Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy.

Methods

COVID-19 patients with moderate pneumonia (SpO₂ ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO₂), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions.

Results

A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher.

Conclusions

The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered.

Trial registration

Clinicaltrials.jp number: JapicCTI-205238.

中文翻译：

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法匹拉韦在未接受氧疗的中度 COVID-19 肺炎患者中的疗效和安全性：一项随机 III 期临床试验

介绍

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 是 2019 年冠状病毒病 (COVID-19) 的病因，是一种有包膜的单链 RNA 病毒。法匹拉韦是一种口服抗病毒药物，其作用机制是选择性抑制依赖于 RNA 的 RNA 聚合酶。一项针对 COVID-19 患者的初步试验报告称，多项临床参数均有显着改善，但这些发现尚未在充分对照良好的试验中得到证实。我们进行了一项随机、单盲、安慰剂对照的 III 期试验，评估法匹拉韦对不需要氧疗的中度肺炎患者的疗效和安全性。

方法

 在发烧（体温≥ 37.5 °C）后 10 天内患有中度肺炎（SpO ₂ ≥ 94%）的COVID-19 患者被分配接受安慰剂或法匹拉韦（第 1 天每天两次 1800 毫克，然后是 800 毫克）每天两次，最多 13 天），比例为 1:2。自适应设计用于重新估计样本量。主要终点是复合结果，定义为温度、氧饱和度水平 (SpO ₂ ) 和胸部成像结果改善的时间，以及恢复到 SARS-CoV-2 阴性的时间。中央委员会在盲法条件下重新审查了这一终点。

结果

共有 156 名患者被随机分组​​。法匹拉韦组和安慰剂组主要终点的中位时间分别为 11.9 天和 14.7 天，差异显着（p  = 0.0136）。具有已知危险因素（如肥胖或共存疾病）的法匹拉韦治疗的患者提供了更好的效果。此外，法匹拉韦组中的早发患者显示出更高的优势比。没有死亡记录。尽管法匹拉韦组的不良事件主要是短暂的，但发生率明显更高。

结论

结果表明，法匹拉韦可能是中度 COVID-19 肺炎治疗的选择之一。然而，应仔细考虑不良事件的风险，包括高尿酸血症。

试用注册

Clinicaltrials.jp 编号：JapicCTI-205238。