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

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.