Data_Sheet_1_Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial.DOCX

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients.Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization.Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC.Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19.Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

引言：严重肺部损伤由 SARS-CoV-2 感染及其后宿主免疫反应在部分 COVID-19 患者中触发。方法：我们进行了一项随机、单中心、开放标签的 II 期临床试验，旨在评估甲基强的松龙脉冲联合他克莫司及标准治疗方案（SoC）与仅使用 SoC 相比，在重症 COVID-19 患者中的疗效与安全性。主要结局指标为随机分组后 56 天内达到临床稳定的时间。结果：自 2020 年 4 月 1 日至 5 月 2 日，共纳入 55 名患者进行后续随机分组；其中 27 名分配至实验组，28 名分配至对照组。实验治疗并未与临床稳定时间的差异相关（风险比 0.73 [95% CI 0.39–1.37]）以及大多数次要结局指标相关。实验组甲基强的松龙累积剂量显著降低（中位数 360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007），且治疗时间较短（中位数 4.00 天 [3.00–17.5] vs. 18.5 天 [3.00–53.2]; p = 0.011）。尽管不具有统计学意义，接受实验治疗的患者全因死亡率较接受 SoC 治疗的患者有所降低，尤其在第 10 天时[2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]。两组的非严重不良事件总数均为 42。接受实验治疗的患者非严重感染不良事件发生率[16 (38%) vs. 10 (24%)]和严重感染不良事件发生率[7 (35%) vs. 3 (23%)]均高于接受 SoC 治疗的患者。结论：甲基强的松龙脉冲联合他克莫司与 SoC 联合使用，与单独使用 SoC 相比，在重症 COVID-19 中并未显著改善临床稳定时间或其他次要结局指标。尽管不具有统计学意义，但接受实验治疗的患者全因死亡率较接受 SoC 治疗的患者有所降低，这支持了近期关于钙调神经磷酸酶抑制剂的未随机研究。值得注意的是，本试验样本量有限，且存在其他局限。因此，应进行更多的随机对照试验，以评估他克莫司在应对 COVID-19 炎症阶段中的疗效与安全性。临床试验注册：标识符 [NCT04341038/EudraCT: 2020-001445-39]。