A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in Participants With HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)

The primary objective of this study is to evaluate the **antiretroviral** activity of a switch to Doravirine/Islatravir (DOR/ISL) compared with continued Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) in participants with HIV-1 infection. This is assessed by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48. Additionally, the study aims to assess the safety and tolerability of switching from BIC/FTC/TAF to DOR/ISL compared with continued BIC/FTC/TAF, as determined by a review of safety data accumulated through Week 48. These objectives are clinically relevant as they address the efficacy and safety of a potential new treatment regimen for maintaining viral suppression in individuals with HIV-1.

Secondary objectives include: - Evaluating the antiretroviral activity of a switch to DOR/ISL compared with continued 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 a switch to DOR/ISL compared with continued BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL at Week 48 and Week 96. - Evaluating the immunologic effect of a switch to DOR/ISL compared with continued 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 to any study intervention at Week 48 and Week 96. - Evaluating the safety and tolerability of a switch from BIC/FTC/TAF to DOR/ISL compared with continued BIC/FTC/TAF, as assessed by review of the safety data accumulated through study duration.

The clinical trial involves a total of **321 participants** diagnosed with **HIV-1 infection**. The study population includes both male and female subjects, aged 18 years and older, who have been receiving BIC/FTC/TAF therapy with documented viral suppression for at least three consecutive months prior to enrollment. Participants are required to have plasma HIV-1 RNA levels of less than 50 copies/mL. The trial includes individuals who are not of childbearing potential or, if they are, are not pregnant or breastfeeding and agree to use an acceptable contraceptive method or abstain from heterosexual intercourse during the study. The selection process ensures that participants have no history of prior virologic treatment failure on any past or current regimen. The trial population is characterized by a diverse range of ages and includes vulnerable populations, reflecting a comprehensive approach to evaluating the antiretroviral activity and safety of a switch to DOR/ISL compared with continued BIC/FTC/TAF therapy.

The clinical trial is a **Phase 3**, randomized, double-blind, active-controlled study designed to evaluate the efficacy and safety of switching to a combination of **doravirine** and **islatravir** in participants with **HIV-1 infection** who are virologically suppressed on a regimen of **bictegravir**, **emtricitabine**, and **tenofovir alafenamide**. The trial aims to assess the antiretroviral activity and safety of the switch by measuring the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48, along with the incidence of adverse events. The study is expected to last until September 2025, with participant recruitment having commenced in May 2023.

Participants will be randomly assigned to either the test group receiving doravirine/islatravir or the control group continuing their current regimen. The trial will be conducted in a double-blind manner, ensuring that neither the participants nor the investigators know which treatment is being administered, thus minimizing bias. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation.

The inclusion criteria require participants to be at least 18 years old, HIV-1 positive with plasma HIV-1 RNA <50 copies/mL, and on a stable regimen of bictegravir/emtricitabine/tenofovir alafenamide for at least three months prior to the study. Female participants of childbearing potential must agree to use contraception or abstain from heterosexual intercourse during the study. The expected duration of participant involvement is up to 96 weeks, with conditions for early termination including adverse events or withdrawal of consent.

Primary endpoints include the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 and the percentage experiencing adverse events. Secondary endpoints extend to Week 96 and include additional virologic measures and changes in CD4+ T-cell counts. The trial is not classified as low intervention and is intended to confirm the safety and efficacy of the treatment in the target population.

The clinical trial involves the administration of **Biktarvy** 50 mg/200 mg/25 mg film-coated tablets, which contain the active substances **emtricitabine**, **tenofovir alafenamide**, and **bictegravir**. These tablets are administered orally. The maximum daily dose is 275 mg, with a total maximum dose of 184,800 mg over a treatment period of 96 weeks. The tablets are de-packed and re-packed for the trial. Participant compliance is monitored to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is a combination of **doravirine** and **islatravir**, formulated as film-coated tablets. The maximum daily dose for this combination is 100.25 mg, with a total maximum dose of 67,368 mg over the same 96-week period. The administration route is oral, and the medication is identified by the sponsor product code MK-8591A. Compliance monitoring is implemented to ensure participants adhere to the prescribed dosing regimen.

The study also includes the use of a placebo to MK-8591A tablets and a placebo to Biktarvy. These placebos are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo tablets are administered orally, and compliance is similarly monitored to ensure adherence to the study protocol.

The efficacy of the clinical trial will be assessed by evaluating the antiretroviral activity of a switch to Doravirine/Islatravir (DOR/ISL) compared with continued Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) in participants with **HIV-1**. 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, HIV-1 RNA <200 copies/mL at Week 48 and Week 96, and HIV-1 RNA <50 copies/mL at Week 48 and Week 96. Additionally, changes from baseline in CD4+ T-cell count at Week 48 and Week 96, as well as the number of participants with viral drug resistance mutations at Week 48 and Week 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 levels and changes in CD4+ T-cell counts between the two treatment groups. The trial is designed to ensure a comprehensive assessment of the efficacy of the treatment switch in maintaining viral suppression and monitoring potential resistance development.