A Phase 3, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Emtricitabine and Tenofovir Alafenamide (F/TAF) Fixed-Dose Combination Once Daily for Pre-Exposure Prophylaxis in Men and Transgender Women Who Have Sex with Men and Are At Risk of HIV-1 Infection.

The primary objective of this Phase 3, randomized, double-blind study is to assess the rates of **HIV-1 infection** in men who have sex with men (MSM) and transgender women (TGW) who have sex with men. Participants are administered daily emtricitabine and tenofovir alafenamide (F/TAF) or emtricitabine and tenofovir disoproxil fumarate (F/TDF), with a minimum follow-up of 48 weeks, ensuring that at least 50% of participants have 96 weeks of follow-up after randomization. This objective is clinically relevant as it evaluates the efficacy of pre-exposure prophylaxis (PrEP) in reducing the incidence of HIV-1 infection in high-risk populations.

Secondary objectives include:

• Comparing bone safety between the treatments as determined by dual-energy X-ray absorptiometry (DXA) tests of hip and spine bone mineral density (BMD) in a subset of participants at Week 48 and Week 96 in the blinded phase.
• Comparing renal safety between the treatments as determined by urine retinol-binding protein (RBP) to creatinine ratio, urine beta-2-microglobulin to creatinine ratio, urine protein to creatinine ratio (UPCR), and serum creatinine at Week 48 and Week 96 in the blinded phase.
• Assessing the rates of HIV-1 infection in MSM and TGW who have sex with men who are administered daily F/TAF or F/TDF, when all participants have 96 weeks of follow-up after randomization.
• Comparing the general safety between the treatments.

The clinical trial involves a total of **2910 participants** focusing on the **Pre-Exposure Prophylaxis of HIV-1 Infection**. The study population comprises men who have sex with men (MSM) and transgender women (TGW) who have sex with men, all of whom were male at birth. Participants are required to be **HIV-1–negative** and aged 18 years or older. The trial exclusively includes male subjects, with no female participants involved. The selection criteria emphasize individuals with specific risk factors, such as recent condomless anal intercourse with multiple male partners, or a documented history of sexually transmitted infections like syphilis, rectal gonorrhea, or chlamydia within the past 24 weeks. Participants must have an estimated glomerular filtration rate (eGFR) of at least 60 mL/min and adequate liver and hematologic function. The trial does not involve a vulnerable population, and participants are expected to be willing and able to comply with study procedures. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3, randomized, double-blind, controlled study** designed to evaluate the safety and efficacy of a fixed-dose combination of **emtricitabine** and **tenofovir alafenamide** for pre-exposure prophylaxis in men and transgender women who have sex with men and are at risk of **HIV-1 infection**. The trial aims to assess the incidence of HIV-1 infection over a minimum follow-up period of 48 weeks, with at least 50% of participants having 96 weeks of follow-up post-randomization. The study is expected to conclude by September 2027, with recruitment having commenced in September 2016.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as HIV-1 negative status, age of 18 years or older, and adequate liver and hematologic function. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including assessments of bone mineral density (BMD) and renal biomarkers at specified intervals, such as Week 48 and Week 96. The end-of-study visit will mark the completion of the participant's involvement in the trial.

The expected duration of participant involvement is up to 96 weeks, with conditions for early termination including the development of HIV-1 infection or inability to comply with study procedures. The primary endpoint is the incidence of HIV-1 infection per 100 person-years, while secondary endpoints include changes in BMD, renal function, and the incidence of treatment-emergent adverse events. The trial is conducted in accordance with regulatory guidelines, ensuring the integrity and scientific validity of the research.

The clinical trial involves the administration of **Descovy 200 mg/25 mg film-coated tablets**, which is an investigational medicinal product containing the active substances **emtricitabine** and **tenofovir alafenamide**. These substances are of chemical origin and are formulated as film-coated tablets for oral use. The dosage regimen for the trial participants is one tablet taken once daily. The maximum treatment period is specified as 552 days. The trial aims to evaluate the safety and efficacy of this fixed-dose combination for pre-exposure prophylaxis in men and transgender women who have sex with men and are at risk of **HIV-1 infection**.

In addition to the experimental treatment, the study may include the use of a comparator treatment, which is not specified in the provided data. The trial is designed as a randomized, double-blind study to ensure unbiased results. Participant compliance with the dosing schedule will be monitored throughout the study duration to ensure adherence to the treatment protocol. The trial's main objective is to assess the rates of HIV-1 infection among the participants, with a minimum follow-up period of 48 weeks, and at least 50% of participants having 96 weeks of follow-up after randomization.

Efficacy in this clinical trial will be assessed primarily by evaluating the incidence of **HIV-1 infection** per 100 person-years (PY). This primary endpoint will be measured when all participants have a minimum follow-up of 48 weeks, with at least 50% of participants having 96 weeks of follow-up after randomization. HIV-1 infection will be defined by specific criteria, including serologic evidence of seroconversion confirmed by a reactive HIV-1/HIV-2 differentiation assay, virologic evidence of HIV-1 infection through positive qualitative or detectable quantitative HIV-1 RNA tests, or evidence of acute HIV-1 infection indicated by reactive p24 antigen or positive RNA tests in the absence of a reactive HIV-1 antibody test.

Secondary endpoints will include the percent change from baseline in hip and spine bone mineral density (BMD) at Week 48 and Week 96 in a subset of participants, assessment of renal biomarkers at Week 48 and Week 96, and changes in serum creatinine levels. Additionally, the percent change from baseline in urine beta-2-microglobulin to creatinine ratio and urine RBP to creatinine ratio will be evaluated, along with the distribution of UP and UPCR categories. The incidence of treatment-emergent adverse events and laboratory toxicities will also be monitored. These assessments will be conducted using validated laboratory tests and measurements at specified time points throughout the trial.