Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults With Post-COVID-19 Condition (PCC)

Phase II Proof-of-concept, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Plitidepsin in Adults With Post-COVID-19 Condition (PCC)

The study aims to prove that plitidepsin could be an efficacious, safe, and well-tolerated therapy for PCC. To this end, we will perform a randomized, double-blind study comparing the clinical and laboratory benefits of plitidepsin vs. placebo in 90 subjects with moderate to severe functional disability. The study consists of an intervention period and a follow-up period, with a total of 135 +/-3 days approximately between both periods.

During the intervention period, four treatment cycles will be administered, scheduled every 15 days (every 2 weeks), with intravenous (IV) infusion over three consecutive days. After completing the intervention period, a 90-day (+/-5) follow-up period will be conducted.

Subjects in arm A will receive the plitidepsin 1.5 mg/day 1h-IV during the four treatment periods on Days 1 to 3, Days 15 to 17, Days 29 to 31 and Days 43 to 45. Subjects in arm B will receive 1h-IV placebo 1 vial /day during the first two treatment periods and will receive the plitidepsin 1.5 mg/day 1h-IV during the last two treatment periods. Subjects in arm C will receive 1h-IV placebo 1 vial/day during the four treatment periods.

Plitidepsin, a marine-derived cyclic depsipeptide that inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A, could be a suitable candidate treatment for "Long COVID" because of a triple mechanism of action; a) it has demonstrated potent anti-SARS-CoV-2 in vitro activity, (b) it has a systemic anti-inflammatory effect, detailed in the text below, and (c) has an anti-herpes antiviral effect, which could provide additional therapeutic benefits to prevent herpesvirus reactivation seen in Long-COVID.

An interim analysis will be conducted upon reaching 30% and 50% of recruitment (patients treated with at least one dose and 28 days (+/- 2 days) of FUP)). The first interim analysis will focus exclusively on safety assessment, based on adverse events reported to date. The second interim analysis (50%) will evaluate safety and futility. A blinded safety report will be prepared, summarizing adverse events, and submitted to the Data Safety Monitoring Board (DSMB) for review and to determine whether to continue, modify, or terminate the study

1. Male or female individuals 18 years old or older.
2. Evidence of SARS-CoV-2 infection at least 90 days prior to study recruitment, defined by either (a) nasopharyngeal SARS-CoV-2 nucleic acid test [polymerase chain reaction (PCR) or transcription mediated amplification (TMA)], (b) validated Nasopharyngeal Lateral Flow Assay rapid antigen test (RAT), or (c) or positive serology against SARS-CoV-2 N protein regardless vaccination status.
3. 3 or more symptoms of PCC affecting at least two organs, after 90 days from the onset of SARS-CoV2 infection and that last for at least 2 months and cannot be explained by an alternative diagnosis. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.
4. Unable to perform all usual duties/activities, defined as grades 3 or 4 in PCFS (Annex 3).
5. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
6. Having understood the information provided and capable of providing informed consent

EXCLUSION CRITERIA

1. Last SARS-CoV-2 vaccine dose during the previous 30 days.

2. Patients with active uncontrolled infections.

3. Patients infected by SARS-CoV-2 virus in the last 90 days prior to the screening visit.

4. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (Annex 1) throughout plitidepsin treatment period and until 24-h washout period.

5. Pacients receiving chronic glucocorticoid therapy (high-dose corticosteroids [ie, 20 mg of prednisone daily or equivalent for ≥2 weeks)

6. Any of the following cardiac conditions or risk factors:

   • Cardiac infarction or cardiac surgery episode within the last six months 14
   • History of known congenital QT prolongation;
   • Known structural cardiomyopathy with abnormal left ventricular ejection fraction (LVEF) <50%;
   • Current clinical evidence of heart failure or acute cardiac ischaemia (New York Heart Association (NYHA) class III-IV).

7. Hypersensitivity to the active ingredient or any of the excipients (mannitol, macrogolglycerol hydroxystearate, and ethanol) or contraindication to receive systemic glucocorticoids, antihistamine H1/H2 receptor agents, or antiserotonine 5HT3 receptors drugs.

8. Mast cell activation syndrome.

9. Females who are pregnant (negative serum or urine pregnancy test required for all females of childbearing potential at screening) or breast-feeding.

10. Females of childbearing potential (females who are not surgically sterile or postmenopausal defined as amenorrhea for >12 months) who are not using highly effective contraceptive methods, while on study treatment and for 6 months after last dose of plitidepsin. Fertile males with partners of childbearing potential must use condom during treatment and for 6 months after last dose of plitidepsin. Refer to Annex 2 for contraception requirements.

11. Unable to consent and/or comply with study requirements, in the opinion of the investigator.

12. Currently participating or participated in a clinical trial within the prior