COVID-19
Conditions
Keywords
DHODH inhibition, antiviral, coronavirus, SARS-CoV-2
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.
Interventions
DRUGBrequinar
DHODH inhibitor, 100 mg daily x 5 days
OTHERStandard of Care
Standard of Care per institutional guidelines for COVID-19 patients
Sponsors
Clear Creek Bio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized 1:2 to standard of care (SOC) alone or SOC + brequinar
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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety/Tolerability Measured by Mortality at Day 29 | Through Day 29 | Safety/tolerability as measured by mortality at Day 29 |
| Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events | Through Day 15. | Safety/tolerability as assessed by number of participants with Grade 3 or 4 post randomization adverse events. |
| Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs). | Through Day 15 | Safety/tolerability as assessed by number of participants with Serious Adverse Events (SAEs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospitalization Status | Days 3, 5, 7, and 15 | All participants were hospitalized at time of study entry. This outcome measures participant hospitalization status at Days 3, 5, 7, and 15 in terms of: hospitalized in intensive care unit (ICU), hospitalized as part of initial admission, re-hospitalized (had been discharged from initial hospitalization and was re-admitted to the hospital) or was dead at the time of the assessment. |
| Duration of Hospitalization | Through Day 15 | Duration in number of days from admission to discharge; days counted as an integer only. |
| NEWS2 Score | Baseline, Days 3, 5, 7, and 15. | Measure Description: National Early Warning Score (NEWS) 2. Composite score of respiratory rate, oxygen saturation, systolic blood pressure, pulse, consciousness, and temperature. The NEWS2 provides a score of illness severity based on respiratory rate, SpO2, whether the patient is breathing room air or on oxygen, systolic blood pressure, heart rate, consciousness, and body temperature. The scale ranges from 20 (worst/sickest) to 0 (all measurements in a normal range). The NEWS2 was assessed at baseline, Days 3, 5, 7, and 15. |
Countries
United States
Participant flow
Recruitment details
First Patient Enrolled: 19 AUG 2020 Last Patient Completed the study: 12 JAN 2021 Patients were hospitalized with COVID-19 and were recruited at the hospital where they were being treated as in-patients.
Pre-assignment details
All subjects were hospitalized as in-patients as part of the inclusion criteria. 25 patients were enrolled, but 2 withdrew consent prior to treatment and had no post-randomization assessments for a total of 23 subjects randomized in the study and included in the modified intent-to-treat population.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19. | 8 |
| Standard of Care + Brequinar Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19 plus brequinar 100 mg daily x 5 days. | 15 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Subject did not return due to COVID-19 restrictions. | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Standard of Care + Brequinar | Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 55.59 years STANDARD_DEVIATION 14.78 | 51.38 years STANDARD_DEVIATION 16.02 | 54.24 years STANDARD_DEVIATION 15.63 |
| 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 | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 7 Participants | 15 Participants |
| Region of Enrollment United States | 15 participants | 8 participants | 23 participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 15 |
| other Total, other adverse events | 0 / 8 | 3 / 15 |
| serious Total, serious adverse events | 1 / 8 | 3 / 15 |
Outcome results
Primary
Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs).
Safety/tolerability as assessed by number of participants with Serious Adverse Events (SAEs).
Time frame: Through Day 15
Population: Modified intent-to-treat population included all subjects with at least one post randomization assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs). | 1 Participants |
| Standard of Care + Brequinar | Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs). | 3 Participants |
Primary
Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events
Safety/tolerability as assessed by number of participants with Grade 3 or 4 post randomization adverse events.
Time frame: Through Day 15.
Population: All subjects in the Modified Intent-to-Treat Population included those with at least one post randomization assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events | 1 Participants |
| Standard of Care + Brequinar | Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events | 1 Participants |
Primary
Safety/Tolerability Measured by Mortality at Day 29
Safety/tolerability as measured by mortality at Day 29
Time frame: Through Day 29
Population: Modified intent-to-treat population included all participants with at least one post-randomization assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Safety/Tolerability Measured by Mortality at Day 29 | 0 Participants |
| Standard of Care + Brequinar | Safety/Tolerability Measured by Mortality at Day 29 | 0 Participants |
Secondary
Duration of Hospitalization
Duration in number of days from admission to discharge; days counted as an integer only.
Time frame: Through Day 15
Population: The modified intent-to-treat population included all participants with at least one post-randomization assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care | Duration of Hospitalization | 2 days |
| Standard of Care + Brequinar | Duration of Hospitalization | 4 days |
Secondary
Hospitalization Status
All participants were hospitalized at time of study entry. This outcome measures participant hospitalization status at Days 3, 5, 7, and 15 in terms of: hospitalized in intensive care unit (ICU), hospitalized as part of initial admission, re-hospitalized (had been discharged from initial hospitalization and was re-admitted to the hospital) or was dead at the time of the assessment.
Time frame: Days 3, 5, 7, and 15
Population: Modified intent-to-treat population which includes all participants with at least one post-randomization study assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard of Care | Hospitalization Status | Day 3 Hospitalized in ICU | 0 Participants |
| Standard of Care | Hospitalization Status | Day 7 Hospitalized in ICU | 0 Participants |
| Standard of Care | Hospitalization Status | Day 5 Hospitalized in ICU | 0 Participants |
| Standard of Care | Hospitalization Status | Day 7 Hospitalized | 1 Participants |
| Standard of Care | Hospitalization Status | Day 3 Died | 0 Participants |
| Standard of Care | Hospitalization Status | Day 7 Discharged | 7 Participants |
| Standard of Care | Hospitalization Status | Day 5 Hospitalized | 3 Participants |
| Standard of Care | Hospitalization Status | Day 15 Died | 0 Participants |
| Standard of Care | Hospitalization Status | Day 3 Discharged | 5 Participants |
| Standard of Care | Hospitalization Status | Day 15 Hospitalized in ICU | 0 Participants |
| Standard of Care | Hospitalization Status | Day 5 Discharged | 5 Participants |
| Standard of Care | Hospitalization Status | Day 15 Hospitalized | 1 Participants |
| Standard of Care | Hospitalization Status | Day 5 Died | 0 Participants |
| Standard of Care | Hospitalization Status | Day 15 Discharged | 6 Participants |
| Standard of Care | Hospitalization Status | Day 7 Died | 0 Participants |
| Standard of Care | Hospitalization Status | Day 15 Missing | 1 Participants |
| Standard of Care | Hospitalization Status | Day 3 Hospitalized | 3 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 15 Missing | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 3 Hospitalized | 9 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 3 Died | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 3 Hospitalized in ICU | 3 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 3 Discharged | 3 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 5 Died | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 5 Hospitalized in ICU | 1 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 5 Hospitalized | 4 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 5 Discharged | 10 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 7 Died | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 7 Hospitalized in ICU | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 7 Hospitalized | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 7 Discharged | 15 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 15 Died | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 15 Hospitalized in ICU | 0 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 15 Hospitalized | 1 Participants |
| Standard of Care + Brequinar | Hospitalization Status | Day 15 Discharged | 14 Participants |
Secondary
NEWS2 Score
Measure Description: National Early Warning Score (NEWS) 2. Composite score of respiratory rate, oxygen saturation, systolic blood pressure, pulse, consciousness, and temperature. The NEWS2 provides a score of illness severity based on respiratory rate, SpO2, whether the patient is breathing room air or on oxygen, systolic blood pressure, heart rate, consciousness, and body temperature. The scale ranges from 20 (worst/sickest) to 0 (all measurements in a normal range). The NEWS2 was assessed at baseline, Days 3, 5, 7, and 15.
Time frame: Baseline, Days 3, 5, 7, and 15.
Population: Participants with at least one post randomization assessment who were able to return to the clinic for a study visit. Multiple subjects were unable to return for scheduled study assessments at various time points due to COVID-19 restrictions in place at the institutions where the study was conducted.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care | NEWS2 Score | Day 3 | 3.0 units on a scale | Standard Error 1.15 |
| Standard of Care | NEWS2 Score | Day 7 | 3.3 units on a scale | Standard Error 1.03 |
| Standard of Care | NEWS2 Score | Day 5 | 2.5 units on a scale | Standard Error 1.55 |
| Standard of Care | NEWS2 Score | Day 15 | 0.00 units on a scale | Standard Error 0 |
| Standard of Care | NEWS2 Score | Baseline (Day 1 pre dose) | 1.9 units on a scale | Standard Error 0.69 |
| Standard of Care + Brequinar | NEWS2 Score | Day 15 | 2.6 units on a scale | Standard Error 0.97 |
| Standard of Care + Brequinar | NEWS2 Score | Baseline (Day 1 pre dose) | 3.9 units on a scale | Standard Error 0.8 |
| Standard of Care + Brequinar | NEWS2 Score | Day 3 | 2.8 units on a scale | Standard Error 0.47 |
| Standard of Care + Brequinar | NEWS2 Score | Day 5 | 3.8 units on a scale | Standard Error 1.07 |
| Standard of Care + Brequinar | NEWS2 Score | Day 7 | 3.8 units on a scale | Standard Error 1.75 |