OPtimisation of antiviral Therapy in Immunocompromised COVID-19 patients: a randomized factorial controlled strategy trial: the OPTICOV Study

The primary objective of the OPTICOV Study is to evaluate the efficacy of a combination antiviral therapy consisting of **nirmatrelvir** and **remdesivir**, as well as the impact of extending the duration of nirmatrelvir treatment from 5 to 10 days. This is assessed by measuring the decrease in the SARS-CoV-2 positivity rate using real-time RT-PCR (CT<32) in nasopharyngeal swabs at day 10. This objective is clinically relevant as it aims to enhance viral clearance in immunocompromised COVID-19 patients, potentially reducing the duration of viral shedding and transmission risk.

Secondary objectives include: - Decreasing the SARS-CoV-2 positivity rate by RT-PCR in nasopharyngeal swabs and blood samples at various time points. - Assessing the decay of SARS-CoV-2 viral load in nasopharyngeal swabs and blood samples. - Limiting the emergence of new SARS-CoV-2 mutations. - Reducing the time to virus clearance and increasing the rate of negative viral culture. - Enhancing clinical recovery rates and reducing hospitalization and/or death rates. - Decreasing COVID-19 related signs and symptoms, including post-COVID-19 conditions. - Evaluating safety and adherence to treatment, as well as the impact on plasma dosage of nirmatrelvir/r and immunosuppressive drugs. - Reducing the need for additional specific treatments with antiviral drugs.

The clinical trial involves a total of **119 participants** diagnosed with **Covid-19**. The study population includes both male and female subjects aged **16 years and older**, with a body weight exceeding 40 kg. Participants are either asymptomatic or exhibit mild to moderate symptoms of Covid-19, as defined by a WHO progression scale of 5 or less. The trial specifically targets individuals who are **immunocompromised**, as determined by the presence of at least one risk factor for severe Covid-19, according to the Swiss Federal Office of Public Health guidelines. This includes conditions such as HIV infection with a CD4 count below 200 cells/μL, neutropenia, lymphocytopenia, hereditary immunodeficiencies, and the use of immunosuppressive drugs. Participants were selected based on laboratory-confirmed SARS-CoV-2 infection via RT-PCR. The trial does not focus on a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study ensures that all participants are willing and able to comply with the study requirements and have provided informed consent.

The clinical trial is designed to evaluate the efficacy of combination antiviral therapy in **immunocompromised** patients with **COVID-19**. This is a randomized, factorial, controlled strategy trial, conducted in a double-blind manner to ensure unbiased results. The trial aims to assess whether a combination of two direct-acting antivirals (DAAs), **nirmatrelvir** and **remdesivir**, or an extended duration of nirmatrelvir treatment from 5 to 10 days, can improve viral efficacy by reducing the SARS-CoV-2 positivity rate in nasopharyngeal swabs at day 10. The trial is expected to run from March 1, 2023, to June 29, 2024, with participant involvement lasting up to 90 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as laboratory-confirmed SARS-CoV-2 infection, age of 16 years or older, and specific immunocompromised conditions. Following the screening, participants will be randomized into treatment arms and will receive either the combination therapy or the extended nirmatrelvir regimen. Study visits will occur at multiple time points, including days 5, 10, 14, 21, and 28, with additional follow-up at day 90. These visits are designed to monitor the primary endpoint, which is the percentage of patients with a viral load of less than 32 cycle threshold (CT) by real-time RT-PCR at day 10, as well as secondary endpoints such as viral load changes, mutation emergence, and clinical progression.

Participants are expected to adhere to the study protocol, and any deviation or occurrence of adverse events may lead to early termination from the study. The trial will also monitor for any drug-drug interactions and adherence to the treatment regimen. The study is categorized as a Phase 4 trial, indicating it is conducted post-marketing to gather additional information on the drug's effectiveness and safety in a broader patient population. The trial's design and procedures are structured to ensure rigorous data collection and analysis, contributing valuable insights into optimizing antiviral therapy for immunocompromised COVID-19 patients.

The clinical trial involves the administration of **Paxlovid**, a combination antiviral therapy consisting of **nirmatrelvir** and ritonavir. Paxlovid is provided in the form of **film-coated tablets** with a dosage of 150 mg of nirmatrelvir and 100 mg of ritonavir per tablet. The tablets are administered orally. The treatment regimen for this trial involves a maximum daily dose of 600 mg, with a total maximum dose of 6000 mg over a treatment period of 10 days. This extended duration of administration, compared to the standard 5-day regimen, is being evaluated for its efficacy in reducing the SARS-CoV-2 positivity rate in immunocompromised COVID-19 patients.

Additionally, the trial includes the use of **Veklury**, which contains the active substance **remdesivir**. Veklury is supplied as a **powder for concentrate for solution for infusion**. The administration route is intravenous, with a maximum daily dose of 200 mg. The treatment period for Veklury is limited to a single day. This medication is being used in combination with Paxlovid to assess the potential benefits of dual antiviral therapy in the study population.

Both medications are chemically synthesized and have been authorized for use in the European Union. The trial aims to determine the effectiveness of these treatments in improving viral clearance as measured by real-time RT-PCR in nasopharyngeal swabs at day 10 of the treatment regimen. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the antiviral therapy in the OPTICOV Study will be assessed primarily by evaluating the percentage of patients with a SARS-CoV-2 viral load of less than 32 cycle threshold (CT) by real-time RT-PCR in nasopharyngeal swabs at Day 10 (D10) after treatment initiation. This primary endpoint aims to determine the effectiveness of the combination antiviral therapy of two direct-acting antivirals (DAAs), **nirmatrelvir** and remdesivir, and the extended duration of nirmatrelvir treatment from 5 to 10 days in reducing the SARS-CoV-2 positivity rate.

Secondary endpoints include the percentage of patients with a viral load of less than 32 CT at Days 5, 14, and 21, as well as the percentage of patients with detectable SARS-CoV-2 viremia at Days 5, 10, and 14. Additional assessments involve measuring the decrease in viral load by copies/ml in nasopharyngeal swabs and blood samples at specified time points, the emergence of mutations, and the time to first negative RT-PCR result until Day 90. The study will also evaluate the absence of virus cultivation from nasopharyngeal swabs, the resolution of symptoms using the FLU-PRO Plus score, and clinical outcomes such as hospitalization and mortality rates at Day 28. The WHO 11-point Clinical Progression Scale will be used to monitor disease progression through Day 28.

Patient adherence to nirmatrelvir will be assessed through patient-reported adherence and residual dosage measurements from plasma samples at Days 5 and 10. The study will also track adverse events, serious adverse events, and any drug-drug interactions leading to dosage adjustments. The rate of post-COVID-19 conditions at Day 90, as defined by the WHO, will be recorded, along with any specific retreatment requirements through Day 90.