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

SARS CoV-2大流行仅在美国就导致超过55万人死亡。危重患者的治疗选择 COVID-19患者数量有限。先前的研究表明，严重低氧血症和肺 甲型流感病毒感染的小鼠的炎症与 肺泡II型（ATII）细胞。用脂核苷酸对甲型流感病毒感染的小鼠进行感染后治疗 CDP-胆碱是磷脂酰胆碱从头合成的重要前体，可改善气体交换 并减少肺部炎症而不改变病毒复制。此外，治疗SARS CoV-2- CDP-胆碱感染K18-hACE 2转基因小鼠可预防低氧血症的发生并减轻肺损伤 炎症最后，治疗同时感染甲型流感病毒和SARS CoV-2感染的人体精确切肺 具有CDP-胆碱的切片减少炎症介质的产生。这些发现表明， ATII细胞从头磷脂合成是病毒性肺损伤的共同特征，其显著促进了肺损伤的发生。 低氧血症和肺部炎症的发展。据推测，胞磷胆碱（ CDP-胆碱的药物形式，在欧洲被批准用于人类使用）将在重症患者中安全 患者的COVID-19和临床效益的初步证据，以支持更大的2期试验将 获得一个或多个胞磷胆碱剂量。这些假设将在里程碑驱动的、设盲的、 一项在知情同意的成年人中进行的胞磷胆碱安慰剂对照和随机化I期剂量范围探索和安全性研究 任何性别、性别、年龄或种族的COVID-19患者入住ICU。该试验被命名为“SCARLET” （补充胞二磷胆碱给药以减少肺损伤功效试验）。SCARLET将显示i. v. 胞磷胆碱在重症COVID-19患者中的三种剂量中的一种或多种是安全的（每剂20），并提供 初步证据表明，静脉注射胞磷胆碱可改善这一人群的肺部预后。主要疗效 结果为研究日血氧饱和度与吸入氧浓度的比值（SpO 2：FiO 2） 3.探索性结局包括序贯器官衰竭评估（SOFA）评分、死腔通气 指数和肺顺应性。胞二磷胆碱对一组COVID相关肺和血液生物标志物的影响也将 下定决心。研究人群将主要包括来自少数民族的COVID-19患者， 哥伦布和中央阿巴拉契亚和应急计划已经到位， 辛辛那提，如果当地COVID-19发病率下降，有必要这样做。如果成功的话， 胞二磷胆碱，结合SMART设计和生存作为主要结局指标，将进行， 证实胞磷胆碱的疗效，这可能有助于胞磷胆碱快速过渡到临床，并可能转化为 重症SARS CoV-2引起的低氧血症性呼吸衰竭的危重患者的管理。

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.