A Phase 3 Open-label Clinical Study of Doravirine/Islatravir (DOR/ISL [100 mg/0.25 mg]) Once Daily for the Treatment of HIV-1 Infection in Participants Who Previously Received DOR/ISL (100 mg/0.75 mg) QD in a Phase 3 Clinical Study

The primary objective of this Phase 3 open-label clinical study is to evaluate the **safety** and tolerability of the combination of **doravirine** and **islatravir** (DOR/ISL 100 mg/0.25 mg) in participants with **HIV-1 infection**. This assessment is based on accumulated safety data collected through Week 96. The clinical relevance of this objective lies in ensuring that the treatment regimen is safe and well-tolerated over an extended period, which is crucial for long-term management of HIV-1 infection.

Secondary objectives include:

• Evaluating the antiretroviral activity of DOR/ISL by assessing the percentage of participants with HIV-1 RNA levels of ≥50 copies/mL, <50 copies/mL, and ≥200 copies/mL at Week 96.
• Assessing the development of viral resistance to DOR/ISL (100 mg/0.25 mg).

These secondary objectives are important for understanding the efficacy of the treatment in suppressing viral load and preventing the emergence of drug-resistant strains of the virus.

The clinical trial involves a total of **956 participants** diagnosed with **HIV-1 infection**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on their current treatment with the doravirine/islatravir (DOR/ISL) adult fixed-dose combination tablet in specific Merck Sharp & Dohme (MSD)-sponsored clinical studies, excluding those who are heavily treatment-experienced. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and ethical treatment. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the participants are already receiving the investigational treatment, which aligns with the trial's objective to evaluate the safety and tolerability of DOR/ISL over a 96-week period.

The clinical trial is designed to evaluate the **safety** and tolerability of a fixed-dose combination of **doravirine** and **islatravir** in participants with **HIV-1 infection**. This is a Phase 3, open-label study, which will assess the treatment's effects over a period of 96 weeks. The trial employs a controlled methodology, with participants receiving the investigational product in the form of a film-coated tablet administered orally. The primary endpoints include the percentage of participants experiencing adverse events and those discontinuing the study due to such events. Secondary endpoints focus on the percentage of participants achieving specific levels of HIV-1 RNA suppression and the presence of viral drug resistance-associated substitutions.

The trial will commence with an inclusion visit, where participants currently receiving the doravirine/islatravir combination in previous Merck-sponsored studies will be screened for eligibility. Following the inclusion visit, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of HIV-1 RNA levels and evaluations for any adverse events. The end-of-study visit will occur at Week 96, marking the conclusion of the participant's involvement in the trial.

Participants are expected to be involved in the study for the entire 96-week duration unless conditions arise that necessitate early termination. Such conditions may include the occurrence of significant adverse events or the participant's decision to withdraw from the study. The trial is scheduled to end by February 17, 2026, with recruitment having started on March 30, 2023. The study aims to provide comprehensive data on the long-term safety and efficacy of the doravirine/islatravir combination in managing HIV-1 infection.

The clinical trial involves the administration of an **experimental medication** consisting of a combination of two active substances: **doravirine** and **islatravir**. This medication is formulated as a **film-coated tablet** and is identified by the sponsor product code MK-8591A. The pharmaceutical form is designed for **oral** administration. The dosage regimen for this trial specifies a daily dose of 100 mg of doravirine and 0.25 mg of islatravir. The maximum daily dose is set at 100.25 mg, with a total maximum dose of 182,956.25 mg over the course of the treatment period, which spans up to 60 days. The trial aims to evaluate the safety and tolerability of this combination therapy in participants with **HIV-1 infection** who have previously received a different dosage of the same combination in a prior Phase 3 study.

In addition to the experimental treatment, the study may include the use of **non-experimental treatments** such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. These treatments are intended to provide a baseline for evaluating the efficacy and safety of the experimental medication. The administration of these non-experimental treatments will follow established guidelines and dosing schedules to ensure consistency and reliability in the trial outcomes.

Participant compliance with the dosing regimen will be closely monitored throughout the study. This will involve regular assessments and documentation of medication intake to ensure adherence to the prescribed treatment plan. The trial is designed to gather comprehensive safety data through Week 96, with a focus on identifying any adverse effects or tolerability issues associated with the experimental medication. The study is conducted under the sponsorship of Merck & Co. Inc., and all substances involved are of chemical origin, ensuring a controlled and scientifically rigorous evaluation of the treatment's impact on **HIV-1 infection**.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on safety, specifically the percentage of participants experiencing one or more adverse events and the percentage of participants who discontinue the study intervention due to adverse events. Secondary endpoints are designed to evaluate the virologic efficacy of the treatment. These include the percentage of participants with **human immunodeficiency virus-1 (HIV-1)** ribonucleic acid (RNA) levels below 50 copies/mL at Week 96, the percentage with HIV-1 RNA levels equal to or above 50 copies/mL, and those with levels equal to or above 200 copies/mL at the same time point. Additionally, the presence of viral drug resistance-associated substitutions will be monitored.