Evaluation of the Antiviral Efficacy and Safety of GSK3739937 in Treatment-Naïve Adults with HIV-1 Infection: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **antiviral activity** of VH3739937 in treatment-naive adults living with **HIV-1** during a 7-day monotherapy period. This is clinically relevant as it aims to determine the efficacy of VH3739937 in reducing viral load in individuals who have not previously received treatment, potentially offering a new therapeutic option for managing HIV-1 infections.

Secondary objectives include:

• Assessing the **safety and tolerability** of VH3739937 when administered as monotherapy over 7 days in HIV-1 infected treatment-naive participants. This is crucial for understanding the potential adverse effects and overall acceptability of the treatment.
• Characterizing the **pharmacokinetics** of VH3739937 in HIV-1 infected treatment-naive participants, which is important for determining the drug's absorption, distribution, metabolism, and excretion, thereby informing appropriate dosing regimens.

The clinical trial involves a total of **10 participants** diagnosed with **HIV infections**. The study population includes both male and female subjects, aged between **18 to 65 years**, who are treatment-naive and have not received any antiretroviral therapies post-diagnosis. Participants are required to be overtly healthy aside from their HIV status, with a **CD4+ T-cell count** of at least 200 cells/mm³ and a **plasma HIV-1 RNA** level between 3,000 and 1,000,000 copies/mL. The trial population was selected based on specific inclusion criteria, ensuring that participants have a body weight of at least 50 kg for men and 45 kg for women, with a **BMI** ranging from 18.5 to 35.0 kg/m². Additionally, female participants must be of non-childbearing potential. The study does not include any vulnerable populations, and all participants are capable of providing informed consent. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is designed as a **randomized**, **double-blind** (sponsor-unblinded), **placebo-controlled**, adaptive study to evaluate the antiviral effect, safety, tolerability, and pharmacokinetics of the investigational drug **GSK3739937** in treatment-naïve adults living with **HIV-1**. The trial will involve a monotherapy phase lasting 7 days, with the primary objective being the assessment of the antiviral activity of GSK3739937. The study is expected to commence recruitment on December 11, 2023, and conclude by June 26, 2024.

Participants will be involved in the study for a total duration of 7 days, with the possibility of early termination if serious adverse events (SAEs) or adverse events (AEs) leading to discontinuation occur. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, health status, and HIV-1 infection parameters; a baseline visit on Day 1 to establish initial measurements; and a series of follow-up visits to monitor the participants' response to the treatment. The end-of-study visit will occur on Day 8, where the primary endpoint, the maximum change from baseline in plasma HIV-1 RNA, will be evaluated.

Participants will be randomly assigned to receive either the active drug GSK3739937 or a matching placebo, both administered orally in tablet form. The study will ensure that participants and investigators remain blinded to the treatment allocation, with the exception of the sponsor. The trial will also assess secondary endpoints, including the incidence of SAEs, deaths, and AEs leading to discontinuation, as well as pharmacokinetic parameters of GSK3739937. Participants must meet specific inclusion criteria, such as being between 18 and 65 years of age, having a documented HIV infection, and being treatment-naïve, among others. The study will exclude individuals who do not meet these criteria or who experience conditions that warrant early withdrawal from the trial.

The clinical trial involves the administration of **GSK3739937**, an experimental medication developed by VIIV Healthcare Limited. **GSK3739937** is formulated as a tablet for **oral use**. The active substance is of chemical origin, and the pharmaceutical form is a tablet. The trial includes two different treatment periods: one with a maximum duration of 1 day and another extending up to 6 days. The dosage is measured in milligrams, although specific dosing amounts are not provided. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.

A **placebo** is also utilized in this study as a comparator treatment. The placebo tablets are designed to visually match the active **GSK3739937** tablets, with the omission of the active ingredient. These placebo tablets are white, round, and film-coated, containing no markings, and are intended for **oral administration**. The use of placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias and enhancing the reliability of the study results.

The efficacy of the investigational product, **VH3739937**, in the clinical trial will be assessed primarily by measuring the maximum change from baseline in plasma HIV-1 RNA levels through Day 8. This endpoint is designed to evaluate the antiviral activity of the drug in treatment-naïve adults living with HIV-1. The trial is structured as a randomized, double-blind, placebo-controlled study, ensuring that the assessment of efficacy is conducted under rigorous conditions to minimize bias.

Secondary endpoints include the incidence of serious adverse events (SAEs), deaths, and adverse events (AEs) leading to discontinuation through Day 8. Additionally, pharmacokinetic (PK) parameters of **VH3739937** will be evaluated following once-daily dosing, with specific measurements taken on Day 1 and Day 7. These measurements include Cmax, tmax, C24, and AUC(0-24) on Day 1, and Cmax,ss, tmax, C24,ss, and AUC(0-24),ss on Day 7. Following a single dose, Cmax, tmax, AUC(0-168), and C168 will also be assessed. These PK parameters will provide further insights into the drug's behavior in the body, complementing the primary efficacy data.