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

• Sponsor: Clear Creek Bio, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04425252
• Collaborator: (none)
• Enrollment: 25
• Locations: 5
• Arms: 2
• Actual Duration (Months): 4.8
• Patients Per Site: 5
• Patients Per Site Per Month: 1

Study Details

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 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized 1:2 to standard of care (SOC) alone or SOC + brequinarRandomized 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: Aug 19, 2020
• Actual Primary Completion Date: Dec 29, 2020
• Actual Study Completion Date: Jan 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: 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; Other Names: Standard of Care + Brequinar

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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).

3. Safety/Tolerability Measured by Mortality at Day 29 [Through Day 29]

   Safety/tolerability as measured by mortality at Day 29

Secondary Outcome Measures

1. 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.

2. Duration of Hospitalization [Through Day 15]

   Duration in number of days from admission to discharge; days counted as an integer only.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

1. 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

	Site	City	State	Country	Postal Code
1	Hartford Hospital	Hartford	Connecticut	United States	06102
2	Baptist Medical Center	Jacksonville	Florida	United States	32207
3	University of South Florida/Tampa General	Tampa	Florida	United States	33606
4	University of New Mexico	Albuquerque	New Mexico	United States	87106
5	Temple University	Philadelphia	Pennsylvania	United States	19140

Sponsors and Collaborators

• Clear Creek Bio, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 10, 2020
• Statistical Analysis Plan - Dec 17, 2020

More Information

Publications

None provided.

• Responsible Party: Clear Creek Bio, Inc.
• ClinicalTrials.gov Identifier: NCT04425252
• Other Study ID Numbers: CCB-CRISIS-01
• First Posted: Jun 11, 2020
• Last Update Posted: Feb 17, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• 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: COVID-19; Coronavirus Infections; Brequinar

Study Results

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 Detail	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.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients.	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients plus brequinar 100 mg daily x 5 days.
Period Title: Overall Study
STARTED	8	15
COMPLETED	4	13
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Standard of Care	Standard of Care + Brequinar	Total
Arm/Group Description	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19.	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19 plus brequinar 100 mg daily x 5 days.	Total of all reporting groups
Overall Participants	8	15	23
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.38 (16.02)	55.59 (14.78)	54.24 (15.63)
Sex: Female, Male (Count of Participants)
Female	4 50%	7 46.7%	11 47.8%
Male	4 50%	8 53.3%	12 52.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 12.5%	3 20%	4 17.4%
White	7 87.5%	8 53.3%	15 65.2%
More than one race	0 0%	4 26.7%	4 17.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	8 100%	15 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Safety/Tolerability Assessed by Rates of Grade 3 or 4 Post Randomization Adverse Events
Description	Safety/tolerability as assessed by number of participants with Grade 3 or 4 post randomization adverse events.
Time Frame	Through Day 15.

Outcome Measure Data

Analysis Population Description

All subjects in the Modified Intent-to-Treat Population included those with at least one post randomization assessment.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients.	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients plus brequinar 100 mg daily x 5 days.
Measure Participants	8	15
Count of Participants [Participants]	1 12.5%	1 6.7%

2. Primary Outcome

Title	Safety/Tolerability as Assessed by Rates of Serious Adverse Events (SAEs).
Description	Safety/tolerability as assessed by number of participants with Serious Adverse Events (SAEs).
Time Frame	Through Day 15

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population included all subjects with at least one post randomization assessment.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients.	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients plus brequinar 100 mg daily x 5 days.
Measure Participants	8	15
Count of Participants [Participants]	1 12.5%	3 20%

3. Primary Outcome

Title	Safety/Tolerability Measured by Mortality at Day 29
Description	Safety/tolerability as measured by mortality at Day 29
Time Frame	Through Day 29

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population included all participants with at least one post-randomization assessment.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients.	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients plus Brequinar 100 mg daily x 5 days.
Measure Participants	8	15
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Hospitalization Status
Description	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

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population which includes all participants with at least one post-randomization study assessment.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19.	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19 plus brequinar 100 mg daily x 5 days.
Measure Participants	8	15
Day 3 Died	0 0%	0 0%
Day 3 Hospitalized in ICU	0 0%	3 20%
Day 3 Hospitalized	3 37.5%	9 60%
Day 3 Discharged	5 62.5%	3 20%
Day 5 Died	0 0%	0 0%
Day 5 Hospitalized in ICU	0 0%	1 6.7%
Day 5 Hospitalized	3 37.5%	4 26.7%
Day 5 Discharged	5 62.5%	10 66.7%
Day 7 Died	0 0%	0 0%
Day 7 Hospitalized in ICU	0 0%	0 0%
Day 7 Hospitalized	1 12.5%	0 0%
Day 7 Discharged	7 87.5%	15 100%
Day 15 Died	0 0%	0 0%
Day 15 Hospitalized in ICU	0 0%	0 0%
Day 15 Hospitalized	1 12.5%	1 6.7%
Day 15 Discharged	6 75%	14 93.3%
Day 15 Missing	1 12.5%	0 0%

5. Secondary Outcome

Title	Duration of Hospitalization
Description	Duration in number of days from admission to discharge; days counted as an integer only.
Time Frame	Through Day 15

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat population included all participants with at least one post-randomization assessment.

Arm/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients.	Subjects were hospitalized for COVID-19 and received standard of care per institutional guidelines for COVID-19 patients plus Brequinar 100 mg daily x 5 days.
Measure Participants	8	15
Median (Inter-Quartile Range) [days]	2	4

6. Secondary Outcome

Title	NEWS2 Score
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Standard of Care	Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19.	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19 plus brequinar 100 mg daily x 5 days.
Measure Participants	8	13
Baseline (Day 1 pre dose)	1.9 (0.69)	3.9 (0.80)
Day 3	3.0 (1.15)	2.8 (0.47)
Day 5	2.5 (1.55)	3.8 (1.07)
Day 7	3.3 (1.03)	3.8 (1.75)
Day 15	0.00 (0.00)	2.6 (0.97)

Adverse Events

Time Frame	29 days
Adverse Event Reporting Description	Events that occurred prior to informed consent were entered as medical history; AEs that occurred after informed consent were entered on the AE form. Subjects were questioned and observed for evidence of AEs, whether or not judged by the Investigator or designated person to be related to study drug.
Arm/Group Title	Standard of Care		Standard of Care + Brequinar
Arm/Group Description	Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19.		Subjects were hospitalized with COVID-19 and received institutional standard of care for COVID-19 plus brequinar 100 mg daily x 5 days.
All Cause Mortality
	Standard of Care		Standard of Care + Brequinar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/15 (0%)
Serious Adverse Events
	Standard of Care		Standard of Care + Brequinar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		3/15 (20%)
Cardiac disorders
Angina pectoris	0/8 (0%)	0	1/15 (6.7%)	1
Atrial fibrillation	1/8 (12.5%)	1	0/15 (0%)	0
Infections and infestations
COVID-19 pneumonia	0/8 (0%)	0	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Fall	1/8 (12.5%)	1	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/8 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Orthostatic hypotension	1/8 (12.5%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Standard of Care		Standard of Care + Brequinar
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		3/15 (20%)
Endocrine disorders
Hyperglycemia	0/8 (0%)	0	3/15 (20%)	3
Investigations
Alanine aminotransferase increased	0/8 (0%)	0	2/15 (13.3%)	2

Limitations/Caveats

CCB-CRISIS-01 was a small, open-label study with small numbers of subjects analyzed. In addition, the study was conducted prior to availability of COVID-19 vaccinations and there were many missed visits and assessments due to COVID-19 restrictions in place at the time that prohibited return visits to the hospital or clinic. Standard of care for these hospitalized subjects included remdesivir and steroids.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.