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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04425252
Recruitment Status : Recruiting
First Posted : June 11, 2020
Last Update Posted : October 5, 2020
Sponsor:
Information provided by (Responsible Party):
Clear Creek Bio, Inc.

Tracking Information
First Submitted Date  ICMJE June 9, 2020
First Posted Date  ICMJE June 11, 2020
Last Update Posted Date October 5, 2020
Actual Study Start Date  ICMJE June 25, 2020
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 9, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 9, 2020)
  • Hospitalization status [ Time Frame: Through Day 15 ]
    In-patient hospitalization, hospitalized in ICU-level care, or discharged
  • Duration of hospitalization [ Time Frame: Through Day 15 ]
    Duration in days from admission to discharge
  • 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.
  • Mortality [ Time Frame: Day 29 ]
    Subject mortality status
  • 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
  • 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
  • DHO Concentration [ Time Frame: Through Day 15 ]
    Plasma concentration of dihydroorotate
  • Brequinar Concentration [ Time Frame: Through Day 15 ]
    Plasma concentration of brequinar
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19
Official Title  ICMJE 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)
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 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Brequinar
    DHODH inhibitor, 100 mg daily x 5 days
  • Other: Standard of Care
    Standard of Care per institutional guidelines for COVID-19 patients
Study Arms  ICMJE
  • Standard of Care
    Subjects are hospitalized for COVID-19 and will receive all supportive/interventional care per institutional guidelines.
    Intervention: Other: Standard of Care
  • Experimental: Brequinar
    Subjects will receive standard of care plus brequinar 100 mg daily (Study Days 1-5).
    Intervention: Drug: Brequinar
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 9, 2020)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Barbara L Powers, Ph.D (617) 765-2252 clinical@clearcreekbio.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04425252
Other Study ID Numbers  ICMJE CCB-CRISIS-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Clear Creek Bio, Inc.
Study Sponsor  ICMJE Clear Creek Bio, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Clear Creek Bio, Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP