Evaluating the Safety and Efficacy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: Oral CAB; Oral TDF/FTC; Placebo for oral CAB; Placebo for oral TDF/FTC; CAB LA; Placebo for CAB LA
Intervention description: CAB 30 mg tablet; TDF/FTC 300 mg/200 mg fixed dose combination tablet; Placebo tablets; Placebo tablets; 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
Intervention MeSH terms: Tenofovir; Emtricitabine; Cabotegravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3224.0
Sex: Female
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

Eligibility criteria:

        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