A Phase III Randomized Controlled Trial of Plitidepsin, a Marine-Derived Compound, in Hospitalized Adults With Moderate COVID-19

Abstract

Background: Plitidepsin has shown potent preclinical activity against severe acute respiratory syndrome coronavirus 2 and was generally well tolerated in a phase I trial of hospitalized patients with coronavirus disease 2019 (COVID-19). NEPTUNO, a phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients.

Methods: Included patients had documented severe acute respiratory syndrome coronavirus 2 infection, required oxygen therapy, and had adequate organ function. The planned sample size was 609 patients. Patients were randomized 1:1:1 to at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, for 3 days) or standard of care (control). The primary endpoint was the time to sustained withdrawal of supplemental oxygen. Secondary endpoints included time to sustained hospital discharge, clinical status, duration of oxygen support, percentage of patients requiring admission to the intensive care unit, and safety.

Results: After randomizing 205 patients, NEPTUNO was discontinued due to a notable drop in COVID-19-related hospitalizations. Available data suggest a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms (hazard ratio, 1.37; 95% confidence interval, .96-1.96; P = .08 for plitidepsin 1.5 mg vs control; hazard ratio, 1.06; 95% confidence interval, .73-1.53; P = .78 for plitidepsin 2.5 mg vs control). Plitidepsin was generally well tolerated.

Conclusions: Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted.Results from this phase III trial suggest that plitidepsin, a first-in-class antiviral, may have a positive benefit-risk ratio in the management of hospitalized patients requiring oxygen therapy for moderate COVID-19.

Trial registration: ClinicalTrials.gov NCT04784559 NCT05705167.

Keywords: COVID-19; SARS-CoV-2; antiviral agents; marine compounds; plitidepsin.

Figure 1.

CONSORT diagram.

Figure 2.

Time to sustained withdrawal of oxygen supplementation for (A) plitidepsin 1.5 mg versus control and (B) plitidepsin 2.5 mg versus control. Sustained withdrawal of oxygen supplementation (in days) with no subsequent reutilization during remaining study period is defined as the first day, from randomization through completion of the trial, on which a patient satisfies categories 0–4 on the 11-point World Health Organization (WHO) Clinical Progression Scale and has no subsequent reutilization of oxygen supplementation (5–10 on the 11-point WHO Clinical Progression Scale). If the patient is discontinued between day 15 and day 31 visits, and there is an attempt of contact and trial discontinuation on or after the day 31 visit due date, the patient is censored at day 31.