Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19 (CRISIS)
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ClinicalTrials.gov Identifier: NCT04425252 |
Recruitment Status :
Completed
First Posted : June 11, 2020
Last Update Posted : January 19, 2021
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Condition or disease | Intervention/treatment | Phase |
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COVID-19 | Drug: Brequinar Other: Standard of Care | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 23 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Randomized 1:2 to standard of care (SOC) alone or SOC + brequinar |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | 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) |
Actual Study Start Date : | August 1, 2020 |
Actual Primary Completion Date : | December 29, 2020 |
Actual Study Completion Date : | December 29, 2020 |

Arm | Intervention/treatment |
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Standard of Care
Subjects are hospitalized for COVID-19 and will receive all supportive/interventional care per institutional guidelines.
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Other: Standard of Care
Standard of Care per institutional guidelines for COVID-19 patients |
Experimental: Brequinar
Subjects will receive standard of care plus brequinar 100 mg daily (Study Days 1-5).
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Drug: Brequinar
DHODH inhibitor, 100 mg daily x 5 days |
- Safety/tolerability measured by rates of post randomization adverse events and hematology/chemistry safety labs. [ Time Frame: Beginning at signing consent through Day 15. ]Adverse events are new onset medical conditions.
- Hospitalization status [ Time Frame: Through Day 15 ]In-patient hospitalization, hospitalized in ICU-level care, or discharged
- Duration of hospitalization [ Time Frame: Through Day 15 ]Duration in days from admission to discharge
- NEWS2 Score [ Time Frame: Through Day 15 ]National Early Warning Score (NEWS) 2. Composite score of respiration rate, oxygen saturation, systolic blood pressure, pulse, consciousness, and temperature.
- Mortality [ Time Frame: Day 29 ]Subject mortality status
- SARS-CoV-2 nasopharyngeal viral load [ Time Frame: Through Day 15 ]Nasopharyngeal viral load by RT-PCR at days 1, 3, 5, 7, and 15
- Inflammatory markers [ Time Frame: Through Day 15 ]Pro-inflammatory cytokines including TNFalpha, INFgamma, IL13, IL12p70, IL10, IL8, IL6, IL4 IL2, IL1-beta and erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-dimer, serum ferritin, and fibrinogen
- DHO Concentration [ Time Frame: Through Day 15 ]Plasma concentration of dihydroorotate
- Brequinar Concentration [ Time Frame: Through Day 15 ]Plasma concentration of brequinar

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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.
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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.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04425252
United States, Connecticut | |
Hartford Hospital | |
Hartford, Connecticut, United States, 06102 | |
United States, Florida | |
Baptist Medical Center | |
Jacksonville, Florida, United States, 32207 | |
University of South Florida/Tampa General | |
Tampa, Florida, United States, 33606 | |
United States, New Mexico | |
University of New Mexico | |
Albuquerque, New Mexico, United States, 87106 | |
United States, Pennsylvania | |
Temple University | |
Philadelphia, Pennsylvania, United States, 19140 |
Responsible Party: | Clear Creek Bio, Inc. |
ClinicalTrials.gov Identifier: | NCT04425252 |
Other Study ID Numbers: |
CCB-CRISIS-01 |
First Posted: | June 11, 2020 Key Record Dates |
Last Update Posted: | January 19, 2021 |
Last Verified: | January 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
DHODH inhibition antiviral coronavirus SARS-CoV-2 |
Coronavirus Infections Coronaviridae Infections Nidovirales Infections RNA Virus Infections Virus Diseases Brequinar |
Antineoplastic Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |