Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention of HIV Among Adolescent Males - A Sub-study of HPTN 083

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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The purpose of this study is to 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. This study will enroll healthy, HIV-uninfected adolescents assigned male at birth, including men who have sex with men (MSM), transgender women (TGW), and gender non-conforming people. The 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 may be provided the opportunity to enroll in a local open label study of CAB, if available. Participants will attend about 18 study visits throughout the study. Visits may include physical examinations, blood collection, urine collection, rectal and oral pharyngeal 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 Males - A Sub-study of HPTN 083

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Cabotegravir (CAB) tablet
* Drug: CAB LA
* Drug: Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Assigned male at birth (includes MSM, TGW, and gender non-conforming people) At enrollment, aged below 18 years At enrollment, body weight ≥ 35 kg (77 lbs.) Willing to provide informed consent for the study Self-reported sexual activity with a male in the past 12 months 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 cells/mm3 Hemoglobin ≥ 11g/dL Calculated creatinine clearance ≥ 60 mL/minute using modified Schwartz equation (≤ grade 2) Alanine aminotransferase (ALT) < 2.0 times the upper limit of normal (ULN) 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 Willing to undergo all required study procedures If currently on pre-exposure prophylaxis (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. 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 which would, in the opinion of the site investigator, would hinder 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 Surgically-placed or injected buttock implants or fillers, per self-report. Contact the CMC for guidance regarding questions about individual cases 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 the 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.

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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Male

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 may be offered the opportunity to join an open label CAB study instead, if such a study is being implemented in their area at the time. | Drug: Cabotegravir (CAB) tablet<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: Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) tablet<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 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 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 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 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 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 from the initial injection through Week 33. | 
| 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 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 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 1.5 years after study entry. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pre-Exposure Prophylaxis, PrEP