Abstract: Background Plitidepsin has shown potent activity against SARS-CoV-2 in preclinical studies and has proven to be feasible in a Phase I study of hospitalized patients with COVID-19 (NCT04382066).
Methods NEPTUNO was a Phase III, multicenter, randomized, controlled trial that included patients with documented SARS-CoV-2 infection, who required oxygen-therapy, and had adequate organ function. Patients were randomized 1:1:1 to receive at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, as a 1-hour IV infusion for 3 days) or standard-of-care (SOC). A sample size of 609 pts (203/arm) and 530 events were needed to detect a target hazard ratio (HR) of 1.4 [decrease from 8 d (SOC) to 5.7 d (plitidepsin)] with a one-sided type I error rate = 1.25% (Bonferroni adjustment) and ? 80% power for each comparison. The primary endpoint was the time to sustained withdrawal of supple mental 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 poor recruitment related to a notable drop in COVID-19-related hospitalizations, unrelated to any tolerability or safety concerns. Table1 shows patients characteristics. There was a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms: HR=1·37 (95%CI:0·96?1·96, p=0·08) for plitidep 1·5 mg vs control; HR=1·06 (95% CI:0·73?1·53, p=0·78) for plitidepsin 2·5 mg vs control (Fig1). A bootstrap simulation of 10000 samples o patients estimated a HR=1·36 (adjusted p=0·0067) for plitidepsin 1·5 mg vs control. Plitidepsin was generally well tolerated. Table2 represen treatment-related adverse events occurring either with a severity ?grade 3 (NCI-CTCAE) or in at least ? 3% pts.
Conclusions Though no definitive treatment benefit could be established, data suggest that plitidepsin may have a positive benefit-risk ratio in the management of adult patients requiring oxygen therapy. Further studies with plitidepsin, including those ongoing in immunosuppressed patients (NEREIDA, NCT05705167), are warranted.
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