Abstract：
Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19.
We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described.
We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively).
Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.
We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described.
We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively).
Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.
摘要：
2019年严重冠状病毒病（COVID-19）的呼吸衰竭与严重的炎症反应有关。乙酰胆碱（ACh）减少实验性细菌和病毒感染中的全身性炎症。吡啶斯的明增加内源性ACh的半衰期，可能减少全身性炎症。我们的目的是确定吡啶斯的明是否会降低重度COVID-19成年患者有创机械通气（IMV）和死亡的复合结局。
我们表演了双盲,安慰剂对照,2/3期随机对照试验,对因确诊的重度COVID-19在纳入时不需要IMV而入院的成年患者进行口服吡啶斯的明(60mg/天)或安慰剂作为附加治疗.主要结果是28天IMV或死亡的复合。次要结果包括炎症标志物和循环细胞因子的减少，90天死亡率。记录并描述与研究治疗相关的不良事件(AE)。
我们招募了188名参与者（每组94名）；112名（59.6%）为男性；中位（IQR）年龄为52（44-64）岁。由于治疗组的主要结局显着降低并且招募难度增加，因此该研究提前终止。主要结局发生在安慰剂组的22名（23.4％）参与者与吡啶斯的明组11人(11.7%)(危害比，0.47，95%置信区间0.24-0.9；P=0.03）。这种影响是由死亡率降低(19vs.8人死亡,分别)。
我们的数据表明，在标准治疗中添加吡啶斯的明可降低重症COVID-19住院患者的死亡率。
我们表演了双盲,安慰剂对照,2/3期随机对照试验,对因确诊的重度COVID-19在纳入时不需要IMV而入院的成年患者进行口服吡啶斯的明(60mg/天)或安慰剂作为附加治疗.主要结果是28天IMV或死亡的复合。次要结果包括炎症标志物和循环细胞因子的减少，90天死亡率。记录并描述与研究治疗相关的不良事件(AE)。
我们招募了188名参与者（每组94名）；112名（59.6%）为男性；中位（IQR）年龄为52（44-64）岁。由于治疗组的主要结局显着降低并且招募难度增加，因此该研究提前终止。主要结局发生在安慰剂组的22名（23.4％）参与者与吡啶斯的明组11人(11.7%)(危害比，0.47，95%置信区间0.24-0.9；P=0.03）。这种影响是由死亡率降低(19vs.8人死亡,分别)。
我们的数据表明，在标准治疗中添加吡啶斯的明可降低重症COVID-19住院患者的死亡率。
