A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine For Pre-Exposure Prophylaxis in HIV-Uninfected Men and Transgender Women Who Have Sex With Men
Overview
- Phase
- Phase 2
- Intervention
- Cabotegravir Oral Tablet
- Conditions
- HIV Infections
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 4570
- Locations
- 82
- Primary Endpoint
- Number of Participants With Documented Incident HIV Infections During Steps 1 and 2
- Status
- Completed
- Last Updated
- last month
Overview
Brief Summary
This study will evaluate the safety and efficacy of the injectable drug cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender women who have sex with men (MSM and TGW).
Detailed Description
The purpose of this study is to evaluate the safety and efficacy of the injectable drug cabotegravir (CAB LA), for pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender women who have sex with men (MSM and TGW). This study will enroll HIV-uninfected MSM and TGW at risk for acquiring HIV infection. Participants will be followed for a total of 4 years. 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 tablets and daily oral TDF/FTC placebo tablets for 5 weeks. Step 2: Participants will receive an intramuscular (IM) injection of CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and daily oral TDF/FTC placebo tablets to Week 153. Arm B: Step 1: Participants will receive daily oral TDF/FTC tablets and daily oral CAB placebo tablets for 5 weeks. Step 2: Participants will receive daily oral TDF/FTC tablets and an IM injection of placebo at two time points 4 weeks apart and every 8 weeks thereafter to Week 153. In Step 3, all participants (Arms A and B) will receive daily oral TDF/FTC tablets starting at Week 153 (last day of Step 2)/Day 0 (first day of Step 3) and continue for 48 weeks. Participants will attend up to 47 study visits throughout the study. Visits may include physical examinations, blood collection, urine collection, an electrocardiogram (ECG), and rectal swab collection. Some participants may have a bone mineral density-energy x-ray absorptimetry (DXA) scan at select visits. All participants will be transitioned to locally available HIV prevention services, including services for PrEP, if available, at the end of their participation in the study. HPTN 083-01 is a sub-study of HPTN 083. The purpose of this study is to evaluate the safety, tolerability, and acceptability of CAB LA for the prevention of HIV among adolescent males. Participants will receive oral CAB for 5 weeks, followed by 29 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. HPTN 083-02 is a qualitative sub-study of participants enrolled in HPTN 083. The purpose of this study is to explore potential barriers, facilitators, and potentially modifiable issues related to adherence to clinic visits in the context of injectable PrEP; to learn about preferences and decision making regarding the use of oral versus injectable PrEP, or other biomedical prevention products; and to gather explanatory qualitative data regarding participants' experiences in HPTN 083 to better interpret study results and guide next prevention strategies. Participants in this sub-study will complete one individual semi-structured qualitative interview.
Investigators
Eligibility Criteria
Inclusion Criteria
- •MSM and TGW, 18 years or older at the time of screening (male at birth)
- •Willing to provide informed consent for the study
- •At high risk for sexually acquiring HIV infection based on self-report of at least one of the following:
- •Any condomless receptive anal intercourse in the 6 months prior to enrollment (condomless anal intercourse within a monogamous HIV seronegative concordant relationship does not meet this criterion)
- •More than five partners in the 6 months prior to enrollment (regardless of condom use and HIV serostatus, as reported by the enrollee)
- •Any stimulant drug use in the 6 months prior to enrollment
- •Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months prior to enrollment
- •SexPro score of less than or equal to 16 (U.S. sites only)
- •In general good health, as evidenced by the following laboratory values, which must be from specimens obtained within 45 days prior to study enrollment:
- •Non-reactive / negative HIV test results. More information on this criterion can be found in the protocol.
Exclusion Criteria
- •One or more reactive or positive HIV test result at Screening or Enrollment, even if HIV infection is not confirmed
- •Active or recent use of any illicit intravenous drugs ("recent" defined as in the 90 days prior to enrollment)
- •Co-enrollment in any other interventional research study or other concurrent studies that may interfere with this study (as provided by self-report or other available documentation. Exceptions may be made if appropriate after consultation with the CMC.)
- •Past or current participation in HIV vaccine trial. An exception will be made for participants that can provide documentation of receipt of placebo (not active arm). Note: Past participation in a monoclonal antibody study is not exclusionary, effective as of Version 1.0 of HPTN
- •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, per the discretion of the Investigator of Record. Mild skin conditions may not be exclusionary at the discretion of the Investigator of Record (IoR) or designee in consultation with the CMC
- •Has a tattoo or other dermatological condition overlying the buttock region which in the opinion of the IoR or designee, in consultation with the CMC, 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)
- •Coagulopathy (primary or iatrogenic) which would contraindicate IM injection (concomitant anticoagulant or anti-platelet therapy use should be discussed with the CMC)
- •Active or planned use of prohibited medications as described in the Investigator's Brochure or listed in the Study Specific Procedures (SSP) Manual (provided by self-report, or obtained from medical history or medical records). In particular, future use of TDF/FTC at any point during the study.
Arms & Interventions
Arm A
In Step 1, participants will receive daily oral CAB and daily oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive CAB LA and daily oral TDF/FTC placebo to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: Cabotegravir Oral Tablet
Arm A
In Step 1, participants will receive daily oral CAB and daily oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive CAB LA and daily oral TDF/FTC placebo to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: TDF/FTC tablets
Arm A
In Step 1, participants will receive daily oral CAB and daily oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive CAB LA and daily oral TDF/FTC placebo to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: Placebo for TDF/FTC tablets
Arm A
In Step 1, participants will receive daily oral CAB and daily oral TDF/FTC placebo for 5 weeks. In Step 2, participants will receive CAB LA and daily oral TDF/FTC placebo to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: CAB LA
Arm B
In Step 1, participants will receive daily oral TDF/FTC and daily oral CAB placebo for 5 weeks. In Step 2, participants will receive daily oral TDF/FTC and placebo for CAB LA to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: TDF/FTC tablets
Arm B
In Step 1, participants will receive daily oral TDF/FTC and daily oral CAB placebo for 5 weeks. In Step 2, participants will receive daily oral TDF/FTC and placebo for CAB LA to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: Placebo for cabotegravir oral tablet
Arm B
In Step 1, participants will receive daily oral TDF/FTC and daily oral CAB placebo for 5 weeks. In Step 2, participants will receive daily oral TDF/FTC and placebo for CAB LA to Week 153. In Step 3, participants will receive daily oral TDF/FTC starting at Week 153 and for 48 weeks.
Intervention: Placebo for CAB LA
Outcomes
Primary Outcomes
Number of Participants With Documented Incident HIV Infections During Steps 1 and 2
Time Frame: HIV tests at enrollment, weeks 2, 4, 5, every injection visit (every 8 weeks) and every safety visit (2 weeks after each injection visit). Analyzed through week 153 or the date of DSMB decision to unblind all participants, whichever is earliest.
All HIV infections included in this analysis have been reviewed and confirmed by an independent, blinded Endpoint Adjudication Committee (EAC).
Number of Participants Experiencing Grade 2 or Higher Clinical and Laboratory Adverse Events
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).
The primary safety endpoint analyses included Grade 2 or higher clinical and laboratory AEs during Steps 1 and 2.
Secondary Outcomes
- Incidence of Resistance Mutations to Study Products (Including But Not Limited to K65R, M184V/I, Q148R) Among Seroconverters(Measured from date of detection of infection, up to 4 years after study entry, with timing/intervals as determined by the HPTN laboratory center)
- Changes in Weight From Baseline(Reported through the week 153 injection, or the date of DSMB decision to unblind all participants, whichever is earliest. Collected at each injection visit (every 8 weeks).)
- Changes in Systolic Blood Pressure From Baseline(Reported through the week 153 injection, or the date of DSMB decision to unblind all participants, whichever is earliest. Assessed at each injection visit (every 8 weeks).)
- Changes in Diastolic Blood Pressure From Baseline(Reported through the week 153 injection, or the date of DSMB decision to unblind all participants, whichever is earliest. Assessed at each injection visit (every 8 weeks).)
- Changes in Pulse Rate From Baseline(Reported through the week 153 injection, or the date of DSMB decision to unblind all participants, whichever is earliest. Assessed at each injection visit (every 8 weeks).)
- Changes in Fasting Glucose Levels From Baseline(Assessed at weeks 57 and 105.)
- Changes in Fasting Lipid Profile From Baseline(Assessed at weeks 57 and 105.)
- Number of Participants With Documented Incident HIV Infections in Step 2(HIV tests at enrollment, weeks 2, 4, 5, every injection visit (every 8 weeks) and every safety visit (2 weeks after each injection visit). Analyzed through week 153 or the date of DSMB decision to unblind all participants, whichever is earliest.)
- Changes From Baseline in Creatinine and Creatinine Clearance Levels(Reported week 57 (injection visit #8) and week 105 (injection visit #14))
- Number of Participants With Grade 3 or 4 Liver-related Adverse Events (AEs)(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 first. Assessed at each visit. (Injection visits q 8 weeks and safety visits q 8 weeks))
- Summary of Overall Satisfaction With Study Product(Assessed at Week 17, 41)
- Summary of Preference Based on Satisfaction With Study Product(Assessed at week 17, 41)
- Change From Baseline of Mean Z-scores of Bone Mineral Density(Measured at enrollment, week 57 and week 105)