Efficacy and Safety Evaluation of Plitidepsin in Adults with Post-COVID-19 Condition: A Randomized, Double-Blind, Placebo-Controlled Phase II Study

The primary objective of this Phase II proof-of-concept, randomized, double-blind, placebo-controlled study is to evaluate the change in overall health in patients with **post-COVID-19 Condition (PCC)** using the Patient Reported Outcomes Measurement Information System score (PROMIS-29®). This is clinically relevant as it aims to assess the efficacy of **plitidepsin** in improving the health status of individuals suffering from persistent symptoms following COVID-19 infection.

Secondary objectives include:

• Comparing the safety and tolerability of plitidepsin versus placebo in terms of adverse events.
• Comparing the incidence of Treatment-Emergent Adverse Events (TEAEs) between groups.
• Assessing changes in functional capacity using the Post-COVID-19 Functional State (PCFS) scale.
• Evaluating symptomatic changes using the Can Ruti Questionnaire.
• Comparing changes in Quality of Life (QoL) for each group.
• Assessing neuropsychological symptomatology among the three treatment arms.
• Evaluating changes in physical activity, fatigue, inflammation markers, immune response markers, and the presence of viral components in plasma among the three treatment arms.
• Comparing alterations in thromboinflammatory components, complement activation, and hormonal components among the three treatment arms.
• Exploratory objective for future investigations: comparing changes in intestinal microbiota among the three treatment arms.

The clinical trial focuses on individuals diagnosed with **post-COVID-19 Condition (PCC)**. The study population includes both male and female participants aged 18 years and older. Participants must have evidence of a SARS-CoV-2 infection at least 90 days prior to recruitment, confirmed through specific testing methods. They should exhibit three or more symptoms of PCC affecting at least two organs, persisting for a minimum of two months, and not attributable to other diagnoses. These symptoms may have emerged following recovery from an acute COVID-19 episode or persisted from the initial illness, with potential fluctuations or relapses over time. Participants are required to be unable to perform all usual duties or activities, as defined by grades 3 or 4 in the Post-COVID Functional Status (PCFS) scale. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to comply with the study protocol and be available for follow-up throughout the study duration.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **plitidepsin** in adults with **post-COVID-19 Condition (PCC)**. The trial is structured as a Phase II proof-of-concept study, with an estimated recruitment start date of December 1, 2024, and an estimated end date of December 1, 2026. The trial involves multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, evidence of prior SARS-CoV-2 infection, and the presence of PCC symptoms. Participants will be randomly assigned to receive either plitidepsin or a placebo, administered via **intravenous infusion**.

The trial duration for each participant is approximately four months, with the treatment period lasting up to four weeks. Study visits are scheduled at baseline, day 10, day 30, and day 90, with assessments including the **PROMIS-29®** health scale, adverse event monitoring, and various secondary endpoints such as changes in neuropsychological symptoms, physical activity, and inflammation markers. The primary endpoint is the difference in the PROMIS-29® health scale T-Score between groups on day 90. Secondary endpoints include the proportion of adverse events and changes in functional capacity and quality of life measures.

Participants are expected to comply with the study protocol and attend all scheduled visits. Conditions that may lead to early termination from the study include the occurrence of adverse events of grade 3 or 4, particularly those of special interest such as cardiac or liver events, or acute-infusional reactions. The study aims to provide insights into the potential benefits of plitidepsin for individuals suffering from PCC, contributing to the understanding of treatment options for this condition.

The clinical trial involves the administration of several treatments, including the experimental medication **Plitidepsin**. Plitidepsin is provided in the form of a **powder and solvent for concentrate for solution for infusion**. It is administered via **intravenous infusion**. The maximum daily dose is 1.5 mg, with a total maximum dose of 18 mg over a treatment period of 4 weeks. Plitidepsin is a marine-derived cyclic depsipeptide, and its role in the trial is as the primary investigational product.

**Dexamethasone Phosphate** is used as an auxiliary treatment in the study. It is available as a **solution for injection** and is administered through **intravenous** routes. The maximum daily dose is 6.6 mg, with a total maximum dose of 79.2 mg over the 4-week treatment period. Dexamethasone Phosphate is classified as a glucocorticoid.

**Palonosetron** is another auxiliary treatment, provided as a **solution for injection**. It is administered intravenously, with a maximum daily dose of 250 µg and a total maximum dose of 3000 µg over the course of the study. Palonosetron functions as a 5-HT3 receptor antagonist.

**Famotidine** is included in the trial as an auxiliary treatment in the form of a **tablet**. It is administered orally, with a maximum daily dose of 40 mg and a total maximum dose of 480 mg over the 4-week period. Famotidine acts as a histamine-2 blocker.

**Dexchlorpheniramine** is also used as an auxiliary treatment, available as a **solution for injection**. It is administered intravenously, with a maximum daily dose of 5 mg and a total maximum dose of 60 mg over the treatment duration. Dexchlorpheniramine is classified as an antihistamine.

The study also includes a **placebo** group, which receives a **powder and solvent for solution for injection**. The placebo is administered via **intravenous administration**. The placebo is a lyophilized powder/cake comprising mannitol, with no active pharmacological effect, serving as a control to evaluate the efficacy and safety of Plitidepsin.

The efficacy of the clinical trial will be assessed using the **Patient Reported Outcomes Measurement Information System (PROMIS-29®)** health scale. The primary endpoint is the difference between groups on the PROMIS-29® health scale measured by T-Score on day 90 (±5) of the follow-up period, after the intervention period. Secondary endpoints include the difference between groups on the PROMIS-29® health scale measured by T-Score on day 10 (±2), day 30 (±2), and day 90 (±5) of the follow-up period. Additionally, the trial will evaluate the difference between groups in functional capacity using the PCFS scale and the EuroQoL-5D questionnaire at the same timepoints.

Further assessments will include changes from baseline in neuropsychological symptoms, physical activity, inflammation markers, immunological assessments, viral components in plasma, thromboinflammatory and complement activation components, and hormonal component alterations. These will be measured on day 10 (±2), day 30 (±2), and day 90 (±5) of the follow-up period. The trial will also explore changes in intestinal microbiota in stool samples at these timepoints. The efficacy parameters will be collected and analyzed using validated scales and laboratory tests, ensuring a comprehensive evaluation of the treatment's impact on post-COVID-19 Condition (PCC).