SAP are 
coverage during periods of self-reported risk of HIV acquisition (“at-risk coverage”) and HIV incidence. We additionally 
describe product use over time between arms. Analysis plans for other endpoints (e.g., implementation metrics and the 
change in endpoints before and after adding CAB-LA to the intervention) are available elsewhere. Power calculations and 
history of changes are given in the Appendix.  
2. POPULATION AND CHARACTERISTICS  
The study population is persons who were enrolled in the 3 randomized Dynamic Choice HIV Prevention trials that 
recruited from antenatal clinics, outpatient departments, and the community.1–3 These trials were designed to evaluate the 
impact of the Dynamic Choice HIV Prevention intervention (offering choice between oral PrEP and  


PEP as biomedical HIV prevention options) versus the SoC on biomedical HIV prevention coverage over 48 weeks 
(Figure 1).   
  
Figure 1: Schematic of the CAB-LA extension study with abbreviations of DCP for Dynamic Choice HIV Prevention 
intervention and SOC for standard-of-care.  
  
  
The Dynamic Choice HIV Prevention trials enrolled participants aged ≥15 years with current or anticipated risk to acquire 
HIV. Inclusion criteria for the CAB-LA extension study are 1) Prior enrollment in a SEARCH Dynamic Choice HIV 
Prevention trial,  2) HIV-negative by country-standard rapid HIV testing algorithm, and  3) Residence in the study region.   
In the extension, participants maintained their original randomization arm and are not blinded to the treatment arm. The 
primary statistician (LBB) will remain blinded to the treatment arm until the official unblinding of the study when the 
primary and secondary effect analyses, described in this SAP, are conducted. Additional details, including randomization 
procedures and eligibility for CAB-LA access among intervention arm participants, are in the Study Protocol.   
To characterize participant flow from original randomization through measurement of the primary endpoint of the 
extension, we will provide a CONSORT diagram. To describe the study population, we will summarize participant 
characteristics at start of the extension, overall and by arm. These characteristics will include recruitment setting, country, 
sex, age, marital status, occupation, pregnancy (women only), circumcision (men only), and alcohol use (having 1+ 
alcoholic drink per week).  
3. ENDPOINT DEFINITION AND MEASUREMENT  
3.1. Biomedical HIV Prevention Coverage  
The primary endpoint of this study is biomedical HIV prevention coverage, defined as the proportion of follow-up time 
covered by either PrEP (TDF/3TC or CAB-LA) or PEP. Thereby, this endpoint has a minimum of 0% (no use) and a 
maximum of 100% (full coverage). For oral PrEP and PEP, coverage is defined using self-report via a structured survey 
administered at 24 and 48 weeks of follow-up. Specifically, for each month of the prior 6 months, participants 
retrospectively report any use of oral PrEP (i.e., pill ingestion) and any use of PEP. For CAB-LA, coverage is defined 
through injection logs. Coverage from CAB-LA begins 3 days after an injection and continues for 67 days.   
3.2 At-Risk Coverage  
A secondary endpoint of this study is at-risk coverage, defined as the proportion of follow-up time that a participant 
reports being at risk of HIV acquisition during which they are covered by a biomedical prevention option. Product use 
over time will be defined analogously to the primary outcome. Self-reported risk of HIV acquisition will be assessed 
retrospectively via the structured survey administered at 24 and 48 weeks of follow-up.  
  
3.3 Incident HIV Acquisition  
A secondary endpoint of this study is incident HIV acquisition. HIV rapid antibody testing and HIV RNA testing  
(Cepheid GeneXpert Diagnostic System, Sunnyvale, California) will be performed at baseline, week-24, and week48. HIV 
testing is also available at the Ministry of Health clinics at all study sites. All participants with detectable HIV RNA and 
negative rapid antibody testing will have repeat antibody testing for confirmation of HIV diagnosis. All possible incident 
HIV infections will be reviewed by two HIV clinical experts blinded to the trial arm to determine if the participant meets 
the definition of confirmed incident HIV infection.  
4. EVALUATION OF THE EFFECT OF THE SEARCH DYNAMIC CHOICE HIV PREVENTION INTERVENTION 
WITH CAB-LA  
4.1. Primary Analysis: Effect on Biomedical HIV Prevention Coverage  
The primary endpoint of biomedical HIV prevention coverage will be compared between arms with targeted minimum 
loss-based estimation (TMLE) to improve efficiency over the unadjusted effect estimator.4–12 Briefly, TMLE combines 
estimates of the outcome regression (i.e., the conditional expectation of the outcome, given the intervention and 


covariates) and the known propensity score (i.e., the conditional probability of the intervention, given the covariates) to 
obtain doubly-robust inference for the estimand of interest.   
The primary analysis will adjust for recruitment setting (antenatal clinic, outpatient department, or community) in the 
outcome regression and adaptively adjust for additional baseline covariates to optimize precision, while preserving Type-I 
error control. Specifically, we will use Adaptive Pre-specification to select the candidate TMLE that maximizes empirical 
efficiency.8,10,12 Using 10-fold cross-validation, we will select from the following prespecified candidates:  
  
Outcome regression estimators: generalized linear models (GLMs) adjusting for a single covariate (beyond setting), main 
terms GLM, LASSO, or no further adjustment.  
Propensity score estimators: GLMs adjusting for a single covariate, main terms GLM, LASSO, or no adjustment  
Candidate variables: sex, age, alcohol use, mobility, or nothing  
  
The primary analysis will estimate the marginal effect on the absolute scale (i.e., the difference in the average of the arm-
specific outcomes). Secondary comparisons will be on the ratio scale. Standard error estimation will be based on the 
estimated influence curve, accounting for clustering from the community-based setting.9,10,13–15 Statistical inference will 
follow from the Central Limit Theorem.4 Specifically, we will create Wald-type 95% confidence intervals and test the null 
hypothesis of no difference in biomedical HIV prevention coverage with a two-sided test at the 5% significance level. We 
will also report point estimates and 95% confidence intervals for the arm-specific estimates.   
In sensitivity analyses, we will assess the robustness of our findings by only adjusting for setting in the outcome regression 
as well as implementing the unadjusted effect estimator. We may conduct an additional sensitivity analysis adjusting for, 
instead of excluding, participants with zero follow-up. Additionally, we will evaluate the effect on coverage when 
restricting follow-up time to periods included in the structured survey administered to assess use of oral PrEP or PEP.  
In additional sensitivity analyses, we will use data from the initial trials through the extension and apply TMLE to adjust 
for differences between participants who did vs. did not continue in the extension and participants who did vs. did not 
have their endpoint ascertained. See Section 6 for details.   
We will repeat these analyses within subgroups defined by sex and age group (15-24 years vs. 25+ years) and apply the 
Bonferroni correction for multiple testing. To further understand effect heterogeneity, we may conduct variable importance 
measures (i.e., unadjusted and adjusted predictor analyses) with TMLE.  
Prior to locking this SAP, we will conduct treatment-blind simulations to verify Type-I error control for all endpoints.12  
4.2. Secondary Endpoint Analysis: Effect on At-Risk Coverage  
We will implement analogous analyses to assess the SEARCH effect on coverage during periods of self-reported HIV risk. 
We will use the same approach for effect estimation, statistical inference, and multiple testing. We will conduct analogous 
subgroup and sensitivity analyses.  
4.3. Secondary Endpoint Analysis: Effect on HIV Incidence  
A key secondary endpoint is incident HIV infection. For each participant, we will calculate person-time-at-risk (PT) as the 
difference between enrollment into the extension and   
  
Last negative HIV test for persons who did not acquire HIV  
Imputed HIV infection date, defined as the midpoint between last negative and first positive test, for persons who did 
acquire HIV.  
  
We will then compare the HIV incidence rate, defined as the sum of incident infections divided by the sum of PT, between 
randomized arms with the unadjusted effect estimator. Due to the anticipated rarity of the outcome, we will not apply 
TMLE for additional precision gains.   
Our approach to inference will be implemented analogously to the primary endpoint.  
As before, the primary comparison will be on the absolute scale (i.e., the difference in the incidence rates between arms) 
with secondary comparisons on the relative scale. Again, standard error estimation will be based on the estimated 
influence curve, accounting for clustering and inference based on the Central Limit Theorem. We will test the null 
hypothesis of no difference in HIV incidence rates with a two-sided test at the 5% significance level. In sensitivity 
analyses, we will, instead, use the non-parametric bootstrap for standard error estimation and exact tests for inference.  
We will repeat these analyses within groups defined by sex and age group. However, we will not conduct hypothesis 
testing for these groups.   
5. ADDITIONAL DESCRIPTIVE ANALYSES  
We will summarize participant follow-up, overall and by arm. Follow-up in the CAB-LA extension study starts at 
enrollment and ends at the earliest of HIV diagnosis, death, withdrawal, or December 31, 2023. Follow-up time is 
censored during periods without data on use of biomedical HIV prevention.  


Overall and by arm, we will report the number and proportion of participants who withdrew, died, or had other adverse 
events. We may also report on outcomes among women who become pregnant after initiating CAB-LA. We will 
summarize data on biomedical HIV prevention product use by arm. These summaries will exclude participants without 
any follow-up data on biomedical prevention use. We will use heatmaps to depict participantlevel use of prevention 
products over months of follow-up in the extension. We will also provide descriptive statistics about product use over 
time, including the month prior to the extension study, at baseline in the extension study, and ever use during the extension 
study. When calculating these descriptive statistics, missing values at baseline product use will be imputed from the first 
follow-up month.  
6. SENSITIVITY ANALYSES  
In this extension study, participants will maintain their original randomization arm. As a result, there is a legitimate 
concern that arms will be imbalanced at the start of the extension study. We will address this concern by conducting the 
following sensitivity analyses for the effect on biomedical HIV prevention coverage (primary endpoint) and atrisk 
coverage (secondary endpoint). These analyses will incorporate data from all persons who participated in the 3 Dynamic 
Choice HIV Prevention trials – regardless if they continued in the extension and/or had their endpoint ascertained in the 
extension.   
This sensitivity analysis is informed by the Causal Roadmap16 and aims address possible bias due to selection and missing 
data. Specifically, we can frame the analysis as asking, “What is the effect of the SEARCH Dynamic Choice HIV 
Prevention intervention (including the option of CAB-LA) if all participants had continued in the extension and had their 
endpoint ascertained?” While the treatment arm is randomized, we need to make the following missing data assumption: 
within values of adjustment variables, participants with their endpoint measured in the extension (and, thus, continued in 
the extension) are representative of participants who do not. Here, our adjustment set includes variables measured at 
recruitment into the initial trials (hereafter “baseline”): age, sex, country, recruitment site, alcohol use, and mobility. 
Importantly, our adjustment set also includes trial arm as well as post-intervention variables measured prior to the 
extension start: biomedical HIV prevention coverage, at-risk coverage, follow-up time, and follow-up time with self-
reported risk of HIV acquisition. We additionally need that there is a positive probability of endpoint ascertainment within 
all possible values of these adjustment variables.  
Under these assumptions, our statistical estimand is given by the Longitudinal G-computation formula:17  
  
𝔼{𝔼[𝔼(𝑌|Δ = 1, 𝐿1, 𝐴 = 1, 𝐿0)|𝐴 = 1, 𝐿0]} - 𝔼{𝔼[𝔼(𝑌|Δ = 1, 𝐿1, 𝐴 = 0, 𝐿0)|𝐴 = 0, 𝐿0]}  
  
where 𝑌 is the endpoint, ∆ is an indicator of having that endpoint measured and, thus, continuing in the extension, 𝐿1 are 
the time-varying covariates, 𝐴 is an indicator of being randomized to the intervention arm, and 𝐿0 are the baseline 
covariates.   
  
For estimation and inference, we will use longitudinal TMLE as implemented in the ltmle package.4,14,18 In the main 
analysis, we will employ Super Learner, which is an ensemble machine learning method, to flexibly adjust and to improve 
efficiency.19  Within Super Learner, we will combine predictions from main terms logistic regression (GLM), generalized 
additive models (GAM), multivariate adaptive splines (MARS), and the mean. The main analysis will also bound the 
estimated propensity scores (for measurement) from below at 1%. We will use the same approach for statistical inference 
and multiple testing as the primary analysis.  
  
We will further examine the sensitivity to our assumptions and analytic choices by implementing TMLE as follows:  
TMLE with Super Learner (as described above) but bounding the estimated propensity scores from below at 2%  
TMLE with main terms logistic regressions (instead of Super Learner)  
TMLE with Super Learner but only adjusting for baseline variables  
TMLE with main terms logistic regressions and only adjusting for baseline variables  
  
We will implement these analyses for biomedical HIV prevention coverage (primary endpoint) and at-risk coverage, 
overall and within the predefined subgroups.  
7. POWER CALCULATIONS  
We assume 70% of participants in the 3 Dynamic Choice HIV Prevention trials enroll in the extension. Of those, we 
assume 90% have measures of biomedical HIV prevention coverage (the primary endpoint). Then using standard formulas 
for continuous outcomes with clustering,20,21 we anticipate at least 80% power to detect at least a 7.5% absolute increase in 
prevention coverage with 485 participants/arm, an outcome standard deviation of 0.35, and a design effect of 1.3. As 
shown in Figure 2, these calculations are fairly robust to alternative assumptions, including lower outcome measurement 


and higher design effects. We further expect these calculations to be conservative given the precision gains due to 
covariate adjustment with TMLE in the primary analysis.  
  
Figure 2: Minimal effect size (difference) detected with 80% power with a two-sample t-test (via power.t.test in R) after 
deflating the sample size by the design effect  
  
8. HISTORY OF CHANGES  
Version 1.0: This version includes updated power calculations (as compared to the Study Protocol v7.0) to reflect 
enrollment into the extension and that the primary analysis pools over and adjusts for (versus stratifies on) recruitment 
setting.  
Version 1.1 (current version): This version includes additional details about the pre-specified sensitivity analyses (Section 
5.0).  
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