Brequinar Combined With Dipyridamole in Patients With Mild to Moderate COVID-19

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

Detailed Description
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This is a Phase 2 clinical trial in two parts. The first part of the trial will study up to 64 subjects using a dose escalation approach, with 16 subjects per cohort for up to 4 cohorts. The brequinar dose will start at 50 mg per day in Cohort 1, escalating in the next cohort of 16 to 100 mg, then to 150 mg, and finally to 200 mg if safety parameters are met. The dipyridamole dose will be 75 mg three times a day (TID) for subjects assigned to the combination arm for all cohorts. All subjects will also receive standard of care (SOC) for treatment of patients with COVID-19 infection. After identifying the highest brequinar dose that is safe and well tolerated, 48 subjects will be treated in an expansion part comparing the chosen brequinar dose in combination with 75 mg dipyridamole TID to the chosen dose of brequinar alone. The combination of brequinar and dipyridamole shows potent in vitro antiviral activity by blocking DHODH and the pyrimidine salvage pathway, respectively, and the purpose of this study is to establish the safety and antiviral effect of the combination. During the dose escalation part of the study, subjects with confirmed mild to moderate COVID-19 will receive 5 days of one of the following oral doses: brequinar alone, brequinar in combination with dipyridamole, or placebo. Subjects will have a Screening Visit followed as soon as possible with Study Day 1. Study visits (virtual or in person) will take place at Screening and on specified days. The visits that include bloodwork must be conducted at the study site or arrangements made for sample collection at the subject's home or other appropriate location. Other visits/visit activities for that visit may be conducted remotely using telemedicine or other remote technique. A viral load sample, vital signs (respiratory rate, heart rate, body temperature and SpO2), and a symptom assessment will be completed on specified days.

Official Title
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A Phase II, Randomized, Assessor-blind, Multicenter, Multi-dose, Placebo-controlled Study Assessing the Safety and Anti-coronavirus Response of Brequinar Combined With Dipyridamole in Patients With Mild to Moderate SARS-CoV-2 Infection.

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Brequinar Sodium
* Drug: Dipyridamole 75 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent for the trial, written, electronic, verbal, or other method deemed acceptable by the institution and IRB. Subjects between ≥18 and ≤65 years of age. 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. 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). 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. 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. 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. Willing to participate in the PK subset if at one of the identified sites. 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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brequinar monotherapy<br>Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. | Drug: Brequinar Sodium<br>* 50 mg, 100 mg, 150 mg, 200 mg x 5 days<br>|
| Placebo Comparator: Placebo<br>Placebo matching brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. | Drug: Placebo<br>* 50 mg, 100 mg, 150 mg, 200 mg x 5 days<br>|
| Experimental: Brequinar-Dipyridamole Combination<br>Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. All subjects assigned to this arm will also receive dipyridamole 75 mg tablets TID. | Drug: Brequinar Sodium<br>* 50 mg, 100 mg, 150 mg, 200 mg x 5 days<br>Drug: Dipyridamole 75 MG<br>* 75 mg TID for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of the Brequinar-dipyridamole Combination in COVID-19 Subjects | There were no subjects who experienced grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to be related to the combination, brequinar alone or placebo alone. therefore frequencies of these events could not be compared. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of SARS-CoV-2 Levels Using qPCR Through Day 29 and at Days 4, 8, 12, 15, 22, and 29 | There were no subjects with detectable viral load after baseline, therefore no analyses could be conducted regarding change in viral load from baseline of SARS-CoV-2 levels using qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29 | Day 29 | 
| Reduction in Time to Symptom Improvement | There were no subjects who had changes in symptom improvement, therefore no analyses of changes in symptom improvement could be conducted. | Day 29 | 
| Reduction in Percentage of Subjects Requiring Hospital Admission/Re-admission as an In-patient for >24 Hours | There were no subjects who required hospital admission/re-admission as an in-patient for >24 hours, therefore no analyses could be conducted for comparative change in percentage of subjects who required hospital admission/readmission for >24 hours. | Day 29 | 
| Reduction in Percentage of Subjects Requiring Medical Attended Visits, e.g., Hospitalization, Emergency Room Visits, Urgent Care/Family Doctor Visits | There were no subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent Care/Family Doctor visits, therefore no analyses could be conducted for comparative change in percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent Care/Family Doctor visits | Day 29 | 
| Reduction in Percentage of Subjects Requiring Supplemental Support Such as Oxygen | There were no subjects that required supplemental support such as oxygen, therefore analyses of comparative change in percentage of subjects requiring supplemental support such as oxygen could not be conducted. | Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Oral antiviral, DHODH Inhibitor, brequinar