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.

中文翻译：

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Plitidepsin（一种海洋衍生化合物）在中度 COVID-19 住院成人中的 III 期随机对照试验


背景 Plitidepsin 已显示出对严重急性呼吸系统综合症冠状病毒 2 的强效临床前活性，并且在 2019 年冠状病毒病 （COVID-19） 住院患者的 I 期试验中普遍耐受性良好。NEPTUNO 是一项 III 期、多中心、随机、对照试验，旨在评估 plitidepsin 在住院成年患者中度 COVID-19 治疗中的疗效和安全性。方法 纳入的患者有严重急性呼吸系统综合症冠状病毒 2 感染记录，需要氧疗，并且具有足够的器官功能。计划样本量为 609 名患者。患者以 1：1：1 的比例随机分配至至少 3 天的地塞米松加 plitidepsin （1.5 mg/天或 2.5 mg/天，持续 3 天） 或标准护理 （对照）。主要终点是持续停用补充氧气的时间。次要终点包括持续出院的时间、临床状态、氧气支持的持续时间、需要入住重症监护病房的患者百分比和安全性。结果 在随机分配 205 名患者后，由于 COVID-19 相关住院人数显着下降，NEPTUNO 被停用。现有数据表明，停止持续氧疗的中位时间延长了 2 天（5 天对 7 天），有利于双组 plitidepsin 组（风险比，1.37;95% 置信区间，.96-1.96;plitidepsin 1.5 mg 与对照组相比 P = .08;风险比，1.06;95% 置信区间，.73–1.53;plitidepsin 2.5 mg 与对照组的 P = .78）。Plitidepsin 通常耐受性良好。结论 尽管存在试验局限性，但这些结果表明，plitidepsin 在需要氧疗的患者管理中可能具有正的收益风险比。 有必要对 plitidepsin 进行进一步研究，包括在免疫抑制患者中的研究。这项 III 期试验的结果表明，plitidepsin 是一种一流的抗病毒药物，在管理需要氧疗的中度 COVID-19 住院患者方面可能具有正的收益风险比。