Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women Who Have Sex With Men

The purpose of this study is to evaluate the safety and efficacy of the injectable drug
cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men
and transgender women who have sex with men (MSM and TGW).

This study will enroll HIV-uninfected MSM and TGW at risk for acquiring HIV infection.
Participants will remain in the study between 1.5 years to 4.5 years, depending on when they
enroll in the study.

This study will take place in three steps. Participants will be randomly assigned to one of
two arms:

Arm A:

Step 1: Participants will receive daily oral CAB tablets and daily oral TDF/FTC placebo
tablets for 5 weeks.

Step 2: Participants will receive an intramuscular (IM) injection of CAB LA at two time
points 4 weeks apart and every 8 weeks thereafter and daily oral TDF/FTC placebo tablets.

Arm B:

Step 1: Participants will receive daily oral TDF/FTC tablets and daily oral CAB placebo
tablets for 5 weeks.

Step 2: Participants will receive daily oral TDF/FTC tablets and an IM injection of placebo
at two time points 4 weeks apart and every 8 weeks thereafter.

In Step 3, all participants (Arms A and B) will receive daily oral TDF/FTC tablets no later
than 8 weeks after the last injection, for up to 48 weeks.

Participants will attend up to 57 study visits throughout the study. Visits may include
physical examinations, blood collection, urine collection, an electrocardiogram (ECG), and
rectal swab collection. Some participants may have a bone mineral density-energy x-ray
absorptimetry (DXA) scan at select visits.

All participants will be transitioned to locally available HIV prevention services, including
services for PrEP, if available, at the end of their participation in the study.

Inclusion Criteria:

- MSM and TGW, 18 years or older at the time of screening (male at birth)

- Willing to provide informed consent for the study

- At high risk for sexually acquiring HIV infection based on self-report of at least one
of the following:

- Any condomless receptive anal intercourse in the 6 months prior to enrollment
(condomless anal intercourse within a monogamous HIV seronegative concordant
relationship does not meet this criterion)

- More than five partners in the 6 months prior to enrollment (regardless of condom
use and HIV serostatus, as reported by the enrollee)

- Any stimulant drug use in the 6 months prior to enrollment

- Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months
prior to enrollment

- SexPro score of less than or equal to 16 (U.S. sites only)

- In general good health, as evidenced by the following laboratory values, which must be
from specimens obtained within 45 days prior to study enrollment:

- Non-reactive / negative HIV test results. More information on this criterion can
be found in the protocol.

- Hemoglobin greater than 11 g/dL,

- Absolute neutrophil count greater than 750 cells/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Calculated creatinine clearance greater than or equal to 60 mL/minute using the
Cockcroft-Gault equation (use sex at birth for calculation)

- Although not protocol exclusionary, sites should carefully consider the
advisability of enrolling participants with calculated creatinine clearance
between 60-70 mL/min, as limited changes in creatinine clearance during
study conduct will lead to protocol-mandated product holds and may alter the
risk-benefit considerations of study participation

- Alanine aminotransferase (ALT) less than 2 times the upper limit of normal (ULN)

- Total bilirubin less than or equal to 2.5 times ULN

- Hepatitis B virus (HBV) surface antigen (HBsAg) negative

- Hepatitis C virus (HCV) Ab negative

- No Grade 3 or higher laboratory abnormalities on any laboratory tests obtained at
screening, including tests obtained as part of a panel of tests ordered to obtain
the protocol-required laboratory test results.

- No medical condition that, in the opinion of the study investigator, would interfere
with the conduct of the study (e.g., provided by self-report, or found upon medical
history and examination or in available medical records)

- Willing to undergo all required study procedures

Exclusion Criteria:

- One or more reactive or positive HIV test result at Screening or Enrollment, even if
HIV infection is not confirmed

- Active or recent use of any illicit intravenous drugs ("recent" defined as in the 90
days prior to enrollment)

- Co-enrollment in any other interventional research study or other concurrent studies
that may interfere with this study (as provided by self-report or other available
documentation. Exceptions may be made if appropriate after consultation with the CMC.)

- Past or current participation in HIV vaccine trial. An exception will be made for
participants that can provide documentation of receipt of placebo (not active arm).

- Clinically significant cardiovascular disease, as defined by history/evidence of
symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG)
surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically
significant cardiac disease

- Inflammatory skin conditions that compromise the safety of intramuscular (IM)
injections, per the discretion of the Investigator of Record. Mild skin conditions may
not be exclusionary at the discretion of the Investigator of Record (IoR) or designee
in consultation with the CMC

- Has a tattoo or other dermatological condition overlying the buttock region which in
the opinion of the IoR or designee, in consultation with the CMC, may interfere with
interpretation of injection site reactions

- Current or chronic history of liver disease (e.g., non-alcoholic or alcoholic
steatohepatitis) or known hepatic or biliary abnormalities (with the exception of
Gilbert's syndrome, asymptomatic gallstones, or cholecystectomy)

- Coagulopathy (primary or iatrogenic) which would contraindicate IM injection
(concomitant anticoagulant or anti-platelet therapy use should be discussed with the
CMC)

- Active or planned use of prohibited medications as described in the Investigator's
Brochure or listed in the Study Specific Procedures (SSP) Manual (provided by
self-report, or obtained from medical history or medical records). In particular,
future use of TDF/FTC at any point during the study.

- Known or suspected allergy to study product components (active or placebo), including
egg or soy products (egg and soy products are contained in Intralipid)

- Surgically-placed or injected buttock implants or fillers, per self-report. Contact
the CMC for guidance regarding questions about individual cases.

- Alcohol or substance use that, in the opinion of the study investigator, would
jeopardize the safety of the participant on study (e.g., provided by self-report, or
found upon medical history and examination or in available medical records).

- History of seizure disorder, per self-report

- QTc interval (B or F) greater than 500 msec