Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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 SOC alone or SOC plus brequinar. The SOC plus brequinar group will receive 5 daily doses of brequinar 100 mg on Days 1 - 5 in addition to SOC. 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, c-reactive protein (CRP), and erythrocyte sedimentation rate (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.

Official Title
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The CRISIS Study: A Randomized Open-label Study Assessing the Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Hospitalized Adults With Coronavirus-19 (COVID-19)

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Brequinar
* Other: Standard of Care


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. 18 years of age or older. 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. 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. Hospitalized (in patient with expected duration ≥ 24 hours) 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 from initial study drug administration until 90 days after the last dose of brequinar. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. Able to swallow capsules. 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: 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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as chemotherapy or radiation therapy within the past month. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, sirolimus. Platelets ≤150,000 cell/mm3. Hemoglobin < 10 gm/dL Absolute neutrophil count < 1500 cells/mm3 Renal dysfunction, i.e., creatinine clearance < 30 mL/min AST and/or ALT > 1.5 ULN, or total bilirubin > ULN History of bleeding disorders or recent surgery in the six weeks preceding enrollment Concomitant use of agents known to cause bone marrow suppression leading to thrombocytopenia History of gastrointestinal ulcer, or history of gastrointestinal bleeding. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis. 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). Life expectancy of < 5 days in the judgment of the treating clinician. 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.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized 1:2 to standard of care (SOC) alone or SOC + brequinar
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of Care<br>Subjects are hospitalized for COVID-19 and will receive all supportive/interventional care per institutional guidelines. | Other: Standard of Care<br>* Standard of Care per institutional guidelines for COVID-19 patients<br>|
| Experimental: Brequinar<br>Subjects will receive standard of care plus brequinar 100 mg daily (Study Days 1-5). | Drug: Brequinar<br>* DHODH inhibitor, 100 mg daily x 5 days<br>* Other names: Standard of Care + Brequinar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events | Safety/tolerability as assessed by number of participants with Grade 3 or 4 post randomization adverse events. | Through Day 15. | 
| Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs). | Safety/tolerability as assessed by number of participants with Serious Adverse Events (SAEs). | Through Day 15 | 
| Safety/Tolerability Measured by Mortality at Day 29 | Safety/tolerability as measured by mortality at Day 29 | Through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalization Status | All participants were hospitalized at time of study entry. This outcome measures participant hospitalization status at Days 3, 5, 7, and 15 in terms of: hospitalized in intensive care unit (ICU), hospitalized as part of initial admission, re-hospitalized (had been discharged from initial hospitalization and was re-admitted to the hospital) or was dead at the time of the assessment. | Days 3, 5, 7, and 15 | 
| Duration of Hospitalization | Duration in number of days from admission to discharge; days counted as an integer only. | Through Day 15 | 
| NEWS2 Score | Measure Description: National Early Warning Score (NEWS) 2. Composite score of respiratory rate, oxygen saturation, systolic blood pressure, pulse, consciousness, and temperature. The NEWS2 provides a score of illness severity based on respiratory rate, SpO2, whether the patient is breathing room air or on oxygen, systolic blood pressure, heart rate, consciousness, and body temperature. The scale ranges from 20 (worst/sickest) to 0 (all measurements in a normal range). The NEWS2 was assessed at baseline, Days 3, 5, 7, and 15. | Baseline, Days 3, 5, 7, and 15. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DHODH inhibition, antiviral, coronavirus, SARS-CoV-2