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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HIV Infections

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>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. | Drug: Cabotegravir Oral Tablet<br>* 30 mg tablet<br>* Other names: Oral cabotegravir;Drug: TDF/FTC tablets<br>* 300 mg/200 mg fixed-dose combination tablets<br>* Other names: Truvada;Drug: Placebo for TDF/FTC tablets<br> <br> * Other names: Placebo for Truvada;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>* Other names: Injectable cabotegravir;|
| Experimental: Arm B<br>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. | Drug: TDF/FTC tablets<br>* 300 mg/200 mg fixed-dose combination tablets<br>* Other names: Truvada;Drug: Placebo for cabotegravir oral tablet<br> <br> * Other names: Placebo for oral cabotegravir;Drug: Placebo for CAB LA<br>* Administered as one 3 mL IM injection in the gluteal muscle at two time points 4 weeks apart and every 8 weeks thereafter<br>* Other names: Placebo for long acting cabotegravir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Documented Incident HIV Infections During Steps 1 and 2 | All HIV infections included in this analysis have been reviewed and confirmed by an independent, blinded Endpoint Adjudication Committee (EAC). | 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. | 
| Number of Participants Experiencing Grade 2 or Higher Clinical and Laboratory Adverse Events | The primary safety endpoint analyses included Grade 2 or higher clinical and laboratory AEs during Steps 1 and 2. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Documented Incident HIV Infections in Step 2 | Evaluate incident HIV-1infections occurring only during Step 2, using the Injection Step 2 Efficacy population | 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 oror the date of DSMB decision to unblind all participants, whichever is earliest. | 
| Changes From Baseline in Creatinine and Creatinine Clearance Levels | 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. | 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) | Laboratory assessment of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBili, creatine phosphokinase (CPK), or clinical assessment of jaundice/icterus. | 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) | 
| Incidence of Resistance Mutations to Study Products (Including But Not Limited to K65R, M184V/I, Q148R) Among Seroconverters | 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. | 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 | 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. | 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 Blood Pressure From Baseline | 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. | 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 | 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. | 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 | Changes in fasting glucose levels from baseline at week 57 and week 105 based on laboratory evaluations. | Assessed at weeks 57 and 105. | 
| Changes in Fasting Lipid Profile From Baseline | Changes in fasting lipid profile from baseline at week 57 and week 105 based on laboratory evaluations. | Assessed at weeks 57 and 105. | 

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