Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical study is to test how well the study drug, lenacapavir (LEN), works in preventing the risk of HIV.

Official Title
-----------------
A Phase 3, Double-Blind, Multicenter, Randomized Study to Evaluate the Efficacy and Safety of Subcutaneous Twice Yearly Long-Acting Lenacapavir for HIV Pre-Exposure Prophylaxis in Cisgender Men, Transgender Women, Transgender Men, and Gender Nonbinary People ≥ 16 Years of Age Who Have Sex With Male Partners and Are at Risk for HIV Infection

Conditions
-----------------
Pre-Exposure Prophylaxis of HIV Infection

Intervention / Treatment
-----------------
* Drug: Oral Lenacapavir (LEN)
* Drug: F/TDF
* Drug: Sub-cutaneous (SC) Lenacapavir (LEN)
* Drug: Placebo SC LEN
* Drug: PTM F/TDF
* Drug: PTM Oral LEN
* Drug: F/TAF (for US participants only)


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Incidence Phase CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV infection. HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months. Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the last 12 months and 1 of the following: Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks. History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks. Self-reported use of stimulants with sex in the last 12 weeks. Randomized Phase Negative local rapid fourth generation HIV-1/2 Ab/Ag, central fourth generation HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification testing (NAAT). Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at screening according to the Cockcroft-Gault formula for creatinine clearance (CLcr). Key Exclusion Criteria: Incidence Phase Prior use of HIV PrEP (including F/TDF or F/TAF) or HIV postexposure prophylaxis (PEP) in the past 12 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or islatravir). Prior recipient of an HIV vaccine or HIV broadly neutralizing antibody formulation. Randomized Phase Acute viral hepatitis A, B or C or evidence of chronic hepatitis B or C infection. Severe hepatic impairment or a history of or current clinical decompensated liver cirrhosis. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinded Phase: LEN + Placebo-to-match (PTM) F/TDF<br>Participants will receive the following for at least 52 weeks: Subcutaneous (SC) lenacapavir (LEN) 927 mg every 26 weeks Oral PTM Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) once daily Oral LEN 600 mg on Days 1 and 2 Participants will receive oral LEN if SC injections are not available | Drug: Oral Lenacapavir (LEN)<br>* Tablets administered orally without regard to food<br>* Other names: GS-6207;Drug: Sub-cutaneous (SC) Lenacapavir (LEN)<br>* Administered via SC injections<br>* Other names: GS-6207;Drug: PTM F/TDF<br>* Tablets administered orally<br>|
| Experimental: Blinded Phase: Placebo LEN + F/TDF<br>Participants will receive the following for at least 52 weeks: SC LEN placebo every 26 weeks Oral F/TDF 200/300 mg once daily PTM Oral LEN on Days 1 and 2 Participants will receive oral LEN placebo if SC injections are not available | Drug: F/TDF<br>* Tablets administered orally<br>* Other names: Truvada®;Drug: Placebo SC LEN<br>* Administered via SC injections<br>Drug: PTM Oral LEN<br>* Tablets administered orally<br>|
| Experimental: LEN Open-Label Extension (OLE) Phase<br>After completion of the Blinded phase, participants will be offered entry into the LEN OLE Phase. Participants randomized to LEN will continue to receive SC LEN 927 mg every 26 weeks for a total of 2 doses. Participants randomized to F/TDF will receive SC LEN 927 mg on OLE Day 1, OLE Week 26, and will also receive oral LEN 600 mg on OLE Days 1 and 2. | Drug: Oral Lenacapavir (LEN)<br>* Tablets administered orally without regard to food<br>* Other names: GS-6207;Drug: Sub-cutaneous (SC) Lenacapavir (LEN)<br>* Administered via SC injections<br>* Other names: GS-6207;|
| Experimental: PK Tail Phase<br>At the completion of the LEN OLE phase, participants will transition into the PK Tail phase. Additionally, participants that prematurely discontinue the study drug during blinded phase and participants that were randomized to LEN who choose not to continue in the LEN OLE Phase are also eligible to transition to the PK Tail Phase. Participants will receive oral F/TDF (or Emtricitabine/Tenofovir Alafenamide (F/TAF) for US participants only) once daily for 78 weeks beginning 26 weeks after the last injection of LEN. | Drug: F/TDF<br>* Tablets administered orally<br>* Other names: Truvada®;Drug: F/TAF (for US participants only)<br>* F/TAF tablets administered orally once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Phase: Background HIV Incidence per 100-Person-Years (PY) |  | At Screening | 
| Randomized Phase: Number of Participants with Diagnosis of HIV-1 Infection |  | When all participants have completed a minimum of 52 weeks of follow-up in the study, or permanent discontinuation, whichever occurs first (maximum approximately 130 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Diagnosis of HIV Among Participants While Adherent to Study Drug |  | When all participants have completed a minimum of 52 weeks of follow-up in the study, or permanent discontinuation, whichever occurs first (maximum approximately 130 weeks) | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events |  | When all participants have completed a minimum of 52 weeks of follow-up in the study, or permanent discontinuation, whichever occurs first (maximum approximately 130 weeks) | 
| Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities |  | When all participants have completed a minimum of 52 weeks of follow-up in the study, or permanent discontinuation, whichever occurs first (maximum approximately 130 weeks) |