CRISIS2: A Phase 2 Study of the Safety and Antiviral Activity of Brequinar in Non-hospitalized Pts With COVID-19
Condition: COVID-19 Infection
MeSH terms: COVID-19
Intervention: Brequinar; Placebo
Intervention description: Dihydroorotate dehydrogenase inhibitor (DHODHi); Placebo capsules
Intervention MeSH terms: Brequinar
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized 1:1 brequinar 100 mg or placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double blind
Enrollment: 115.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study will assess the efficacy and safety of DHODHi (brequinar) as an antiviral via 5
      days of treatment of participants with positive COVID-19 and at least one symptom of COVI019
      in an out-patient setting. The study is multi-center, randomized, and placebo-controlled.
    

Eligibility criteria:

        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. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase chain
             reaction (RT-PCR) or other FDA-approved commercial or public health assay.

          4. Out-patient (never hospitalized as an in-patient for COVID-19 or was evaluated/treated
             for COVID-19 only in the Emergency Room with a stay of < 24 hours)

          5. 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.

          6. Male subjects must agree to refrain from sperm donation and female subjects must agree
             to refrain from ovum donation from initial study drug administration until 90 days
             after the last dose of brequinar.

          7. Must have 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, anosmia, dysgeusia, or other symptom commonly associated with
             COVID-19 in the opinion of the investigator. Symptom onset must be ≤7 days prior to
             first dose. Subject must have one or more symptoms at first dose.

          8. Able to swallow capsules.

        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. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy
             test

          3. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other
             agents known to cause bone marrow suppression leading to thrombocytopenia

          4. Platelets ≤150,000 cell/mm3

          5. Hemoglobin < 10 gm/dL

          6. Absolute neutrophil count < 1500 cells/mm3

          7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min

          8. AST or ALT > 2 x ULN, or total bilirubin > ULN. Gilbert's Syndrome is allowed.

          9. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding
             enrollment

         10. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of
             randomization.

         11. Chronic hepatitis B infection, active hepatitis C infection, active liver disease
             and/or cirrhosis per subject report.

         12. 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).