IMPOWER 022

Primary Sponsor Details

Secondary Sponsor Details

South Africa, United States of America, Zimbabwe, Eswatini, Zambia, Malawi, Uganda and Kenya

A participant will be eligible for inclusion in the study if the participant:

Type of Participant and Disease Characteristics

1. Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results before

randomization.

Note: If a positive result is obtained for any HIV test prior to randomization, the

participant is not eligible for the study. Additional testing to confirm suspected HIV

infection during screening will be performed in accordance with local guidelines. If HIV

infection is confirmed, participants will be referred for appropriate care, as necessary.

2. Has been sexually active with a male sexual partner in the 30 days prior to Screening.

3. Is at high risk for HIV-1 infection as defined by a risk score ≥5 using a VOICE risk score

tool (ex-US sites) or meets the CDC criteria for PrEP eligibility (US sites).

Demographics

4. Was assigned female sex at birth, is cisgender, 16 years to 45 years of age, inclusive, at

the time of providing informed consent/assent.

Female Participants

5. A female participant is eligible to participate if she is not pregnant or breastfeeding,

and at least one of the following conditions applies:

• Is not a WOCBP

OR

• Is a WOCBP and using an acceptable contraceptive method, as described in Appendix 5

during the intervention period and for at least 42 days after the last dose (corresponding

to the time needed to eliminate any study intervention [approximately 5 terminal halflives]).

• A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as

required by local regulations) within 24 hours before the first dose of study intervention.

• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum

pregnancy test is required. In such cases, the participant must be excluded from

participation if the serum pregnancy result is positive.

• Additional requirements for pregnancy testing during and after study intervention are

located in Appendix 2.

• The investigator is responsible for review of medical history, menstrual history, and

recent sexual activity to decrease the risk for inclusion of a woman with an early

undetected pregnancy.

• Contraceptive use by women should be consistent with local regulations regarding the

methods of contraception for those participating in clinical studies.

Informed Consent

6. The participant (or legally acceptable representative) has provided documented

informed consent/assent for the study. The participant may also provide

consent/assent for future biomedical research. However, the participant may

participate in the main study without participating in future biomedical research.

Additional Categories

7. Has no plans to relocate or travel away from the site for ≥4 consecutive weeks during

study participation.

The participant must be excluded from the study if the participant:

Medical Conditions

1. Has hypersensitivity or other contraindication to any of the components of the study

interventions as determined by the investigator.

2. Has active HBV infection (defined as HBsAg-positive or HBV DNA positive)

3. Current or chronic history of liver disease (eg, nonalcoholic or alcoholic steatohepatitis)

or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome,

asymptomatic gallstones, or cholecystectomy), unless the participant has stable liver

function tests and no significant hepatic synthetic dysfunction.

Note: Hepatic synthetic dysfunction is defined as a serum albumin <2.8 g/dL or an INR

>1.7 in the absence of another explanation for the abnormal laboratory value.

4. Has a history of malignancy within 5 years of screening except for adequately-treated

basal cell or squamous cell skin cancer, or in situ cervical cancer.

5. Has a history or current evidence of any condition (including active tuberculosis

infection), therapy, laboratory abnormality or other circumstance (including drug or

alcohol use or dependence) that might, in the opinion of the investigator, confound the

results of the study or interfere with the participant’s participation for the full duration

of the study, such that it is not in the best interest of the participant to enroll.

Prior/Concomitant Therapy

6. Has taken cabotegravir at any time (past or current use)

7. Is currently receiving or is anticipated to require any prohibited therapies outlined in

Section 6.5 from 30 days prior to Day 1 through the duration of the study.

Prior/Concurrent Clinical Study Experience

8. Is currently participating in or has participated in an interventional clinical study with

an investigational compound or device, including HIV prevention compounds or

devices within 30 days prior to Day 1 through the duration of the study.

Diagnostic Assessments

9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed below.

Laboratory Assessment Exclusionary Values

Absolute neutrophil count ≤750 cells/mm3

Alkaline Phosphatase >3 × ULN

AST >3 × ULN

ALT >3 × ULN

Bilirubin ≥2.5 × ULN

Calculated CrCl <60 mL/mina based on the Cockcroft-Gault

equation (Appendix 9).

Hemoglobin <10.0 g/dL

Platelet count <100,000/mm3

ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; ULN=upper

limit of normal.

a Although not protocol exclusionary, sites should carefully consider the advisability of enrolling

participants with calculated CrCl between 60 to 70 mL/min, as limited changes in CrCl during study

conduct will lead to protocol-mandated product holds and may alter the risk-benefit considerations of study participation.

Other Exclusions

10. Is expecting to conceive or donate eggs at any time during the study.

Primary Outcome Measures

1. The primary efficacy objective will be assessed based on the incidence rate per year of

confirmed incident HIV-1 infections.

1. Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs and laboratory tests.

9.0 DESIGN OF THE TRIAL

If controlled