PDF(Pubmed)
Abstract：
BACKGROUND: Targeting receptor-interacting serine/threonine protein kinase 1 could mitigate the devastating sequelae of the hyperinflammatory state observed in severe cases of COVID-19. This study explored the immunomodulatory and clinical effects of the receptor-interacting serine/threonine protein kinase 1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19.
METHODS: In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored.
RESULTS: Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0.85 (0.49-1.45; p = 0.30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0.056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0.38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia.
CONCLUSIONS: Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo.
RESULTS:
UNASSIGNED: NCT04469621, first posted on clinicaltrials.gov on July 14, 2020.
METHODS: In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored.
RESULTS: Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0.85 (0.49-1.45; p = 0.30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0.056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0.38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia.
CONCLUSIONS: Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo.
RESULTS:
UNASSIGNED: NCT04469621, first posted on clinicaltrials.gov on July 14, 2020.
摘要：
背景：靶向受体相互作用的丝氨酸/苏氨酸蛋白激酶1可以减轻在COVID-19严重病例中观察到的高炎性状态的破坏性后遗症。这项研究探讨了受体相互作用的丝氨酸/苏氨酸蛋白激酶1抑制剂SAR443122（eclitasertib）对重症COVID-19患者的免疫调节和临床作用。
方法：在此阶段1b，双盲,安慰剂对照研究（NCT04469621）共筛选82例患者，其中68例患者符合资格,并随机(2:1)接受eclitasertib600mg(300mg,每日2次)或安慰剂治疗14天.主要结果是C反应蛋白从基线到第7天的相对变化。使用7点序数量表进行临床改善的时间，呼吸机/无呼吸衰竭天数,SpO2/FiO2比值的变化，并探索了重症COVID-19的生物标志物。
结果：与eclitasertib相比，C反应蛋白相对于基线的相对变化的几何平均比（点估计[90％置信区间]）第7天的安慰剂为0.85(0.49-1.45;p=0.30).C反应蛋白从基线下降50%的中位时间为3天，与5天（p=0.056）与eclitasertib安慰剂。7点临床症状量表改善≥2点的中位时间为8天。10天与eclitasertibvs.安慰剂（p=0.38）。平均无呼吸机/呼吸衰竭天数，基线调整后的SpO2/FiO2比值的变化，与eclitasertib相比，临床生物标志物显示出一致的数值改善安慰剂。最常报告的因治疗引起的不良事件是胃肠道疾病和病情加重/恶化的COVID-19肺炎。
结论：与安慰剂相比，重度COVID-19患者的炎症生物标志物迅速消退和临床改善趋势一致。
结果：
■NCT04469621，于2020年7月14日首次发布在clinicaltrials.gov上。
方法：在此阶段1b，双盲,安慰剂对照研究（NCT04469621）共筛选82例患者，其中68例患者符合资格,并随机(2:1)接受eclitasertib600mg(300mg,每日2次)或安慰剂治疗14天.主要结果是C反应蛋白从基线到第7天的相对变化。使用7点序数量表进行临床改善的时间，呼吸机/无呼吸衰竭天数,SpO2/FiO2比值的变化，并探索了重症COVID-19的生物标志物。
结果：与eclitasertib相比，C反应蛋白相对于基线的相对变化的几何平均比（点估计[90％置信区间]）第7天的安慰剂为0.85(0.49-1.45;p=0.30).C反应蛋白从基线下降50%的中位时间为3天，与5天（p=0.056）与eclitasertib安慰剂。7点临床症状量表改善≥2点的中位时间为8天。10天与eclitasertibvs.安慰剂（p=0.38）。平均无呼吸机/呼吸衰竭天数，基线调整后的SpO2/FiO2比值的变化，与eclitasertib相比，临床生物标志物显示出一致的数值改善安慰剂。最常报告的因治疗引起的不良事件是胃肠道疾病和病情加重/恶化的COVID-19肺炎。
结论：与安慰剂相比，重度COVID-19患者的炎症生物标志物迅速消退和临床改善趋势一致。
结果：
■NCT04469621，于2020年7月14日首次发布在clinicaltrials.gov上。
