Clinical trial NCT04575038: CRISIS2: A Phase 2 Study of the Safety and Antiviral Activity of Brequinar in Non-hospitalized Pts With COVID-19
Official title: The CRISIS2 Study: A Phase 2, Randomized, Double Blind, Placebo-controlled, Multi-center Study Assessing the Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Out-patient Adults With SARS-CoV-2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19 Infection
Lead sponsor: Clear Creek Bio, Inc.
Sponsor class: INDUSTRY
First posted: 2020-10-05
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized 1:1 brequinar 100 mg or placebo
Primary purpose: TREATMENT

Brief summary: This study will assess the efficacy and safety of DHODHi (brequinar) as an antiviral via 5 days of treatment of participants with positive COVID-19 and at least one symptom of COVI019 in an out-patient setting. The study is multi-center, randomized, and placebo-controlled.

Detailed description: Brequinar is a potent DHODH inhibitor that has been previously studied in more than 1,000 cancer, psoriasis, and organ transplant patients. Brequinar has been found to have potent in vitro antiviral activity against many RNA viruses including SARS-CoV-2. The antiviral activity of brequinar against SARS-CoV-2 is likely due to DHODH inhibition and shows nanomolar potency and a high selectivity index in inhibiting viral replication in in vitro studies.

The CRISIS2 trial will study out-patients (non-hospitalized patients) who have a positive SARS-CoV-2 test and are symptomatic. Subjects will be randomized to receive standard of care (SOC) + 5 days of brequinar or SOC + 5 days of placebo. The purpose of this study is to determine if the in vitro antiviral activity of brequinar can be duplicated in patients infected with SARS-CoV-2 by measuring the effect of brequinar on viral shedding. Importantly, the safety and tolerability of brequinar will also be determined in these patients. The results of this proof-of-concept study will inform future studies that will help determine if brequinar is a safe and effective drug for the treatment of SARS-CoV-2 infection.

This will be a phase II randomized, placebo-controlled, double blind, multi-center study with approximately 100 subjects. All subjects will receive standard of care (SOC) per institutional guidelines for treatment of patients with COVID-19 infection. In addition to SOC, the subjects will self-administer one capsule once daily for 5 days.

Subjects will have a Screening Visit followed as soon as possible with Study Day 1. Study visits (virtual or in person) will take place at Screening and on specified days. The visits that include bloodwork must be conducted at the study site or arrangements made for sample collection at the subject's home or other appropriate location. Other visits/visit activities for that visit may be conducted remotely using telemedicine or other remote technique. Subjects are to self-collect a viral load sample, obtain their respiratory rate, heart rate, body temperature and SpO2, and complete a symptom assessment checklist on specified days.

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. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase chain reaction (RT-PCR) or other FDA-approved commercial or public health assay.
4. Out-patient (never hospitalized as an in-patient for COVID-19 or was evaluated/treated for COVID-19 only in the Emergency Room with a stay of \< 24 hours)
5. 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.
6. Male subjects must agree to refrain from sperm donation and female subjects must agree to refrain from ovum donation from initial study drug administration until 90 days after the last dose of brequinar.
7. Must have 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, anosmia, dysgeusia, or other symptom commonly associated with COVID-19 in the opinion of the investigator. Symptom onset must be ≤7 days prior to first dose. Subject must have one or more symptoms at first dose.
8. Able to swallow capsules.

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. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test
3. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other agents known to cause bone marrow suppression leading to thrombocytopenia
4. Platelets ≤150,000 cell/mm3
5. Hemoglobin \< 10 gm/dL
6. Absolute neutrophil count \< 1500 cells/mm3
7. Renal dysfunction, i.e., creatinine clearance \< 30 mL/min
8. AST or ALT \> 2 x ULN, or total bilirubin \> ULN. Gilbert's Syndrome is allowed.
9. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding enrollment
10. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of randomization.
11. Chronic hepatitis B infection, active hepatitis C infection, active liver disease and/or cirrhosis per subject report.
12. 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).

Primary outcomes:
measure: Log10 SARS-CoV-2 Viral Load
timeFrame: Days 4, 8, 12, 15, 22, and 29
Secondary outcomes:
measure: Rates of AEs and SAEs Including Laboratory Assessments
timeFrame: Through Day 29
measure: Viral Shedding Duration
timeFrame: Through Day 36
measure: Hospital Admission
timeFrame: Day 29
Other outcomes:
Locations:
city: Homewood
country: United States
facility: Central Alabama Research
state: Alabama
city: Long Beach
country: United States
facility: Ark Clinical Research
state: California
city: Doral
country: United States
facility: Doral Medical Research
state: Florida
city: Somers Point
country: United States
facility: South Jersey Infectious Disease
state: New Jersey
city: Monroe
country: United States
facility: Monroe Biomedical Research
state: North Carolina
city: Wilmington
country: United States
facility: Wilmington Health
state: North Carolina
city: Columbus
country: United States
facility: Remington-Davis, Inc.
state: Ohio
city: Toledo
country: United States
facility: Toledo Institute of Clinical Research
state: Ohio
city: Gaffney
country: United States
facility: VitaLink - Gaffney
state: South Carolina
city: Greenwood
country: United States
facility: Self Regional Healthcare Research Center - Self Medical Group
state: South Carolina
city: Spartanburg
country: United States
facility: VitaLink Research
state: South Carolina
city: Franklin
country: United States
facility: Clinical Trials Center of Middle Tennessee
state: Tennessee
city: McAllen
country: United States
facility: Centex Studies, Inc. - McAllen
state: Texas
city: Salt Lake City
country: United States
facility: Synexus Clinical Research US, Inc. - Olympus Family Medicine
state: Utah
Study officials:
References: