Introduction

The administration of systemic corticosteroids is a key strategy for improving COVID-19 outcomes. However, evidence is lacking on combination therapies of antiviral agents and systemic corticosteroids. The objective of this study was to investigate the efficacy and safety of the combination therapy of favipiravir and methylprednisolone in preventing respiratory failure progression in patients with COVID-19 and non-critical respiratory failure.

Methods

We conducted a multicenter, open-label, single-arm phase II study. The patients received favipiravir 3600 mg on the first day, followed by 1600 mg for a total of 10–14 days. Methylprednisolone was administered intravenously at 1 mg/ideal body weight (IBW)/day from days 1 to 5, followed by 0.5 mg/IBW/day from days 6 to 10 if clinically indicated. The primary endpoint was the proportion of patients requiring mechanical ventilation (MV) (including noninvasive positive pressure ventilation) or those who met the criteria for tracheal intubation within 14 days of the study treatment initiation (MVCTI-14).

Results

Sixty-nine patients were enrolled and underwent the study treatment. Of them, the MVCTI-14 proportion was 29.2% (90% confidence interval 20.1–39.9, p = 0.200). The proportion of patients who required MV or who died within 30 days was 26.2%, and 30-day mortality was 4.9%. The most significant risk factor for MVCTI-14 was a smoking history (odds ratio 4.1, 95% confidence interval 1.2–14.2). The most common grade 3–4 treatment-related adverse event was hyperglycemia, which was observed in 21.7%.

Conclusion

The MVCTI-14 proportion did not reach a favorable level in the clinical trial setting with the threshold of 35%. However, the proportion of MV or death within 30 days was 26.6%, which might be close to the findings (28.1%) of the RECOVERY trial, which showed the efficacy of dexamethasone for patients with COVID-19 and non-critical respiratory failure. Further evaluation of this combination therapy is needed.

Clinical Trial Registration

Japan Registry of Clinical Trials (jRCT) identifier jRCTs041200025.

中文翻译：

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法匹拉韦和甲基强的松龙联合治疗 COVID-19 非重症呼吸衰竭的 II 期临床试验

介绍

全身性皮质类固醇的给药是改善 COVID-19 结果的关键策略。然而，缺乏抗病毒药物和全身皮质类固醇联合治疗的证据。本研究的目的是调查法匹拉韦和甲基强的松龙联合治疗在预防 COVID-19 和非危重呼吸衰竭患者呼吸衰竭进展中的有效性和安全性。

方法

我们进行了一项多中心、开放标签、单臂 II 期研究。患者在第一天接受法匹拉韦 3600 毫克，然后是 1600 毫克，总共 10-14 天。从第 1 天到第 5 天，以 1 毫克/理想体重 (IBW)/天的剂量静脉注射甲基强的松龙，如果有临床指征，则在第 6 天到第 10 天以 0.5 毫克/IBW/天的剂量静脉给药。主要终点是需要机械通气 (MV)（包括无创正压通气）或在研究治疗开始后 14 天内符合气管插管标准的患者比例 (MVCTI-14)。

结果

69 名患者入组并接受了研究治疗。其中，MVCTI-14 比例为 29.2%（90% 置信区间 20.1-39.9，p  = 0.200）。需要 MV 或在 30 天内死亡的患者比例为 26.2%，30 天死亡率为 4.9%。MVCTI-14 最重要的危险因素是吸烟史（比值比 4.1，95% 置信区间 1.2-14.2）。最常见的 3-4 级治疗相关不良事件是高血糖，发生率为 21.7%。

结论

MVCTI-14 比例在临床试验环境中没有达到有利的水平，阈值为 35%。然而，30 天内 MV 或死亡的比例为 26.6%，这可能接近 RECOVERY 试验的结果（28.1%），该试验显示了地塞米松对 COVID-19 和非危重呼吸衰竭患者的疗效。需要进一步评估这种联合疗法。

临床试验注册

日本临床试验注册 (jRCT) 标识符 jRCTs041200025。