Phase II Randomized Trial Evaluating Doravirine and Raltegravir Dual Therapy for Virological Maintenance in HIV-1 Patients with Suppressed Plasma Viremia

The primary objective of this study is to evaluate the **virological efficacy** at week 48 of once-daily doravirine plus raltegravir dual therapy in patients with HIV-1 who are currently suppressed on antiretroviral therapy (ART). This is clinically relevant as maintaining virological suppression is crucial for preventing disease progression and reducing the risk of HIV transmission.

Secondary objectives include:

• Assessing HIV-RNA viral load and minimal drug concentration (Cmin) of doravirine/raltegravir at specified visits in the human male genital compartment.
• Evaluating the virological efficacy of the doravirine plus raltegravir dual therapy.
• Determining the proportion of patients achieving therapeutic success up to weeks 48 and 96.
• Analyzing the resistance profile in cases of virological failure.
• Monitoring the evolution of CD4 and CD8 T-cells, and the CD4/CD8 ratio.
• Assessing the clinical and biological tolerability of the dual therapy.
• Utilizing quality of life and observance questionnaires.

The clinical trial involves **HIV Disease** patients who are **18 years or older** and have a documented HIV-1 infection with a CD4 count of at least 200/mm³. Participants are required to be on a stable combined antiretroviral therapy (ART) regimen with at least two drugs for a minimum of six months, and must have maintained an HIV-RNA plasma viral load of 50 copies/mL or less during the last 18 months, with specific conditions for isolated viral load fluctuations. The study includes both male and female subjects, and does not involve a vulnerable population. Participants must be naive to doravirine and show no resistance to doravirine or raltegravir, as determined by available genotypic data. The trial population was selected based on these criteria, and all participants provided signed informed consent. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is a **randomized**, **controlled**, phase II study designed to evaluate the efficacy of a dual combination therapy consisting of **doravirine** and **raltegravir** in maintaining virological success in patients with **HIV Disease**. The trial aims to assess the virological efficacy at week 48 of once-daily doravirine plus raltegravir dual therapy in HIV-1 infected patients who are already suppressed on antiretroviral therapy (ART). The study is expected to run until November 1, 2025, with recruitment having commenced on October 1, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), documented HIV-1 infection, and a stable ART regimen. The primary endpoint is the proportion of patients experiencing virological failure by week 48, defined as two consecutive plasma viral loads (pVL) >50 copies/mL two weeks apart. Secondary endpoints include the maintenance of viral suppression, changes in CD4 and CD8 T-cell counts, and the occurrence of virological blips.

Study visits are scheduled at baseline (D0), and at weeks 24, 48, 72, and 96, with assessments including viral load measurements, quality of life questionnaires, and observance evaluations. The end-of-study visit will occur at week 96, marking the conclusion of participant involvement. Participants are expected to remain in the study for the full duration unless they meet conditions for early termination, such as significant protocol deviations or adverse events that compromise safety.

The trial is conducted under a double-blind design to ensure unbiased results, with participants and investigators unaware of the treatment assignments. The study is authorized in multiple countries, including France, Spain, and Italy, with each site adhering to the same protocol to maintain consistency across the trial. The trial's findings will contribute to understanding the potential of doravirine and raltegravir as a viable dual therapy option for maintaining virological suppression in HIV-1 infected patients.

The clinical trial involves the administration of **Pifeltro** 100 mg film-coated tablets, which contain the active substance **doravirine**. Doravirine is a chemical compound classified under the ATC code J05AG06. The pharmaceutical form of Pifeltro is a film-coated tablet, and it is administered orally. The dosage regimen for this trial involves a once-daily administration of the 100 mg tablet. Doravirine is produced by Merck Sharp & Dohme B.V. and is not a paediatric formulation. The trial aims to evaluate the virological efficacy of doravirine in combination with another antiretroviral agent.

In conjunction with doravirine, the trial also utilizes **Raltegravir** 600 mg film-coated tablets. Raltegravir, another chemical compound, is classified under the ATC code J05AJ01. The pharmaceutical form is similarly a film-coated tablet, administered orally. The dosage for raltegravir in this study is also once daily, with each tablet containing 600 mg of the active substance. This medication is manufactured by Dr. Reddy's Laboratories (UK) Ltd. and is used as part of the dual therapy regimen being evaluated in the trial. The combination of doravirine and raltegravir is intended to maintain virological success in patients with HIV-1 infection who have achieved viral suppression under their current antiretroviral regimen.

Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment regimen. The study does not include any non-experimental treatments such as placebo or comparator treatments, focusing solely on the efficacy of the dual combination therapy. The trial's main objective is to assess the virological efficacy at week 48 of the dual therapy in HIV-1 infected patients who are already suppressed on antiretroviral therapy (ART).

The efficacy of the clinical trial will be assessed primarily by evaluating the proportion of patients experiencing **virological failure** before or at week 48. Virological failure is defined as two consecutive plasma viral load (pVL) measurements greater than 50 copies/mL, taken two weeks apart. Secondary endpoints include the proportion of patients maintaining viral suppression with pVL less than 50 copies/mL, using the Snapshot approach, and the evolution of CD4 and CD8 T-cells, as well as the CD4/CD8 ratio. Additional secondary endpoints involve the proportion of patients experiencing virological blips, the resistance profile in cases of protocol-defined virological failure, and the proportion of patients with acquired resistance mutations among those with virological failure.

Quality of life will be assessed through self-questionnaires at various timepoints, including screening, day 0, week 24, week 48, week 72, and week 96. Observance will also be evaluated using self-questionnaires at day 0, week 24, week 48, and week 96. The trial will further assess HIV-RNA viral load and minimal drug concentration (Cmin) of doravirine/raltegravir at specified visits for patients in both the "Immediate switch" and "Delayed switch" arms. Additionally, the maintenance of HIV viral suppression and changes in neuronal injury and inflammatory markers in cerebrospinal fluid will be evaluated at day 0 and week 48 in a cerebrospinal fluid sub-study involving patients in Spanish centers.