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

• ClinicalTrials.gov Identifier: NCT04425252
• Recruitment Status: Recruiting
• First Posted: June 11, 2020
• Last Update Posted: June 29, 2020
• 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)
• Estimated Enrollment: 24 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: June 25, 2020
• Estimated Primary Completion Date: September 2020
• Estimated Study Completion Date: October 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 and at least one of the following co-morbidities by subject history or present in the institution's electronic health record: hypertension, diabetes, chronic kidney disease, chronic obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease or congestive heart failure), liver cirrhosis, age > 65, BMI > 30.
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 laboratory for a laboratory sample as well as a contact (phone call or other digital media) on Study Days 7 and 15 and contact only on Day 29.
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase chain reaction (RT-PCR) or other 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 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. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea), moderate (any symptom of mild illness or shortness of breath with exertion), or severe (any symptom of moderate illness or shortness of breath at rest, or respiratory distress).
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate ≥ 90 beats per minute) or severe (respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300)

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, teriflunomide), tacrolimus, sirolimus, or pre-existing prednisone at higher than 20 mg daily (ongoing or within 2 weeks of study entry).
5. Platelets ≤150,000 cell/mm3.
6. Hemoglobin < 12 gm/dL
7. Absolute neutrophil count < 1500 cells/mm3
8. Renal dysfunction, i.e., creatinine clearance < 50 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 thrombocytopenia
12. Concomitant use of corticosteroids, regardless of dose; or use of corticosteroids at any dose in the two weeks preceding enrollment.
13. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.
14. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.
15. History of known cardiovascular disease including unstable angina, myocardial infarction, uncontrolled arrythmias, and heart failure.

16. Baseline COVID-19 severity characterized as "Critical" based on the FDA Guidance "COVID-19: Developing Drugs and Biological Products for the Treatment or Prevention" (https://www.fda.gov/media/137926/download). Evidence of critical illness defined by at least one of the following:

    1. Respiratory failure based on resource utilization requiring at least one of the following:
    2. Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), 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)
    3. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg or requiring vasopressors)
17. Multi-organ dysfunction/failure.

Contacts and Locations

Contacts

Contact: Barbara L Powers, Ph.D; (617) 765-2252; clinical@clearcreekbio.com

Locations

United States, Connecticut

Hartford Hospital; Not yet recruiting

Hartford, Connecticut, United States, 06102

Contact: Samuel Pope, MD 860-547-1876 spope@harthosp.org

Principal Investigator: James S Pope, MD

United States, Florida

University of South Florida/Tampa General; Recruiting

Tampa, Florida, United States, 33606

Contact: Karel Calero, MD 813-259-0619 kcalero@health.usf.edu

Principal Investigator: Karel Calero, MD

United States, Pennsylvania

Temple University; Not yet recruiting

Philadelphia, Pennsylvania, United States, 19140

Contact: Gerard J Criner, MD 215-707-8113 gerard.criner@tuhs.temple.edu

Principal Investigator: Gerard J Criner, MD

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: June 29, 2020
• Last Verified: June 2020

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