Phase 3 Randomized Double‑Blind Study of Doravirine/Islatravir Versus Bictegravir Combination Therapy in Treatment‑Naïve HIV‑1 Infection

The primary objective of this Phase 3, randomized, active-controlled, double-blind clinical study is to evaluate the **antiretroviral activity** of Doravirine/Islatravir (DOR/ISL) compared to Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF). This is assessed by the percentage of participants with **HIV-1 RNA** levels below 50 copies/mL at Week 48. Additionally, the study aims to assess the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF through a review of accumulated safety data up to Week 48. These objectives are clinically relevant as they provide insights into the efficacy and safety of a new antiretroviral regimen for treatment-naïve individuals with HIV-1 infection, potentially offering alternative therapeutic options.

Secondary objectives include:

• Evaluating the antiretroviral activity of DOR/ISL compared with BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL at Week 96.
• Evaluating the antiretroviral activity of DOR/ISL compared with BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <200 copies/mL at Week 48 and Week 96.
• Evaluating the immunologic effect of DOR/ISL compared with BIC/FTC/TAF, as assessed by the mean change from baseline in **CD4+ T-cell** count at Week 48 and Week 96.
• Evaluating the development of viral drug resistance in participants who receive DOR/ISL and in those who receive BIC/FTC/TAF.
• Evaluating the effect of DOR/ISL compared with BIC/FTC/TAF on weight, as assessed by the mean change from baseline to Week 48 and Week 96.
• Evaluating the safety and tolerability of DOR/ISL compared with BIC/FTC/TAF as assessed by review of the accumulated safety data through study duration.

The clinical trial involves a total of **457 participants** diagnosed with **HIV-1 Infection**. The study population includes individuals aged 18 years and older, encompassing both male and female participants. Participants are required to be **naïve to antiretroviral therapy (ART)**, meaning they have not received any prior therapy with antiretroviral agents following their diagnosis. The trial includes individuals with plasma HIV-1 RNA levels of 500 copies/mL or higher at screening. Female participants are either not of childbearing potential or, if they are, must not be pregnant or breastfeeding and must agree to use an acceptable contraceptive method or abstain from heterosexual intercourse for the study's duration. The trial population was selected to include a vulnerable population, ensuring a comprehensive evaluation of the antiretroviral activity and safety of the treatments under investigation. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, and **controlled** study designed to evaluate the antiretroviral activity, safety, and tolerability of a combination of **doravirine** and **islatravir** in treatment-naïve participants with **HIV-1 infection**. The trial will compare this combination to a regimen of **bictegravir**, **emtricitabine**, and **tenofovir alafenamide**. The study is expected to last until August 2026, with participant involvement spanning up to 96 weeks. The primary objectives include assessing the percentage of participants achieving HIV-1 RNA levels of less than 50 copies/mL at Week 48 and evaluating safety through the incidence of adverse events.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL and being naïve to antiretroviral therapy. Following randomization, participants will attend regular follow-up visits to monitor viral load, safety, and tolerability. The end-of-study visit will occur at Week 96, where final assessments will be conducted. Conditions that may lead to early termination from the study include experiencing significant adverse events or failing to adhere to the study protocol.

The trial will utilize film-coated tablets for both the investigational and comparator products, administered orally. Participants will be monitored for changes in CD4+ T-cell counts, body weight, and the incidence of viral drug resistance. Secondary endpoints include the percentage of participants with HIV-1 RNA <200 copies/mL at Weeks 48 and 96, and the percentage experiencing adverse events through Week 96. The study aims to provide comprehensive data on the efficacy and safety of the investigational regimen in a real-world setting.

The clinical trial involves the administration of **doravirine**/**islatravir** as the experimental medication. This investigational product is formulated as film-coated tablets, with each tablet containing 100 mg of doravirine and 0.25 mg of islatravir. The tablets are administered orally once daily. The maximum daily dose is 100.25 mg, and the treatment period extends up to 96 weeks. The active substances, doravirine and islatravir, are of chemical origin and are provided by Merck & Co. Inc. The tablets are identified by the sponsor product code MK-8591A.

The comparator treatment in the study is **Biktarvy**, which consists of film-coated tablets containing 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. These tablets are also administered orally once daily. The maximum daily dose is 275 mg, with a total treatment period of 96 weeks. The active substances are of chemical origin, and the product is manufactured by Gilead Sciences Ireland UC. The tablets are repackaged into high-density polyethylene (HDPE) bottles with induction seals and child-resistant plastic closures, including a desiccant to maintain stability.

Two placebo treatments are utilized in the trial. The first is a placebo to doravirine/islatravir, and the second is a placebo to bictegravir/emtricitabine/tenofovir alafenamide. Both placebos are used to maintain the double-blind nature of the study. The pharmaceutical form, active substances, and administration routes for these placebos are not specified in the available data.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The trial aims to evaluate the antiretroviral activity, safety, and tolerability of the experimental medication compared to the standard-of-care therapy, as assessed by the percentage of participants with HIV-1 RNA levels below 50 copies/mL at Week 48.

The efficacy of the clinical trial will be assessed by evaluating the **antiretroviral activity** of Doravirine/Islatravir (DOR/ISL) compared to Biktarvy (BIC/FTC/TAF) in HIV-1 infected treatment-naïve participants. The primary efficacy endpoint is the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48. Secondary efficacy endpoints include the percentage of participants with HIV-1 RNA <50 copies/mL at Week 96, the percentage of participants with HIV-1 RNA <200 copies/mL at Weeks 48 and 96, and changes from baseline in CD4+ T-cells at Weeks 48 and 96. Additionally, the incidence of viral drug resistance and changes from baseline in body weight at Weeks 48 and 96 will be evaluated.

The efficacy parameters will be measured and collected at specified timepoints, including Week 48 and Week 96, using laboratory tests to determine HIV-1 RNA levels and CD4+ T-cell counts. The analysis will involve comparing the percentage of participants achieving the specified RNA thresholds and assessing changes in CD4+ T-cell counts and body weight from baseline. The trial is designed to provide a comprehensive evaluation of the antiretroviral activity, safety, and tolerability of the investigational treatment over a 96-week period.