Injectable Cabotegravir Compared to TDF/FTC For PrEP in HIV-Uninfected Men and Transgender Women Who Have Sex With Men

Phase 2

Active, not recruiting

Conditions: HIV Infections

Interventions: Drug: Cabotegravir Oral Tablet
Drug: TDF/FTC tablets
Drug: Placebo for cabotegravir oral tablet
Drug: Placebo for CAB LA
Drug: Placebo for TDF/FTC tablets
Drug: CAB LA

Registration Number: NCT02720094

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 4570

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.
- Hemoglobin greater than 11 g/dL,
- Absolute neutrophil count greater than 750 cells/mm^3
- Platelet count greater than or equal to 100,000/mm^3
- Calculated creatinine clearance greater than or equal to 60 mL/minute using the 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
- Alanine aminotransferase (ALT) less than 2 times the upper limit of normal (ULN)
- Total bilirubin less than or equal to 2.5 times ULN
- Hepatitis B virus (HBV) surface antigen (HBsAg) negative
- Hepatitis C virus (HCV) Ab negative
- No Grade 3 or higher laboratory abnormalities on any laboratory tests obtained at screening, including tests obtained as part of a panel of tests ordered to obtain the protocol-required laboratory test results.
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)
Willing to undergo all required study procedures

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 083.
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.
Known or suspected allergy to study product components (active or placebo), including egg or soy products (egg and soy products are contained in Intralipid)
Surgically-placed or injected buttock implants or fillers, per self-report. Contact the CMC for guidance regarding questions about individual cases.
Alcohol or substance use that, in the opinion of the study investigator, would jeopardize the safety of the participant on study (e.g., provided by self-report, or found upon medical history and examination or in available medical records).
History of seizure disorder, per self-report
QTc interval (B or F) greater than 500 msec

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	Cabotegravir Oral Tablet	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.
Arm A	CAB LA	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.
Arm B	Placebo for cabotegravir oral tablet	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.
Arm B	Placebo for CAB LA	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.
Arm B	TDF/FTC tablets	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.
Arm A	TDF/FTC tablets	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.
Arm A	Placebo for TDF/FTC tablets	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Documented Incident HIV Infections During Steps 1 and 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.	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	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 Outcome Measures

Name	Time	Method
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.	Evaluate incident HIV-1infections occurring only during Step 2, using the Injection Step 2 Efficacy population
Changes From Baseline in Creatinine and Creatinine Clearance Levels	Reported week 57 (injection visit #8) and week 105 (injection visit #14)	Change from baseline at each visit is the difference between the creatine (and creatinine clearance) value as measured on the date of visit, compared to the value as measured at the enrollment visit.
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)	Laboratory assessment of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBili, creatine phosphokinase (CPK), or clinical assessment of jaundice/icterus.
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	Frequency of the detection of specific viral mutations known to confer resistance to specific classes of antiviral drugs as identified in specimens collected from infected participants during follow-up after HIV infection.
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).	Change in weight from baseline is the difference between the weight (kg) as collected at each study visit and the weight collected at the enrollment visit.
Changes in 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).	Change in blood pressure from baseline is the difference between the blood pressure as collected at each study visit and the blood pressure collected at the enrollment visit. Reported in separate tables for systole and diastole.
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).	Change in pulse rate from baseline is the difference between the pulse rate as collected at each study visit and the pulse rate collected at the enrollment visit.
Changes in Fasting Glucose Levels From Baseline	Assessed at weeks 57 and 105.	Changes in fasting glucose levels from baseline at week 57 and week 105 based on laboratory evaluations.
Changes in Fasting Lipid Profile From Baseline	Assessed at weeks 57 and 105.	Changes in fasting lipid profile from baseline at week 57 and week 105 based on laboratory evaluations.

Trial Locations

Locations (43): San Miguel CRS
🇵🇪
Lima, Peru
Penn Prevention CRS
🇺🇸
Philadelphia, Pennsylvania, United States
Fenway Health (FH) CRS
🇺🇸
Boston, Massachusetts, United States
Ohio State University CRS
🇺🇸
Columbus, Ohio, United States
Houston AIDS Research Team CRS
🇺🇸
Houston, Texas, United States
UCLA Vine Street Clinic CRS
🇺🇸
Los Angeles, California, United States
UCLA CARE Center CRS
🇺🇸
Los Angeles, California, United States
East Bay AIDS Center (EBAC) CRS
🇺🇸
Oakland, California, United States
The Ponce de Leon Center CRS
🇺🇸
Atlanta, Georgia, United States
The Hope Clinic of the Emory Vaccine Center CRS
🇺🇸
Decatur, Georgia, United States
Adolescent & Young Adult Research at The CORE Center (AYAR at CORE)
🇺🇸
Chicago, Illinois, United States
UIC Project WISH CRS
🇺🇸
Chicago, Illinois, United States
Johns Hopkins University CRS
🇺🇸
Baltimore, Maryland, United States
Washington University Therapeutics (WT) CRS
🇺🇸
Saint Louis, Missouri, United States
New Jersey Medical School Clinical Research Center CRS
🇺🇸
Newark, New Jersey, United States
Bronx Prevention Research Center CRS
🇺🇸
Bronx, New York, United States
Weill Cornell Chelsea CRS
🇺🇸
New York, New York, United States
Greensboro CRS
🇺🇸
Greensboro, North Carolina, United States
Harlem Prevention Center CRS
🇺🇸
New York, New York, United States
New York Blood Center CRS
🇺🇸
New York, New York, United States
Fundacion Huesped CRS
🇦🇷
Buenos Aires, Argentina
Centro de Referencia e Treinamento DST/AIDS CRS
🇧🇷
São Paulo, Sao Paulo, Brazil
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
🇧🇷
Rio de Janeiro, Brazil
Centro de Pesquisas Clínicas IC-HCFMUSP CRS
🇧🇷
Sao Paulo, Brazil
Groote Schuur HIV CRS
🇿🇦
Cape Town, Western Cape Province, South Africa
Bridge HIV CRS
🇺🇸
San Francisco, California, United States
Cincinnati Clinical Research Site
🇺🇸
Cincinnati, Ohio, United States
Hospital Nossa Senhora da Conceicao CRS
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
🇹🇭
Pathum Wan, Bangkok, Thailand
George Washington Univ. CRS
🇺🇸
Washington, District of Columbia, United States
Via Libre CRS
🇵🇪
Lima, Peru
Hospital General de Agudos JM Ramos Mejía CRS
🇦🇷
Ciudad de Buenos Aires, Buenos Aires, Argentina
ACSA CRS
🇵🇪
Iquitos, Maynas, Peru
Yen Hoa Health Clinic CRS
🇻🇳
Hanoi, Vietnam
Barranco CRS
🇵🇪
Lima, Peru
Silom Community Clinic CRS
🇹🇭
Bangkok, Nonthaburi, Thailand
CMU HIV Prevention CRS
🇹🇭
Chiang Mai, Thailand
St. Jude Children's Research Hospital CRS
🇺🇸
Memphis, Tennessee, United States
CITBM - UNIDEC, Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales CRS
🇵🇪
Bellavista, Callao, Peru
Alabama CRS
🇺🇸
Birmingham, Alabama, United States
Children's Hospital Colorado CRS
🇺🇸
Aurora, Colorado, United States
New Orleans Adolescent Trials Unit CRS
🇺🇸
New Orleans, Louisiana, United States
Chapel Hill CRS
🇺🇸
Chapel Hill, North Carolina, United States

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