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

补充胞二磷胆碱减少肺损伤疗效试验（SCARLET）

基本信息

批准号：
10406027
负责人：
ELLIOTT D CROUSER
金额：
$ 57.66万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406027
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Adult Adverse effects Age Alveolar American Antiinflammatory Effect Antiviral Agents Appalachian Region Attenuated Autopsy Biological Markers Biology Biometry Blinded Blood Bolus Infusion Bypass COVID-19 COVID-19 pandemic COVID-19 pathogenesis COVID-19 patient COVID-19 treatment Caring Cell physiology Cells Cessation of life China Clinic Clinical Clinical Sciences Clinical Trials Clinical Trials Design Consent Coronavirus Critical Care Critical Illness Cytidine Diphosphate Choline Data Data Analyses Development Dexamethasone Dose Drug Kinetics Enrollment Ethnic Origin Europe Experimental Models Functional disorder Gases Gender Hour Human Hygiene Hypoxemia Hypoxemic Respiratory Failure Immune Impairment Incidence Infection Infection Control Inflammation Inflammation Mediators Influenza A virus K-18 conjugate Lecithin Long COVID Lung Lung Compliance Measurement Measures Mechanical Ventilators Medicine Mus Names Organ failure Outcome Outcome Measure Oxygen Patient-Focused Outcomes Patients Peptide Hydrolases Pharmacologic Substance Phase Phase I Clinical Trials Phospholipids Placebo Control Population Pre-Clinical Model Procedures Production Public Health Pulmonary Inflammation Randomized Research Personnel Resources Risk SARS-CoV-2 antigen SARS-CoV-2 infection Safety Sampling Slice Social Distance Survivors TMPRSS2 gene Testing Therapeutic Transgenic Mice Translational Research Universities Vaccines Viral Virus Virus Diseases Virus Replication Vulnerable Populations alveolar type II cell clinical center clinical efficacy coronavirus disease design efficacy outcomes efficacy trial high risk human subject improved improved outcome indexing lung injury medical countermeasure mortality mutant novel phase II trial prevent primary outcome pulmonary function receptor research clinical testing safety study severe COVID-19 sex small molecule socioeconomics study population tocilizumab underserved minority vaccine acceptance ventilation

项目摘要

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.

仅在美国，SARS CoV-2 大流行就已导致超过 55 万人死亡。先前的研究表明，患有 COVID-19 的患者会出现严重的低氧血症和肺部疾病。甲型流感病毒感染小鼠的炎症与磷脂从头合成的抑制有关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，可改善气体交换肺部可在不改变病毒复制的情况下减少炎症。此外，还可以治疗 SARS CoV-2-。用 CDP-胆碱感染 K18-hACE2 转基因小鼠可预防低氧血症的发生并减弱肺功能最后，治疗甲型流感病毒感染者和SARS CoV-2感染者的精确切割肺。 CDP-胆碱产生的切片减少了炎症介质的产生。 ATII 细胞从头合成磷脂是病毒性肺损伤的一个共同特征，对重新认识到胞磷胆碱（胞二磷胆碱）的使用。 CDP-胆碱的药物形式（在欧洲已被批准用于人类）对于危重患者来说是安全的患有 COVID-19 的患者，并且支持更大规模的 2 期试验的临床益处的初步证据将这些假设将以里程碑驱动的、盲法的方式进行测试。在同意的成年人中进行安慰剂对照、随机 1 期胞磷胆碱剂量范围和安全性研究任何因性别、性别、年龄或种族而入住 ICU 的 COVID-19 试验被命名为“SCARLET”。（补充胞二磷胆碱减少肺损伤的功效试验将表明静脉注射）。对于重症 COVID-19 患者，胞磷胆碱服用三剂中的一剂或多剂是安全的（每剂 20 剂），并提供初步证据表明静脉注射胞磷胆碱可改善该人群的肺部结局。结果将是研究当天的血氧饱和度与吸入氧浓度 (SpO2:FiO2) 的比率 3. 探索性结果包括序贯器官衰竭评估（SOFA）评分、死腔通气指数和肺顺应性对一组与新冠病毒相关的肺和血液生物标志物的影响。研究人群将主要包括来自服务不足的少数族裔的 COVID-19 患者。哥伦布和阿巴拉契亚中部已经制定了应急计划，以招募来自哥伦布大学的患者如果成功，辛辛那提应该进行 2 期试验，以减少当地的 COVID-19 发病率。胞二磷胆碱，结合 SMART 设计，并以生存为主要结局指标，将进行确认胞磷胆碱的功效，这可以促进胞磷胆碱快速过渡到临床并有可能转化严重 SARS CoV-2 引起的低氧性呼吸衰竭危重患者的治疗。