COVID-19 Infection
Conditions
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.
Interventions
DRUGBrequinar
Dihydroorotate dehydrogenase inhibitor (DHODHi)
DRUGPlacebo
Placebo capsules
Sponsors
Clear Creek Bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Randomized 1:1 brequinar 100 mg or placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log10 SARS-CoV-2 Viral Load | Days 4, 8, 12, 15, 22, and 29 | Median Change from Baseline in Quantitative Log10 SARS-CoV-2 viral load at Days 4, 8, 12, 15, 22, and 29. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of AEs and SAEs Including Laboratory Assessments | Through Day 29 | Safety measured by number of participants with AEs and SAEs including laboratory assessments. |
| Viral Shedding Duration | Through Day 36 | Duration of viral shedding was defined as the time to viral clearance (two consecutive negative test results) for the Microbiology Evaluable Set population. |
| Hospital Admission | Day 29 | Percentage of subjects requiring admission as an inpatient for \>24 hours |
Countries
United States
Participant flow
Recruitment details
Subjects were all confirmed to be positive for COVID-19 by means of either a rapid antigen or RT-PCR test. Subjects were out-patients (not hospitalized) at the time of study entry. The first subject was enrolled on 19-NOV-2020; the last subject completed the study on 29-MAR-2021.
Pre-assignment details
A total of 182 subjects were screened for the study at 14 centers in the US. The Screening period was not more than 7 days in order to provide subjects the earliest possible opportunity for antiviral treatment. The primary screen fail reason was failure to meet one of the laboratory eligibility criteria including low hemoglobin, low platelets, low neutrophil count, and elevated liver function test. Qualifying subjects were enrolled into the study and randomized on the same day.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care + Brequinar 100 mg Standard of Care + Brequinar oral capsules 100 mg x 5 days
Brequinar: Dihydroorotate dehydrogenase inhibitor (DHODHi) | 56 |
| Standard of Care + Placebo Standard of Care + Placebo for Brequinar oral capsules x 5 days
Placebo: Placebo capsules | 59 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Standard of Care + Brequinar 100 mg | Standard of Care + Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 3 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 105 Participants | 53 Participants | 52 Participants |
| Age, Continuous | 46.0 years | 46.5 years | 45.0 years |
| Body Temperature | 36.7 Degrees Celsius | 36.7 Degrees Celsius | 36.7 Degrees Celsius |
| COVID-19 Symptom Type Anosmia | 53 Participants | 25 Participants | 28 Participants |
| COVID-19 Symptom Type Body Aches | 0 Participants | 0 Participants | 0 Participants |
| COVID-19 Symptom Type Chills/Rigors | 32 Participants | 17 Participants | 15 Participants |
| COVID-19 Symptom Type Cough | 87 Participants | 43 Participants | 44 Participants |
| COVID-19 Symptom Type Dysgeusia | 35 Participants | 18 Participants | 17 Participants |
| COVID-19 Symptom Type Dyspnea | 5 Participants | 5 Participants | 0 Participants |
| COVID-19 Symptom Type Fatigue | 9 Participants | 5 Participants | 4 Participants |
| COVID-19 Symptom Type Fever | 41 Participants | 18 Participants | 23 Participants |
| COVID-19 Symptom Type Gastrointestinal Symptoms | 43 Participants | 22 Participants | 21 Participants |
| COVID-19 Symptom Type Headache | 84 Participants | 44 Participants | 40 Participants |
| COVID-19 Symptom Type Malaise | 83 Participants | 44 Participants | 39 Participants |
| COVID-19 Symptom Type Muscle Pain | 45 Participants | 23 Participants | 22 Participants |
| COVID-19 Symptom Type Nasal Congestion | 16 Participants | 6 Participants | 10 Participants |
| COVID-19 Symptom Type Other | 25 Participants | 12 Participants | 13 Participants |
| COVID-19 Symptom Type Shortness of Breath | 41 Participants | 19 Participants | 22 Participants |
| COVID-19 Symptom Type Sore Throat | 62 Participants | 28 Participants | 34 Participants |
| Detectable Log 10 SARS-CoV-2 Viral Load Detectable | 88 Participants | 43 Participants | 45 Participants |
| Detectable Log 10 SARS-CoV-2 Viral Load Inconclusive | 0 Participants | 0 Participants | 0 Participants |
| Detectable Log 10 SARS-CoV-2 Viral Load Missing | 8 Participants | 6 Participants | 2 Participants |
| Detectable Log 10 SARS-CoV-2 Viral Load Undetectable | 19 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 36 Participants | 18 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 79 Participants | 38 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 98 Participants | 53 Participants | 45 Participants |
| Region of Enrollment United States | 115 participants | 56 participants | 59 participants |
| Respiratory Rate | 16.0 Breaths per minute | 16.0 Breaths per minute | 16.0 Breaths per minute |
| Sex: Female, Male Female | 59 Participants | 37 Participants | 22 Participants |
| Sex: Female, Male Male | 56 Participants | 19 Participants | 37 Participants |
| SpO2 | 98.0 Percentage of blood oxygen saturation | 98.0 Percentage of blood oxygen saturation | 97.0 Percentage of blood oxygen saturation |
| WHO Ordinal Scale Missing | 11 Participants | 4 Participants | 7 Participants |
| WHO Ordinal Scale WHO Score of 0 | 0 Participants | 0 Participants | 0 Participants |
| WHO Ordinal Scale WHO Score of 1 | 0 Participants | 0 Participants | 0 Participants |
| WHO Ordinal Scale WHO Score of 2 | 104 Participants | 52 Participants | 52 Participants |
| WHO Ordinal Scale WHO Score of 3 | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 59 |
| other Total, other adverse events | 3 / 56 | 4 / 59 |
| serious Total, serious adverse events | 1 / 56 | 0 / 59 |
Outcome results
Primary
Log10 SARS-CoV-2 Viral Load
Median Change from Baseline in Quantitative Log10 SARS-CoV-2 viral load at Days 4, 8, 12, 15, 22, and 29.
Time frame: Days 4, 8, 12, 15, 22, and 29
Population: Microbiology Evaluable Set (MES) consisted of all randomized subjects with detectable Log10 SARS-CoV-2 viral load at baseline and at least one non-missing postbaseline viral load assessment. Microbiology evaluable subjects were analyzed according to their randomized treatment. SARS-CoV-2 viral load (log 10 copies/mL) was reported as below.~* Number of copies/mL;~* \<Number of copies/mL, if detected but under the lower limit of quantification (LLOQ);~* No SARS-CoV-2 detected, if not detected.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 8 Change from Baseline | -2.413 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 15 Change from Baseline | -4.140 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 4 Change from Baseline | -1.651 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 22 Change from Baseline | -4.874 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 12 Change from Baseline | -3.907 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Day 29 Change from Baseline | -4.170 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Brequinar 100 mg | Log10 SARS-CoV-2 Viral Load | Baseline | 5.056 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 29 Change from Baseline | -3.839 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Baseline | 5.110 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 4 Change from Baseline | -1.881 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 8 Change from Baseline | -3.231 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 12 Change from Baseline | -3.514 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 15 Change from Baseline | -3.143 Log 10 SARS-CoV-2 Viral Load Copies/mL |
| Standard of Care + Placebo | Log10 SARS-CoV-2 Viral Load | Day 22 Change from Baseline | -3.575 Log 10 SARS-CoV-2 Viral Load Copies/mL |
Secondary
Hospital Admission
Percentage of subjects requiring admission as an inpatient for \>24 hours
Time frame: Day 29
Population: Intent-to-treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care + Brequinar 100 mg | Hospital Admission | 1 Participants |
| Standard of Care + Placebo | Hospital Admission | 0 Participants |
Secondary
Rates of AEs and SAEs Including Laboratory Assessments
Safety measured by number of participants with AEs and SAEs including laboratory assessments.
Time frame: Through Day 29
Population: The Safety Analysis Set (Safety) consisted of all subjects who received at least one dose of study drug. Safety analysis subjects were analyzed according to their actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Any AE | 10 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 1 AE | 8 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 2 AE | 1 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 3 AE | 1 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 4 AE | 0 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 5 AE | 0 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Study Drug-Related AE | 3 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | AE Leading to Study Drug Discontinuation | 0 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | Severity Grade 3 or Higher Study Drug Related AE | 0 Participants |
| Standard of Care + Brequinar 100 mg | Rates of AEs and SAEs Including Laboratory Assessments | SAE | 1 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | AE Leading to Study Drug Discontinuation | 0 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Any AE | 13 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 5 AE | 0 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 1 AE | 8 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | SAE | 0 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 2 AE | 2 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Study Drug-Related AE | 3 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 3 AE | 3 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Severity Grade 3 or Higher Study Drug Related AE | 0 Participants |
| Standard of Care + Placebo | Rates of AEs and SAEs Including Laboratory Assessments | Maximum Grade 4 AE | 0 Participants |
Secondary
Viral Shedding Duration
Duration of viral shedding was defined as the time to viral clearance (two consecutive negative test results) for the Microbiology Evaluable Set population.
Time frame: Through Day 36
Population: Microbiology Evaluable Set (MES) consisted of all randomized subjects with detectable Log10 SARS-CoV-2 viral load at baseline and at least one non-missing postbaseline viral load assessment. Microbiology evaluable subjects were analyzed according to their randomized treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care + Brequinar 100 mg | Viral Shedding Duration | 12.0 Days |
| Standard of Care + Placebo | Viral Shedding Duration | 8.0 Days |