Clinical trial NCT04425252: Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: COVID-19
Keywords: DHODH inhibition
antiviral
coronavirus
SARS-CoV-2
Lead sponsor: Clear Creek Bio, Inc.
Sponsor class: INDUSTRY
First posted: 2020-06-11
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized 1:2 to standard of care (SOC) alone or SOC + brequinar
Primary purpose: TREATMENT

Brief summary: 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: 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.

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. 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.
4. 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.
5. Hospitalized (in patient with expected duration ≥ 24 hours)
6. 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.
7. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of brequinar.
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician.
9. Able to swallow capsules.
10. 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:

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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as chemotherapy or radiation therapy within the past month.
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, sirolimus.
5. Platelets ≤150,000 cell/mm3.
6. Hemoglobin \< 10 gm/dL
7. Absolute neutrophil count \< 1500 cells/mm3
8. Renal dysfunction, i.e., creatinine clearance \< 30 mL/min
9. AST and/or ALT \> 1.5 ULN, or total bilirubin \> ULN
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment
11. Concomitant use of agents known to cause bone marrow suppression leading to thrombocytopenia
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.
13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.
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).
15. Life expectancy of \< 5 days in the judgment of the treating clinician.
16. 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.

Primary outcomes:
measure: Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events
timeFrame: Through Day 15.
measure: Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs).
timeFrame: Through Day 15
measure: Safety/Tolerability Measured by Mortality at Day 29
timeFrame: Through Day 29
Secondary outcomes:
measure: Hospitalization Status
timeFrame: Days 3, 5, 7, and 15
measure: Duration of Hospitalization
timeFrame: Through Day 15
measure: NEWS2 Score
timeFrame: Baseline, Days 3, 5, 7, and 15.
Other outcomes:
Locations:
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: Baptist Medical Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida/Tampa General
state: Florida
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
Study officials:
References: