Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Brequinar Sodium; Dipyridamole 75 MG; Placebo
Intervention description: 50 mg, 100 mg, 150 mg, 200 mg x 5 days; 75 mg TID for 5 days; 50 mg, 100 mg, 150 mg, 200 mg x 5 days
Intervention MeSH terms: Brequinar; Dipyridamole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: All subjects will receive standard of care. In addition, subjects will be randomly assigned to one of 3 treatments: brequinar (50 mg, 100 mg, 150 mg, or 200 mg), placebo (50 mg, 100 mg, 150 mg, or 200 mg), or brequinar + dipyridamole (75 mg TID) in a 2:1:1 ratio in Part 1 of the study using a dose escalation approach. An expansion cohort is planned with the highest safe brequinar dose.
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: All staff will be blinded to treatment with the exception of the pharmacist and any staff recording study drug administration.
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: SARS-CoV-2; Oral antiviral; DHODH Inhibitor; brequinar

Summary:

      A Phase 2 multi-center, assessor-blind, randomized study to assess the safety, tolerability,
      and antiviral activity of brequinar in combination with dipyridamole.
    

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. Subjects between ≥18 and ≤65 years of age.

          3. Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse
             transcription polymerase chain reaction (RT-PCR) using ICMR-validated kit.

             Note: Test need not be repeated in those with possession of confirmed positive report,
             but positive result test date must be ≤5 days of first dose of study drug.

          4. Mild or Moderate COVID-19 as per latest updated version of CLINICAL MANAGEMENT
             PROTOCOL for COVID-19 (in adults) released by Government of India Ministry of Health
             and Family Welfare Directorate General of Health Services (EMR Division).

          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. At least one non-respiratory COVID-19 symptom characterized as mild to moderate by the
             Investigator including but not limited to fatigue, chills, fever, body aches, nasal
             congestion, nausea, vomiting, or other sign or symptom commonly associated with
             COVID-19 in the opinion of the investigator. Symptom onset must be ≤5 days prior to
             first dose. Subject must have one or more signs/symptoms present at first dose.

          8. Willing to participate in the PK subset if at one of the identified sites.

          9. Able to swallow capsules.

        Exclusion Criteria:

          -  1. Have an oxygen saturation of <90% while breathing ambient air. 2. 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 subject.

             3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy
             test.

             4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other
             agents known to cause bone marrow suppression leading to thrombocytopenia.

             5. Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine.
             Remdesivir and ivermectin are prohibited through Study Day 8. Steroids are permitted
             per the guidelines.

             6. Platelets ≤125,000 cell/mm3. 7. Hemoglobin <10 gm/dL. 8. Absolute neutrophil count
             <1000 cells/mm3. 9. Renal dysfunction, i.e., creatinine clearance <30 mL/min. 10. AST
             or ALT >3 x ULN, or total bilirubin >ULN. Gilbert's Syndrome is allowed.

             11. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding
             enrollment.

             12. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of
             first dose.

             13. Chronic hepatitis B infection, active hepatitis C infection, active liver disease
             and/or cirrhosis per subject report.

             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).