Data_Sheet_2_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.PDF

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].

研究背景：部分新冠病毒（SARS-CoV-2）感染患者会出现重度肺损伤，其诱因既包括病毒感染本身，也包括后续引发的宿主免疫应答反应。
研究方法：本研究开展一项随机单中心开放标签II期临床试验，旨在评估甲泼尼龙（methylprednisolone）冲击联合他克莫司（tacrolimus）附加标准治疗方案（standard of care, SoC）对比单纯标准治疗方案，用于住院重症新冠患者的疗效与安全性。本研究的主要终点为随机分组后56天内达到临床稳定的时间。
研究结果：2020年4月1日至5月2日期间，共前瞻性纳入55名患者并完成随机分组，其中27名被分配至试验组，28名被分配至对照组。试验组治疗方案未显著改善患者达到临床稳定的时间（风险比0.73 [95%置信区间0.39–1.37]），且对多数次要终点亦无显著影响。与对照组相比，试验组患者的甲泼尼龙累积中位剂量显著更低（360 mg [四分位数间距360–842] vs. 870 mg [四分位数间距364–1451]; p = 0.007），给药中位时长也更短（试验组为4.00天 [3.00–17.5]，对照组为18.5天 [3.00–53.2]; p = 0.011）。尽管未达到统计学显著性，试验组患者的全因死亡率数值上低于对照组，尤其是在第10天[2例（7.41%）vs. 5例（17.9%）；优势比0.39（95%置信区间0.05–2.1）; p = 0.282]。两组的非严重不良事件总数均为42例。试验组患者的非严重感染性不良事件发生率[16例（38%）vs. 10例（24%）]与严重感染性不良事件发生率[7例（35%）vs. 3例（23%）]均高于对照组。
研究结论：在重症新冠患者中，相较于单纯标准治疗方案，甲泼尼龙冲击联合他克莫司附加标准治疗方案并未显著改善患者达到临床稳定的时间或其他次要终点。尽管未达到统计学显著性，试验组患者的全因死亡率仍低于对照组，这与近期针对钙调磷酸酶抑制剂的非随机对照研究结果一致。值得注意的是，本试验样本量有限且存在其他若干局限性，因此需开展进一步的随机对照试验（RCT）以评估他克莫司用于干预新冠炎症阶段的疗效与安全性。
临床试验注册：标识符[NCT04341038/EudraCT: 2020-001445-39]。