Supplemental Citicoline Administration for Reduction of Lung Injury Efficacy Trial (SCARLET)

仅在美国，SARS CoV-2大流行就已导致550,000人死亡。危重病人的治疗选择 新冠肺炎患者是有限的。先前的研究表明，严重的低氧血症和肺部的发展 甲型流感病毒感染小鼠的炎症与血管内皮细胞磷脂合成的抑制有关 肺泡II型(ATII)细胞。脂核苷酸对甲型流感病毒感染小鼠的感染后治疗作用 CDP-胆碱是从头合成磷脂酰胆碱的重要前体，它促进了气体交换 并在不改变病毒复制的情况下减少肺部炎症。此外，SARS CoV-2的治疗- CDP-胆碱感染K18-hACE2转基因小鼠预防低氧血症及健肺作用 发炎。最后，对感染甲型流感和感染SARS CoV-2的人精密肺进行治疗 含有CDP-胆碱的切片可减少炎症介质的产生。这些发现表明，受损的 ATII细胞新生磷脂合成是病毒性肺损伤的共同特征，它在很大程度上促进了 出现低氧血症和肺部炎症。假设胞二磷胆碱的给药( 在欧洲被批准用于人类的CDP-胆碱的药剂型)对危重病人是安全的 新冠肺炎患者和临床受益的初步证据将支持更大规模的第二阶段试验 获得一个或多个胞二磷胆碱剂量。这些假设将在一个里程碑驱动的、盲目的 胞磷胆碱在同意的成人中的安慰剂对照、随机1期剂量范围和安全性研究 任何性别、性别、年龄或种族都可以通过新冠肺炎进入ICU。这次试验被命名为“猩红”。 (补充胞二磷胆碱以减少肺损伤的疗效试验)。斯卡利特会证明静脉注射。 胞二磷胆碱在三种剂量中的一种或多种(每次20剂)对危重新冠肺炎患者是安全的，并提供 初步证据表明，静脉注射。胞二磷胆碱可改善这一人群的肺部结局。初见成效 结果将是研究日的血氧饱和度与吸入氧浓度的比率(SpO2：FiO2) 3.探查结果包括序贯器官衰竭评估(SOFA)评分、死腔通气量 指数和肺顺应性。胞磷胆碱对一组与COVID相关的肺和血液生物标志物的影响也将 要下定决心。研究人群将主要由来自未得到充分服务的少数民族的新冠肺炎患者组成 哥伦布和阿巴拉契亚中部和应急计划已经到位，以招收哥伦比亚大学的患者 辛辛那提应该局部减少新冠肺炎的发病率，这是有必要的。如果成功，将进行第二阶段试验 胞二磷胆碱，结合智能设计，以生存为主要结果衡量标准，将被用于 确认胞二磷胆碱的有效性，这可以促进胞二磷胆碱快速转化为临床和潜在的转化 重症SARS CoV-2所致低氧性呼吸衰竭的救治

The SARS CoV-2 pandemic has resulted in >550,000 deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that development of severe hypoxemia and lung inflammation in influenza A virus-infected mice is associated with inhibition of de novo phospholipid synthesis in alveolar type II (ATII) cells. Post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improves gas exchange and reduces pulmonary inflammation without altering viral replication. In addition, treatment of SARS CoV-2- infected K18-hACE2-transgenic mice with CDP-choline prevents development of hypoxemia and attenuates lung inflammation. Finally, treatment of both influenza A-infected and SARS CoV-2-infected human precision cut lung slices with CDP-choline reduces production of inflammatory mediators. These findings suggest that impaired ATII cell de novo phospholipid synthesis is a common feature of viral lung injury that contributes significantly to development of hypoxemia and pulmonary inflammation. It is hypothesized that administration of citicoline (the pharmaceutical form of CDP-choline, which is approved for human use in Europe) will be safe in critically ill patients with COVID-19 and that preliminary evidence of clinical benefit to support a larger Phase 2 trial will be obtained for one or more citicoline doses. These hypotheses will be tested in a milestone-driven, blinded, placebo-controlled, and randomized Phase 1 dose-ranging and safety study of citicoline in consented adults of any sex, gender, age, or ethnicity admitted to the ICU with COVID-19. The trial is named “SCARLET” (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). SCARLET will show that i.v. citicoline is safe at one or more of three doses in critically ill COVID-19 patients (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the ratio of blood oxygen saturation to inspired oxygen concentration ( SpO2:FiO2) on Study Day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined. The study population will consist primarily of COVID-19 patients from underserved minorities in Columbus and central Appalachia and contingency plans are in place to enroll patients from the University of Cincinnati should a local decrease in COVID-19 incidence necessitate this. If successful, a Phase 2 trial of citicoline, incorporating SMART design and with survival as the primary outcome measure, will be conducted to confirm citicoline efficacy, which could facilitate rapid transition of citicoline to the clinic and potentially transform the management of critically ill patients with severe SARS CoV-2-induced hypoxemic respiratory failure.