HIV Infections
Conditions
Brief summary
This study will evaluate the safety and efficacy of the long-acting injectable agent cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in HIV-uninfected women.
Detailed description
The purpose of this study is to evaluate the safety and efficacy of the long-acting injectable integrase inhibitor cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) in a population of sexually active HIV-uninfected women at risk for HIV. 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 and TDF/FTC placebo for 5 weeks. Step 2: Participants will receive injections of CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and daily TDF/FTC placebo beginning at Week 5. Arm B: Step 1: Participants will receive daily TDF/FTC and oral CAB placebo for 5 weeks. Step 2: Participants will receive daily TDF/FTC and intramuscular (IM) placebo injections at two time points 4 weeks apart and every 8 weeks thereafter beginning at Week 5. Step 2 will continue until the last enrolled participant reaches approximately 76 weeks on Step 2 (Week 81 for the last enrolled participant). In Step 3, all participants (Arms A and B) will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection. At the end of Step 3, all participants will then transition to locally available HIV prevention services, including services for PrEP, if available. Study visits will occur at Day 0 and at Weeks 2 and 4 during Step 1. During Step 2, participants will attend up to 24 visits, depending on when they enroll in the study. Study visits will occur every 12 weeks during Step 3. Study visits may include physical examinations; blood, urine, and vaginal swab collection; risk reduction, adherence counseling, and contraception counseling. HPTN 084-01 is a sub-study of HPTN 084. The purpose of this study is to examine the safety, tolerability, and acceptability of CAB LA for the prevention of HIV among adolescent females. Participants will receive oral CAB for 5 weeks, followed by 34 weeks on CAB LA, then quarterly visits for 48 weeks after final injection. All participants who have received at least one injection will be followed for 48 weeks after their last injection. Total study duration per participant will be approximately 21 months.
Interventions
DRUGOral CAB
CAB 30 mg tablet
DRUGOral TDF/FTC
TDF/FTC 300 mg/200 mg fixed dose combination tablet
DRUGPlacebo for oral CAB
Placebo tablets
DRUGPlacebo for oral TDF/FTC
Placebo tablets
DRUGCAB LA
600 mg administered as one 3 mL (600 mg) intramuscular injection in the gluteal muscle
Administered as one 3 mL intramuscular injection in the gluteal muscle
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Born female * 18-45 years at the time of screening * Willing and able to provide informed consent * Willing and able to undergo all required study procedures * Non-reactive HIV test results at Screening and Enrollment. Note: HIV-uninfected, based on HIV test results obtained at Screening and just prior to randomization at the Enrollment visit. All HIV test results from the Screening visit must be obtained and must all be negative/non-reactive. This includes testing for acute HIV infection, which must be performed within 14 days of Enrollment. In addition, at least one HIV test result using blood drawn at the Enrollment visit must be obtained prior to randomization into the study and must be negative/non-reactive. Individuals who have one or more reactive or positive HIV test result(s) will not be enrolled, even if subsequent confirmatory testing indicates that they are not HIV-infected (see SSP Manual). Those with any enrollment HIV test result positive will proceed through the HIV algorithm per the SSP but will not be able to receive study product regardless of subsequent test results. * Sexually active (i.e., vaginal intercourse on a minimum of two separate days in the 30 days prior to Screening) * Score of greater than or equal to 5 using a modified VOICE risk score * No plans to re-locate or travel away from the site for greater than or equal to 8 consecutive weeks during study participation * Creatinine clearance of greater than or equal to 60 mL/min (using 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 * Hepatitis B virus (HBV) surface antigen (HBsAg) negative and accepts vaccination * Alanine aminotransferase (ALT) less than 2 x upper limit of normal (ULN) and total bilirubin (Tbili) less than or equal to 2.5 x ULN * HCV antibody negative * If of reproductive potential (defined as pre-menopausal women who have not had a sterilization procedure per self-report, such as hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy), must have a negative beta human chorionic gonadotropin (βHCG) pregnancy test (sensitivity of less than or equal to 25 mIU/mL) performed (and results known) on the same day as and before initiating the protocol-specified study product(s) at Enrollment. * Have documented evidence of surgical sterilization, OR documented evidence of no uterus (e.g., hysterectomy), OR must agree to use a reliable form of long acting contraception, during the trial and for 52 weeks after stopping the long acting injectable, or 30 days after stopping oral study product, from the list below: * Intrauterine device (IUD) or intrauterine system (IUS) that meets less than 1% failure rate as stated in the product label * Hormone-based contraceptive that meets less than 1% failure rate when used consistently and correctly as stated in the product label (implants or injectables only; this excludes combined oral contraception) * 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) * No alcohol or substance use 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)
Exclusion criteria
* One or more reactive HIV test results at Screening or Enrollment, even if HIV infection is not confirmed * Pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed during the study * Co-enrollment in any other HIV interventional research study (provided by self-report or other available documentation), with one exception: IMPAACT 2026 (co-enrollment in IMPAACT 2026 is permitted for participants who become pregnant) * Current or past enrollment in an HIV vaccine or broadly neutralizing antibody trial * 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) * History of seizure disorder, per self-report * 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 IM injections, per the discretion of the Investigator of Record (IoR). Mild skin conditions may not be exclusionary at the discretion of the IoR or designee * Has a tattoo or other dermatological condition overlying the buttock region which in the opinion of the IoR or designee may interfere with interpretation of injection site reactions (ISRs) * Coagulopathy (primary or iatrogenic) which would contraindicate IM injection * Active or planned use of prohibited medications as described in the Investigator Brochure (IB) or listed in the Study Specific Procedures Manual (SSP) (provided by self-report, or obtained from medical history or medical records) * Known or suspected allergy to study product components (active or placebo), including egg or soy products (egg and soy products are contained in Intralipid) * If potentially able to conceive, unwilling to adhere to long acting contraception (IUD/IUS, injection, or implant) with a less than 1% failure rate when used consistently and correctly as stated in the product package insert/ manufacturer's guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pariicipants With Documented Incident HIV Infections | HIV tests at enrollment, weeks 2, 4, and 5, then every 4 weeks through week 25, then every 8 weeks. Analyzed through week 185 or the date of DSMB decision to unblind all participants, whichever is earliest. | The number of participants with an incident HIV infection that is confirmed by the HPTN Laboratory Center and Endpoint Adjudication Committee. |
| Number of Participants Who Experienced Grade 2 or Higher Clinical and Laboratory Adverse Events (AEs) in Steps 1 and 2 | Treatment emergent AE measured with onset date through participant's last study visit, or the date of DSMB decision to unblind all participants, whichever is earliest. Assessed at each visit (injections visits q 8 weeks and safety visits q 8 weeks) | AEs will be summarized using MedDRA System Organ Class and preferred terms. |
Countries
Botswana, Eswatini, Kenya, Malawi, South Africa, Uganda, Zimbabwe
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: CAB + Placebo TDF/FTC + CAB LA During Step 1, participants will receive daily oral CAB and oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive injections of CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and daily oral TDF/FTC placebo beginning at Week 5. In Step 3, participants will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection.
Oral CAB: CAB 30 mg tablet
Oral TDF/FTC: TDF/FTC 300 mg/200 mg fixed dose combination tablet
Placebo for oral TDF/FTC: Placebo tablets
CAB LA: 600 mg administered as one 3 mL (600 mg) intramuscular injection in the gluteal muscle | 1,614 |
| Arm B: TDF/FTC + Placebo CAB + Placebo CAB LA During Step 1, participants will receive daily TDF/FTC and oral CAB placebo for 5 weeks. In Step 2, participants will receive daily TDF/FTC and placebo for CAB LA injections at two times points 4 weeks apart and every 8 weeks thereafter beginning at Week 5. In Step 3, participants will receive daily TDF/FTC for up to 48 weeks, starting no later than 8 weeks after the last injection.
Oral TDF/FTC: TDF/FTC 300 mg/200 mg fixed dose combination tablet
Placebo for oral CAB: Placebo tablets
Placebo for CAB LA: Administered as one 3 mL intramuscular injection in the gluteal muscle | 1,610 |
| Total | 3,224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Ongoing | 1,586 | 1,586 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 15 |
Baseline characteristics
| Characteristic | Arm A: CAB + Placebo TDF/FTC + CAB LA | Arm B: TDF/FTC + Placebo CAB + Placebo CAB LA | Total |
|---|---|---|---|
| Age, Continuous | 25.0 years | 25.0 years | 25.0 years |
| Age, Customized <25 | 800 Participants | 794 Participants | 1594 Participants |
| Age, Customized >=25 | 814 Participants | 816 Participants | 1630 Participants |
| Country Botswana | 46 Participants | 45 Participants | 91 Participants |
| Country Kenya | 31 Participants | 35 Participants | 66 Participants |
| Country Malawi | 113 Participants | 111 Participants | 224 Participants |
| Country South Africa | 653 Participants | 655 Participants | 1308 Participants |
| Country Swaziland | 80 Participants | 80 Participants | 160 Participants |
| Country Uganda | 300 Participants | 296 Participants | 596 Participants |
| Country Zimbabwe | 391 Participants | 388 Participants | 779 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1614 Participants | 1610 Participants | 3224 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 2 Participants | 3 Participants | 5 Participants |
| Race Black or African American | 1612 Participants | 1606 Participants | 3218 Participants |
| Race Mixed Race | 0 Participants | 0 Participants | 0 Participants |
| Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race White | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 1614 Participants | 1610 Participants | 3224 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 1,614 | 0 / 1,610 |
| other Total, other adverse events | 1,486 / 1,614 | 1,486 / 1,610 |
| serious Total, serious adverse events | 33 / 1,614 | 33 / 1,610 |
Outcome results
Primary
Number of Pariicipants With Documented Incident HIV Infections
The number of participants with an incident HIV infection that is confirmed by the HPTN Laboratory Center and Endpoint Adjudication Committee.
Time frame: HIV tests at enrollment, weeks 2, 4, and 5, then every 4 weeks through week 25, then every 8 weeks. Analyzed through week 185 or the date of DSMB decision to unblind all participants, whichever is earliest.
Population: All enrolled participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: CAB + Placebo TDF/FTC + CAB LA | Number of Pariicipants With Documented Incident HIV Infections | 4 Participants |
| Arm B: TDF/FTC + Placebo CAB + Placebo CAB LA | Number of Pariicipants With Documented Incident HIV Infections | 36 Participants |
Primary
Number of Participants Who Experienced Grade 2 or Higher Clinical and Laboratory Adverse Events (AEs) in Steps 1 and 2
AEs will be summarized using MedDRA System Organ Class and preferred terms.
Time frame: Treatment emergent AE measured with onset date through participant's last study visit, or the date of DSMB decision to unblind all participants, whichever is earliest. Assessed at each visit (injections visits q 8 weeks and safety visits q 8 weeks)
Population: All enrolled participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: CAB + Placebo TDF/FTC + CAB LA | Number of Participants Who Experienced Grade 2 or Higher Clinical and Laboratory Adverse Events (AEs) in Steps 1 and 2 | 1487 Participants |
| Arm B: TDF/FTC + Placebo CAB + Placebo CAB LA | Number of Participants Who Experienced Grade 2 or Higher Clinical and Laboratory Adverse Events (AEs) in Steps 1 and 2 | 1486 Participants |