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

Phase 2CompletedNCT04692077

National Institute of Allergy and Infectious Diseases (NIAID)9 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

HIV Infections

Interventions

Cabotegravir (CAB) tabletDRUG

30 mg tablets

CAB LADRUG

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.

Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) tabletDRUG

300 mg/200 mg fixed-dose combination tablets

Eligibility

Sex: MALEMax age: 17 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (4)

University of Colorado Denver ATN CRS

Aurora, Colorado, United States

John H. Stroger Jr. Hosp. of Cook County ATN CRS

Chicago, Illinois, United States

The Fenway Institute ATN CRS

Boston, Massachusetts, United States

St. Jude Children's Research Hosp. ATN CRS

Memphis, Tennessee, United States

Outcomes

Primary Outcomes

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.

Number and percent of participants experiencing any Grade 2 or higher clinical adverse events (AEs) or laboratory abnormalities (reported as adverse events) from the first injection visit to 8 weeks after the last Step 2 injection visit, or Week 41, whichever comes first.

Time frame: Measured through participant's first injection visit up to 8 weeks after the last Step 2 injection visit or Week 41, whichever comes first.

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.

Number and percent 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 or burden of study procedures. Reasons for intolerability may include: 1. Injection site reaction 2. Burden of study procedure 1. Participant refused further participation 2. Participant is unwilling or unable to comply with required study procedures 3. Participant refused further study product use 4. Participant unable to adhere to visit schedule

Time frame: Measured through participant's first injection visit up to 8 weeks after the last Step 2 injection visit or Week 41, whichever comes first.

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.

Definition of completing all scheduled injections for participants who are confirmed HIV positive or discontinue product due to the following reasons: * Death * Early study closure * HBV infection During Step 2: Both enrolled and injection populations: completed all injections whose target window closed prior to death/seroconversion/product discontinuation date

Time frame: Measured through participant's first injection visit up to 8 weeks after the last Step 2 injection visit or Week 41, whichever comes first.

Data from ClinicalTrials.gov

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Secondary Outcomes

Count of Participant-study Visits Above the Protein-adjusted Inhibitor Concentration (90%; PA-IC90)

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. Count of participants for injection 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.

Time frame: Measured from the participant's first injection visit up to 8 weeks after the last Step 2 injection visit or Week 41

Measure Study Product Concentrations in Enrolled Participants With HPTN Laboratory Center (LC) Confirmed HIV Infection Throughout Study.

For infections occurring prior to (or on the first day of) Step 3, we will include visit level plasma CAB concentrations, for individual seroconverters. For infections occurring after the start of Step 3, we will include visit level plasma CAB concentrations as well as concentrations of TFV and TFV-DP (if applicable).

Time frame: Measured through seroconverter's first Oral visit up through end of study participation (step1, 2, 3)

Count and Percentage of Participants Experiencing Grade 2 or Higher Clinical AEs and LaboratoryAbnormalities in the Oral Phase and the Aggregate Oral and Injection Phases

Number and percent of participants experiencing any Grade 2 or higher clinical adverse events (AEs) or laboratory abnormalities from: 1. enrollment to week 5 (oral phase (step 1), including interim visits). 2. enrollment to 8 weeks following the last injection received (aggregate over oral + injection phases (step 1-step 2) including interim visits)

Time frame: Measured through participant's first oral visit up to 8 weeks after the last Step 2 injection visit or Week 41, whichever comes first.

Proportion of Participants Receiving One or More Injections Who Experience Grade 2 or Higher Clinical AEs and Laboratory Abnormalities From Initial Injection to 36 Weeks Later.

Number and percent of participants experiencing any Grade 2 or higher clinical adverse events (AEs) or laboratory abnormalities from the first injection visit to approximately 36 weeks later regardless of whether participants received all 5 injections.

Time frame: Measured through participant's first injection visit up to 8 weeks after the last Step 2 injection visit or Week 41, whichever comes first.

Proportion of Injection Visits That Occurred "On-time".

Number and percentage of injections given, using the number of injections expected as the denominator. while the number and percent of injection visits (up to 5 per participant) that occur "on-time", using the number of injections given as the denominator. This will be presented along with the total number and percent of injections given, among all intended injections (i.e. 5 injections per participant). Those who have been terminated, are HIV infected, or have permanently discontinued study products at the time of visit will be excluded from the number of expected injections.

Time frame: Measured through participant's last step 2 injection.

Change From Enrollment of Self-reported Sexual Behavior (Number of Sexual Partners) During the Study Period

Counts of sexual partners will be summarized (mean and sd) at enrollment and each regular Step 1 and Step 2 follow-up visit (W4, W5, W9, W17, W25, W33).

Time frame: Measured through participant's first oral visit up to last Step 2 injection visit.

Change From Enrollment of Self-reported Sexual Behavior (Number of Episodes of Anal Intercourse Without a Condom) During the Study Period

Counts of episodes of anal intercourse without a condom will be summarized (mean and sd) at enrollment and each regular Step 1 and Step 2 follow-up visit (W4, W5, W9, W17, W25, W33).

Time frame: Measured through participant's first oral visit up to the last Step 2 injection visit.

Evaluate Rates of HIV Drug Resistance Among Participants Who Acquire HIV Infection During the Study

Data from steps 1, 2, and 3 will be included. The number of cases of drug resistance will be summarized. All cases of drug resistance among incident HIV infections will be described.

Time frame: Measured through participant's last study visit, up to approximately 1.5 years after study entry.