Phase 3b Randomized Study on Efficacy and Safety of Cabotegravir and Rilpivirine in HIV-1 Patients with Viremia and Suboptimal Oral ART Response

The primary objective of this study is to demonstrate a superior **viral suppression** rate after 6 months of treatment with CAB LA (cabotegravir) and RPV LA (rilpivirine), administered every 2 months, compared with oral antiretroviral therapy (ART) in treatment-experienced persons with HIV (PWH) who have viremia. This objective is clinically relevant as achieving higher rates of viral suppression is crucial in managing HIV infections, reducing transmission risk, and improving patient outcomes.

Secondary objectives include:

• Comparing the time to viral suppression over 6 months between the injectable regimen and oral ART.
• Assessing the time to treatment-related discontinuation (considered as failure) over 6 months between the two treatment modalities.
• Evaluating the rate of confirmed virologic failure after 6 months of treatment with the injectable regimen compared to oral ART.
• Comparing the incidence of treatment-emergent resistance-associated mutations (RAMs) after 6 months between the two treatment approaches.
• Determining the incidence of treatment-emergent RAMs after 12 and 24 months of treatment with the injectable regimen.

These secondary objectives aim to provide comprehensive insights into the efficacy, safety, and potential resistance development associated with the long-acting injectable regimen compared to standard oral ART, which is vital for optimizing treatment strategies in HIV management.

The clinical trial involves a total of **276 participants** diagnosed with **HIV infections**. The study population includes both male and female subjects, aged 12 years and older, with a minimum weight of 35 kg. Participants are required to have documented HIV-1 infection with plasma HIV-1 RNA levels between 1,000 and 100,000 copies/mL. The trial specifically targets individuals who have experienced insufficient virologic response to their current oral antiretroviral therapy (ART) regimen. This includes those with less than a 1 log10 decrease in HIV-1 RNA or HIV-1 RNA levels above 200 copies/mL at two time points at least four weeks apart, despite being on oral ART for at least three consecutive months. Additionally, participants may have had a documented lapse in their current oral ART regimen or a need for a change in regimen due to safety or tolerability issues. The trial population was selected based on these criteria, ensuring that participants are currently on an oral ART regimen and are willing to continue until their Month 6 viral load result is available. The study also includes vulnerable populations, and informed consent is required from participants or their legal guardians. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase IIIb**, open-label, randomized, standard-of-care control arm, multicenter study designed to evaluate the efficacy, safety, and tolerability of injectable **cabotegravir** and **rilpivirine** in participants with **HIV-1** infection. The trial aims to demonstrate a superior viral suppression rate after six months of treatment with these injectable agents, administered every two months, compared to oral antiretroviral therapy (ART) in treatment-experienced individuals with viremia. The study is expected to commence recruitment on December 22, 2024, and conclude by December 8, 2027.

Participants will be randomly assigned to receive either the injectable regimen or continue with their current oral ART. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor virologic response and safety, and an end-of-study visit to assess overall outcomes. The primary endpoint is the virologic response, defined as achieving **HIV-1 RNA** levels of less than 50 copies/mL at Month 6, using the Snapshot Algorithm. Secondary endpoints include the time to virologic suppression, time to treatment-related discontinuation, and the occurrence of resistance-associated mutations.

Participant involvement is expected to last up to 24 months, with the injectable treatment administered intramuscularly. Conditions that may lead to early termination from the study include protocol-defined virologic failure, adverse events related to the drug, intolerability of injections, or lack of efficacy. The trial is not classified as low intervention, and it involves a comprehensive assessment of the investigational products' impact on viral suppression in a real-world setting.

The clinical trial involves the administration of **Vocabria**, a **prolonged-release suspension for injection** containing the active substance **cabotegravir**. This medication is provided in a dosage of 600 mg and is administered via **intramuscular use**. The dosing schedule for Vocabria is every two months, with a maximum treatment period of 24 months. The total maximum dose administered over the course of the study is 7800 mg. Vocabria is a chemically synthesized product developed by VIIV Healthcare B.V. and is not a pediatric formulation. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

In addition to Vocabria, the trial also includes the administration of **REKAMBYS**, another **prolonged-release suspension for injection**. This medication contains the active substance **rilpivirine** and is provided in a dosage of 900 mg, also administered via **intramuscular use**. Similar to Vocabria, REKAMBYS is administered every two months, with a maximum treatment period of 24 months and a total maximum dose of 11700 mg. REKAMBYS is a chemically synthesized product developed by Janssen-Cilag International NV and is not a pediatric formulation. Compliance with the dosing schedule is similarly monitored to ensure participant adherence.

The trial is designed to evaluate the efficacy, safety, and tolerability of the combination of CAB LA (cabotegravir long-acting) and RPV LA (rilpivirine long-acting) in participants living with **HIV-1**. The study aims to demonstrate a superior viral suppression rate after six months of treatment with these injectable medications compared to standard oral antiretroviral therapy (ART) in treatment-experienced individuals with viremia. The trial includes a standard-of-care control arm to provide a comparator for assessing the effectiveness of the experimental treatment regimen.

The efficacy of the clinical trial will be assessed by evaluating the **virologic response** in participants living with HIV-1. The primary endpoint for efficacy is the achievement of HIV-1 RNA levels below 50 copies/mL, as determined by the Snapshot Algorithm at Month 6. This endpoint will provide a measure of the viral suppression rate in participants receiving the injectable combination of CAB LA and RPV LA compared to those on oral antiretroviral therapy (ART).

Secondary endpoints include the time to virologic suppression from baseline through Month 6, time to treatment-related discontinuation or failure (TRDF) from baseline through Month 6, and protocol-defined virologic failure (VF) through Month 6. Additionally, the occurrence of developing resistance-associated mutations (RAMs) will be monitored through Month 6, with a focus on integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs through Months 12 and 24.