Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19
Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19
This will be a phase 1a randomized, open label, multi-center study with approximately 24
 subjects. All subjects will receive standard of care (SOC) per institutional guidelines for
 treatment of hospitalized patients with COVID-19 infection. In addition to SOC, the brequinar
 group will receive 5 daily doses of brequinar 100 mg.
This will be a phase 1a randomized, open label, multi-center study with approximately 24
 subjects. All subjects will receive standard of care (SOC) per institutional guidelines for
 SARS-CoV-2 infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care
 alone or standard of care plus brequinar. The brequinar group will receive 5 daily doses of
 brequinar 100 mg on Days 1 - 5. Physical examinations, vital signs, laboratory assessments,
 SARS-CoV-2 testing, and other observations will be conducted by experienced personnel
 throughout the study based on the Schedule of Events. Blood chemistry tests include blood
 urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), alanine amino transferase (ALT),
 aspartate amino transferase (AST), bilirubin, total protein, albumin, glucose, serum
 electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, and calcium), lactate
 dehydrogenase (LDH). Plasma will be collected for inflammatory markers such as D-dimer,
 ferritin, CRP, and ESR. Pro-inflammatory markers will be measured. Serum is to be collected
 for research purposes. Hematology tests include hemoglobin, hematocrit, complete blood count
 with full differential, and platelet count. Nasopharyngeal swabs for viral load will be
 collected Days 1, 3, 5, 7, and 15. Survival will be assessed through Day 29.
Inclusion Criteria:

 1. Willing and able to provide informed consent for the trial, written, electronic,
 verbal or other method deemed acceptable by the institution and IRB.

 2. 18 years of age or older.

 3. If discharged from the hospital prior to Study Day 15 or if follow up is needed for
 study drug-related adverse event, willing to go to an outpatient facility if feasible
 or be in contact with the study team (phone call or other digital media) for remaining
 study assessments.

 4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase chain
 reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared commercial or
 public health assay.

 5. Hospitalized (in patient with expected duration ≥ 24 hours)

 6. The effects of brequinar on the developing human fetus are unknown. For this reason,
 women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry and for
 the duration of study participation. Should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately. Men and women treated or enrolled on this protocol
 must also agree to use adequate contraception for the duration of study participation
 and for 90 days after completion of brequinar administration.

 7. Male subjects must agree to refrain from sperm donation from initial study drug
 administration until 90 days after the last dose of brequinar.

 8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician.

 9. Able to swallow capsules.

 10. At least one COVID-19 symptom including but not limited to fever, cough, sore throat,
 malaise, headache, muscle pain, gastrointestinal symptoms, shortness of breath,
 dyspnea, dysgeusia, or other symptom commonly associated with COVID-19.

 Exclusion Criteria:

 1. Any physical examination findings and/or history of any illness that, in the opinion
 of the study investigator, might confound the results of the study or pose an
 additional risk to the patient.

 2. Active malignancy other than squamous cell carcinoma; anticancer treatment such as
 chemotherapy or radiation therapy within the past month.

 3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy
 test.

 4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide),
 tacrolimus, sirolimus.

 5. Platelets ≤150,000 cell/mm3.

 6. Hemoglobin < 10 gm/dL

 7. Absolute neutrophil count < 1500 cells/mm3

 8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min

 9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN

 10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment

 11. Concomitant use of agents known to cause bone marrow suppression leading to
 thrombocytopenia

 12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.

 13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.

 14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina,
 uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke,
 myocardial infarction, hospitalization due to heart failure, or revascularization
 procedure).

 15. Life expectancy of < 5 days in the judgment of the treating clinician.

 16. Evidence of critical illness defined by at least one of the following:

 a. Respiratory failure requiring at least one of the following: i. Endotracheal
 intubation and mechanical ventilation, noninvasive positive pressure ventilation,
 ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for one of the
 preceding therapies, but preceding therapies may not be able to be administered in
 setting of resource limitation) ii. Shock (defined by systolic blood pressure < 90 mm
 Hg, or diastolic blood pressure < 60 mm Hg or requiring vasopressors) b. Multi-organ
 dysfunction/failure.