Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention of HIV Among Adolescent Females - A Sub-study of HPTN 084

Study Overview
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Brief Summary
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This study will establish the minimum safety, tolerability and acceptability data needed to support the use of cabotegravir long-acting injection (CAB LA) in an adolescent population, potentially transforming the field of HIV prevention for young people.

Detailed Description
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This study will enroll sexually-active, healthy, HIV-uninfected adolescents assigned female sex at birth. Total participant commitment for the entire study is approximately 1.5 years. This study will take place in three steps. In Step 1, participants will receive daily oral CAB tablets for 5 weeks. In Step 2, participants will receive a series of five intramuscular (IM) injections of CAB LA, administered at 8-week intervals after a 4-week loading dose (injections at Weeks 5, 9, 17, 25 & 33). A safety visit will follow each injection to ascertain safety data, including injection site reactions. In Step 3, all participants who have received at least one injection will be followed quarterly (every 3 months) for 48 weeks after their last injection. Participants will receive oral TDF/FTC for daily use for 48 weeks or join and open-label extension CAB study in their area, if available. Participants will attend about 18 study visits throughout the study. Visits may include physical examinations, blood collection, urine collection, vaginal swab collection, risk reduction and adherence counseling, and behavioral or acceptability assessments.

Official Title
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Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention of HIV Among Adolescent Females - A Sub-study of HPTN 084

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Oral cabotegravir (CAB)
* Drug: CAB LA
* Drug: Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Assigned female at birth At enrollment, below 18 years of age At enrollment, body weight ≥ 35 kg (77 lbs.) Willing and able to provide informed assent/consent for the study and/or able to obtain written parental/guardian informed consent Self-reported sexual activity with a male (oral, anal or vaginal) in the past 12 months Willing and able to undergo all study procedures In general, good health, as evidenced by the following laboratory values: Non-reactive / negative HIV test results**, Absolute neutrophil count > 799 cells/mm3, Platelet count ≥ 100,000/mm3, Hemoglobin ≥ 11g/dL, Calculated creatinine clearance ≥ 60 mL/minute using the modified Schwartz equation, Alanine aminotransferase (ALT) < 2.0 times the upper limit of normal (ULN) (≤ grade 1) and total bilirubin (Tbili) ≤ 2.5 x ULN, Hepatitis B virus (HBV) surface antigen (HBsAg) negative) and accepts vaccination, Hepatitis C virus (HCV) Antibody negative Must have a negative beta human chorionic gonadotropin (βHCG) pregnancy test (sensitivity of ≤ 25 mIU/mL) performed (and results known) on the same day as Enrollment and before initiating study product Must agree to use a reliable form of long acting contraception, during the trial and for 48 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 <1% failure rate as stated in the product label Hormone-based contraceptive that meets <1% failure rate when used consistently and correctly as stated in the product label (implants or injectables only; this excludes combined oral contraception) If currently on PrEP from a non-study source, willing to stop said PrEP prior to enrollment and agree to switch to oral CAB for the lead-in period and CAB LA injections. HIV-uninfected, based on HIV test results obtained at Screening and 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. 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). Exclusion Criteria: Co-enrollment in any other HIV interventional research study or other concurrent studies which may interfere with this study (as provided by self-report or other available documentation) Past or current participation in HIV vaccine trial with exception for participants who can provide documentation of receipt of placebo Exclusively had sex with biological females in lifetime In the last 6 months (at the time of screening): active or planned use of any substance use which would, in the opinion of the site investigator, interfere with study participation (including herbal remedies), as described in the Investigator's Brochure (IB) or listed in the Study Specific Procedures (SSP), and/ or Protocol Section 4.4, Known history of 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 Tattoo or other dermatological condition overlying the buttock region that 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) Known history of clinically significant bleeding A history of seizure disorder, per self-report Medical, social or other condition that, in the opinion of the site investigator, would interfere with the conduct of the study or safety of the participant (e.g., provided by self-report, or found upon medical history and examination or in available medical records) Plans to move out of the geographic area within the next 18 months or otherwise unable to participate in study visits, according to the site investigator Pregnant or currently breastfeeding at the time of screening or intends to become pregnant and/or breastfeed while on study

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAB LA<br>In Step 1, participants will receive one CAB tablet orally every day for 5 weeks. In Step 2, participants will receive an intramuscular (IM) injection of CAB LA at Weeks 5, 9, 17, 25, and 33. In Step 3, participants will receive a TDF/FTC tablet orally every day for 48 weeks or join an open-label extension CAB study in their area, if available. | Drug: Oral cabotegravir (CAB)<br>* 30 mg tablets<br>Drug: CAB LA<br>* Administered as one 3 mL (600 mg) IM injection in the gluteal muscle at two time points 4 weeks apart and every 8 weeks thereafter<br>Drug: Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)<br>* 300 mg/200 mg fixed-dose combination tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint: Proportion of participants experiencing any Grade 2 or higher clinical adverse events (AEs) and laboratory abnormalities among participants who receive at least one injection of CAB LA. |  | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Tolerability endpoint: Proportion of participants who receive at least 1 injection and who discontinue receiving injections prior to the full course of injections due to intolerability of injection, frequency of injections or burden of study procedures. |  | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Acceptability endpoint: Proportion of participants who complete all scheduled injections and proportion of participants who receive at least one injection whom would consider using CAB LA for HIV prevention in the future. |  | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma CAB Drug Measurements | CAB drug concentrations will be measured in plasma to generate CAB-LA concentration-time profiles among study participants. Measurements will occur at study visits during the injection phase of the study as well as during the pharmacologic tail phase. | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Proportion of participant-study visits above the protein-adjusted inhibitor concentration (90%; PA-IC90) | CAB drug concentrations will be measured throughout the study, to determine the proportion of visits in which a participant remains above the 1x (0.166 mcg/mL), 4x (0.664 mcg/mL) and 8x (1.33 mcg/mL) PA-IC90. Concentrations above the 3 PA-IC90 are associated with rectal protection in a non-human primate study, and concentrations above the 8x PA-IC90 are expected to be associated with protection in humans. | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Measurement of pharmacokinetic parameters, mean and median drug concentrations at each injection visit. | CAB drug concentrations will be measured throughout the study, and the study team will characterize variability in concentrations at each visit by determining mean and median concentrations, as well as associated deviations and %CVs. | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Terminal half-life estimates for CAB-LA. | CAB drug concentrations will be measured during the tail phase of the study, up to one year after a participant's last injection visit. This will allow the study team to estimate the terminal half-life of CAB-LA. | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| Characterize CAB drug concentrations in individuals who acquire HIV. | CAB drug measurements will be conducted in all participants, including those who acquire HIV; these data will be used to determine the CAB drug concentration at the first HIV positive visit, and serve as a possible explanatory variable in potential HIV acquisition. Drug concentrations will be evaluated within the context of CAB's PA-IC90. | Measured through participant's last study visit, up to approximately 1.5 years after study entry. | 
| TFV and TFV-DP may be measured to evaluate oral PrEP use (F/TDF, F/TAF) in cases of incident infection after cessation of study product |  | Measured through participant's last study visit, up to approximately 1.5 years after study entry. |