Assessment of Efficacy and Safety of Switching from Boosted Protease Inhibitor to Fostemsavir Trometamol in HIV-1 Patients with Limited Therapeutic Options

The primary objective of this study is to assess the proportion of patients with **HIV-1** viral load ≥ 50 copies/mL at week 48. This is clinically relevant as maintaining a low viral load is crucial for the effective management of HIV-1, reducing the risk of disease progression and transmission.

Secondary objectives include:

• Rates of individuals with viral load (VL) < 50 copies/mL at weeks 24 and 48.
• Rates of individuals with VL < 200 copies/mL at weeks 24 and 48.
• Evaluation of CD4 count, CD4:CD8 ratio, and lymphocyte subsets at week 48.
• Assessment of potential drug-drug interactions for those switching from their current antiretroviral therapy (cART) to fostemsavir.
• Occurrence and severity of adverse events, and treatment discontinuations due to tolerability.
• Safety and tolerability of fostemsavir, including effects on lipids, glucose, insulin resistance (HOMA-IR), weight, and waist circumference.
• Patient-reported benefits of switching, including changes in quality of life and health perception.
• Changes from baseline in clinical outcomes such as bone health, kidney function, cardiovascular risk, weight, BMI, and waist circumference.

The clinical trial involves a total of **40 participants** diagnosed with **HIV-1**. The study population includes both male and female adults over the age of 18, who are on a stable and suppressive combination antiretroviral therapy (cART) with a viral load of 50 copies/mL or less for at least one year. Participants are required to have no significant laboratory abnormalities or medical/psychiatric conditions that could impede their participation. Additionally, individuals with alcohol or drug use that may be considered a barrier to participation are excluded. The trial population was selected based on their adherence to current treatment regimens and the absence of major adherence issues. Participants are also required to be non-childbearing or agree to use highly effective contraception methods. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring that all participants are willing to sign an informed consent to partake in the study.

The clinical trial is designed to evaluate the **efficacy** and safety of switching from a boosted protease inhibitor to **fostemsavir trometamol** in individuals living with **HIV-1** who have limited therapeutic options. This is a Phase IV, randomized, double-blind, controlled trial, which will be conducted over an estimated duration of 48 weeks. The trial aims to assess the proportion of patients with an HIV viral load of ≥50 copies/mL at week 48 as the primary endpoint. Secondary endpoints include the rates of individuals with viral loads <50 copies/mL and <200 copies/mL at weeks 24 and 48, as well as evaluations of CD4 count, CD4:CD8 ratio, and lymphocyte subsets at week 48.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being an HIV-1 infected adult on stable and suppressive combination antiretroviral therapy (cART) with a viral load ≤50 copies/mL for one year. The inclusion visit will also ensure no significant laboratory abnormalities or medical conditions that could impede participation. Following the screening, participants will be randomized and commence the trial medication. Follow-up visits will be scheduled at regular intervals to monitor viral load, safety, and tolerability, as well as to collect data on patient-reported outcomes and potential drug-drug interactions. The end-of-study visit will occur at week 48, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement is approximately 48 weeks, aligning with the trial's duration. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial will adhere to ethical standards, ensuring informed consent is obtained from all participants prior to enrollment. The study will be conducted in accordance with regulatory guidelines to ensure the safety and well-being of all participants throughout the trial period.

The clinical trial involves the administration of **Rukobia 600 mg prolonged-release tablets**, which contain the active substance **fostemsavir trometamol**. This medication is formulated as a **prolonged-release tablet** and is intended for oral administration. The dosage regimen for the trial specifies a maximum daily dose of 600 mg, with a total maximum dose of 201,600 mg over the course of the study. The treatment period is set for a maximum of 48 weeks. The active substance, fostemsavir trometamol, is of chemical origin and is classified under the ATC code J05AX29. The trial aims to evaluate the efficacy and safety of switching from a boosted protease inhibitor to fostemsavir in people living with HIV (PLWH) who have limited therapeutic options.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Rukobia as the investigational product. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial's main objective is to assess the proportion of patients with an HIV viral load of 50 copies/mL or greater at week 48, providing insights into the potential benefits of fostemsavir in this patient population.

Efficacy in this clinical trial will be assessed primarily by evaluating the proportion of patients with a confirmed **HIV** viral load of ≥50 copies/mL at week 48. This primary endpoint will provide insight into the effectiveness of switching from a boosted protease inhibitor to fostemsavir in patients with limited therapeutic options. Secondary endpoints will include the rates of individuals with viral loads <50 copies/mL and <200 copies/mL at weeks 24 and 48, using the FDA Snapshot algorithm. Additionally, CD4 count, CD4:CD8 ratio, and lymphocyte subsets (CD4 and CD8) will be measured at week 48 to further assess immune response.

Patient-reported outcomes will be collected to evaluate changes in quality of life and health perception following the drug switch. Specific questionnaires, such as the wellness thermometer, PHQ9, and GAD-7, will be administered to gather this data. The trial will also monitor the potential for drug-drug interactions, adverse events, and treatment discontinuations due to tolerability. Safety assessments will include evaluations of lipids, glucose, insulin resistance (HOMA-IR), weight, and waist circumference. Changes from baseline in clinical outcomes, such as bone health, kidney function, cardiovascular risk, weight, BMI, and waist circumference, will be assessed using data from routine care clinical records.