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

• ClinicalTrials.gov Identifier: NCT04425252
• Recruitment Status: Completed
• First Posted: June 11, 2020
• Last Update Posted: January 19, 2021
• Sponsor: Clear Creek Bio, Inc.
• Information provided by (Responsible Party): Clear Creek Bio, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Brequinar; Other: Standard of Care	Phase 1; Phase 2

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 standard of care alone or standard of care plus brequinar. The brequinar group will receive 5 daily doses of brequinar 100 mg on Days 1 - 5. 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, CRP, and 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.

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
Standard of Care; Subjects are hospitalized for COVID-19 and will receive all supportive/interventional care per institutional guidelines.	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).	Drug: Brequinar; DHODH inhibitor, 100 mg daily x 5 days

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Hospitalization status [ Time Frame: Through Day 15 ]
   In-patient hospitalization, hospitalized in ICU-level care, or discharged
2. Duration of hospitalization [ Time Frame: Through Day 15 ]
   Duration in days from admission to discharge
3. 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.
4. Mortality [ Time Frame: Day 29 ]
   Subject mortality status
5. 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
6. 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
7. DHO Concentration [ Time Frame: Through Day 15 ]
   Plasma concentration of dihydroorotate
8. Brequinar Concentration [ Time Frame: Through Day 15 ]
   Plasma concentration of brequinar

Eligibility Criteria

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

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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

Clear Creek Bio, Inc.

More Information

• Responsible Party: Clear Creek Bio, Inc.
• ClinicalTrials.gov Identifier: NCT04425252
• Other Study ID Numbers: CCB-CRISIS-01
• First Posted: June 11, 2020
• 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

Keywords provided by Clear Creek Bio, Inc.:

DHODH inhibition; antiviral; coronavirus; SARS-CoV-2

Additional relevant MeSH terms:

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