A Phase 3, Randomized, Active-Controlled, Open-Label Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in Participants With HIV-1 Who Are Virologically Suppressed on Antiretroviral Therapy

The primary objective of this study is to evaluate the **antiretroviral** activity of a switch to Doravirine/Islatravir (DOR/ISL) compared with continued baseline antiretroviral therapy (ART) in participants with HIV-1 infection. This is assessed by the percentage of participants with HIV-1 ribonucleic acid (RNA) levels of ≥50 copies/mL at Week 48. Additionally, the study aims to assess the safety and tolerability of the switch to DOR/ISL compared to continued baseline ART, through a review of accumulated safety data. These objectives are clinically relevant as they address the efficacy and safety of a new treatment regimen, which could potentially improve patient outcomes by maintaining viral suppression and minimizing adverse effects.

Secondary objectives include: - Evaluating the antiretroviral activity of a switch to DOR/ISL at different time points and conditions, such as at Week 48 and Week 96, and in participants who switch at different stages of the study. - Assessing the immunologic effect of the switch, as measured by changes in CD4+ T-cell counts at various intervals. - Evaluating the development of viral drug resistance at Week 48 and Week 96. - Assessing the impact on fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) levels. - Evaluating the overall safety and tolerability of the switch to DOR/ISL through Week 96.

The clinical trial involves a total of **391 participants** diagnosed with **HIV-1 Infection**. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, typically encompassing adults. Participants were selected based on their stable health status, specifically those who have been receiving continuous, stable oral 2-drug or 3-drug combination antiretroviral therapy (ART) with documented viral suppression for at least three consecutive months prior to enrollment. The trial includes individuals who are not of childbearing potential or those who use acceptable contraceptive methods. The study population also considers vulnerable groups, ensuring comprehensive representation. Lifestyle factors such as diet and physical activity are not specified, but participants are required to maintain their current ART regimen. The trial aims to evaluate the antiretroviral activity and safety of a switch to Doravirine/Islatravir compared to continued baseline ART.

The clinical trial is a **Phase 3**, randomized, active-controlled, open-label 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 antiretroviral therapy (ART). The trial aims to assess the antiretroviral activity of the switch by measuring the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48, alongside evaluating safety and tolerability through the review of accumulated safety data. The study is expected to last until September 2025, with participant recruitment having commenced in May 2023.

Participants will be randomly assigned to either continue their baseline ART or switch to the doravirine/islatravir regimen. The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility, which requires participants to have plasma HIV-1 RNA <50 copies/mL and a history of stable ART with documented viral suppression for at least three months. Female participants of childbearing potential must use acceptable contraception or abstain from penile-vaginal intercourse, confirmed by a negative pregnancy test.

Following the screening, participants will attend regular follow-up visits to monitor their health status, adherence to the medication regimen, and any adverse events. The primary endpoint will be assessed at Week 48, with additional secondary endpoints evaluated at Week 96, including changes in CD4+ T-cell count and lipid profiles. The end-of-study visit will conclude the trial, where final assessments will be conducted.

Participant involvement is expected to last up to 96 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include the occurrence of adverse events leading to discontinuation of the study intervention or failure to adhere to the study protocol. The trial is not classified as low intervention, emphasizing its focus on confirming the safety and efficacy of the treatment in the target population.

The clinical trial involves the administration of **Tybost** 150 mg film-coated tablets, which contain the active substance **cobicistat**. This medication is provided in the form of film-coated tablets and is administered orally. The role of Tybost in the trial is as a comparator, and it is not a pediatric formulation. The maximum treatment period for Tybost is 48 weeks. The pharmaceutical product is manufactured by Gilead Sciences Ireland UC and is of chemical origin. The administration schedule and participant compliance are monitored to ensure adherence to the trial protocol.

The experimental treatment in this trial is a combination of **doravirine** and **islatravir**, provided in a single film-coated tablet. This combination is identified by the sponsor product code MK-8591A and is administered orally once daily. The maximum daily dose is 100.25 mg, with a total maximum dose of 67,368 mg over a treatment period of 96 weeks. The product is manufactured by Merck & Co. Inc. and is of chemical origin. The trial aims to evaluate the antiretroviral activity and safety of switching to this combination therapy in participants with HIV-1 who are virologically suppressed on antiretroviral therapy.

Additionally, the trial includes a comparator treatment categorized under the ATC code J05A, which refers to direct-acting antivirals. This treatment is also administered orally, and its role in the trial is as a comparator. The maximum treatment period for this comparator is 48 weeks. The specific pharmaceutical form and active substances for this comparator are not detailed in the trial data provided.

Efficacy in this clinical trial will be assessed by evaluating the antiretroviral activity of a switch to Doravirine/Islatravir (DOR/ISL) compared with continued baseline antiretroviral therapy (ART). The primary efficacy endpoint is the percentage of participants with **HIV-1** ribonucleic acid (RNA) ≥50 copies/mL at Week 48. Secondary efficacy endpoints include the percentage of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL at both Week 48 and Week 96, as well as the mean change from baseline in CD4+ T-cell count at Week 48 and Week 96.

The efficacy parameters will be measured 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 specific RNA thresholds and changes in CD4+ T-cell counts from baseline. The trial will also monitor the number of participants with viral resistance-associated substitutions and changes in fasting LDL-C and HDL-C levels from baseline to Week 48.