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Principal Investigator: ELLIOTT D CROUSER
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2023
Award: $543,218
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><ACE2><ARDS><Actemra><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Admission><Admission activity><Adult><Adult ARDS><Adult Human><Adult RDS><Adult Respiratory Distress Syndrome><Adverse effects><Age><Alveolar><American><Antiinflammatory Effect><Antiviral Agents><Antiviral Drugs><Antivirals><Appalachia><Appalachian><Appalachian Region><Attenuated><Autopsy><Biological Markers><Biology><Biometrics><Biometry><Biostatistics><Blinded><Blood><Blood Reticuloendothelial System><Bolus><Bolus Infusion><Bypass><CDP Choline><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 antigen><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 pathogenesis><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Caring><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><China><Choline Glycerophospholipids><Choline Phosphoglycerides><Cidifos><Citicoline><Clinic><Clinical><Clinical Evaluation><Clinical Sciences><Clinical Testing><Clinical Trials><Clinical Trials Design><CoV disease><CoV-2><CoV2><Consent><Coronaviridae><Coronavirus><Critical Care><Critical Illness><Critically Ill><Cytidine Diphosphate Choline><Da Nang Lung><Data><Data Analyses><Data Analysis><Death><Development><Dexamethasone><Dose><Drug Kinetics><Dysfunction><Early-Stage Clinical Trials><Enrollment><Epitheliasin Gene><Esteroproteases><Ethnic Origin><Ethnicity><Europe><Experimental Models><Functional disorder><Gases><Gender><Hospital Admission><Hospitalization><Hour><Human><Hygiene><Hypoxemia><Hypoxemic Respiratory Failure><Hypoxic Respiratory Failure><Immune><Immunes><Impairment><Incidence><Infection><Infection Control><Inflammation><Inflammation Mediators><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Investigators><K-18><K-18 conjugate><K18><K18 combination><Lecithin><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lung><Lung Compliance><Lung Inflammation><Lung Respiratory System><Lung damage><Mainland China><Measurement><Measures><Mechanical Ventilators><Medicine><Mice><Mice Mammals><Modern Man><Murine><Mus><Names><O element><O2 element><Organ failure><Orthomyxovirus Type A><Outcome><Outcome Measure><Oxygen><PRSS10><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptidases><Peptide Hydrolases><Pharmaceutical Agent><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Phosphatides><Phosphatidylcholines><Phospholipids><Physical distancing><Physiopathology><Placebo Control><Pneumonitis><Population><Pre-Clinical Model><Preclinical Models><Procedures><Production><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Public Health><Pulmonary Inflammation><Pulmonary Ventilators><Randomized><Receptor Protein><Research Personnel><Research Resources><Researchers><Resources><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 antigen><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 antigen><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Slice><Social Distance><Stiff lung><Subcellular Process><Survivors><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic><Transgenic Mice><Translational Research><Translational Science><Type A Influenza><Type II Pneumocyte><Universities><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Vulnerable Populations><Wuhan coronavirus><accept vaccination><accept vaccine><adulthood><ages><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-inflammatory effect><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><attenuate><attenuates><bio-markers><biologic marker><biomarker><chronic COVID><chronic COVID-19><chronic 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