Conditions: COVID-19 Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 115
Healthy volunteers: no

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.

Arms:
arm 1: Brequinar oral capsules 100 mg x 5 days arm 2: Placebo for Brequinar capsules x 5 days

Interventions: intervention 1: Brequinar intervention 2: Placebo
Intervention descriptions: intervention 1: Dihydroorotate dehydrogenase inhibitor (DHODHi) intervention 2: Placebo capsules

Protocol document:
Prot_000.pdf: 
CCB-CRISIS-02 
STUDY PROTOCOL 
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  
NCT04575038 
Original Protocol Date: 08/20/20 V1 
Amendment 01 Date: 09/15/2020 V2 
Amendment 02 Date: 09/23/2020 V3 
Amendment 03 Date: 10/01/2020 V4 
Amendment 04 Date: 11/19/2020 V5 


Table of Contents
STUDY PROTOCOL COVER PAGE .........................................................................................
TABLE OF CONTENTS..............................................................................................................
CCB-CRISIS-02 Protocol v1.0 20AUG020 .................................................................................
2 SYNOPSIS.....................................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Coronavirus-19 (COVID-19) ........................................................................
3.1.1 Coronavirus Biology ........................................................................
3.2  Host Nucleotide Synthesis .............................................................................
3.3  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.4  Brequinar........................................................................................................
3.5  Rationale for the Planned Trial ......................................................................
3.5.1 Brequinar Dose Selection.................................................................
3.5.2    Risk/Benefit of Brequinar .............................................................
3.6  Risks Associated with Participation in the Clinical Study.............................
3.7  Possible Interactions with Concomitant Medical Treatments........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
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8.3 Study Discontinuation.....................................................................................
8.4 Stopping Criteria .............................................................................................
8.4.1 Individual Stopping Criteria.............................................................
8.4.2 Study-Level Stopping Criteria .........................................................
8.5 Concomitant Medication/Treatment ...............................................................
8.6 Treatment Compliance....................................................................................
8.7 Storage, Stability, Labeling and Packaging ....................................................
8.7.1 Storage and Stability ........................................................................
8.7.2 Labeling and Packaging ...................................................................
8.7.3 Blinding and Randomization............................................................
8.7.4 Unblinding/Expectedness.................................................................
8.7.5 Study Drug Accountability...............................................................
8.8 Prohibited Medications ...................................................................................
8.9 Study Adjustments Due to COVID-19............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board..............................................................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Non-Childbearing Potential.............................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Follow Up of Grade 3 or 4 Toxicities ...........................................................
10.2 Infection Follow Up ......................................................................................
10.3 Classification of Causality ............................................................................
10.4 Classification of Severity ..............................................................................
10.5 Serious Adverse Event (SAE) Reporting ....................................................
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.7 Pregnancies....................................................................................................
10.8 Safety Monitoring for Hematologic Toxicities.............................................
10.9 Data Monitoring Committee .........................................................................
10.9.1 DMC Safety Review Schedule.......................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
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11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Sample Size Considerations..........................................................................
11.5 Randomization ..............................................................................................
11.6 Pooling of Study Centers ..............................................................................
11.7 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: WHO Ordinal Scale.................................................................
CCB-CRISIS-02_Protocol_v2.0 15SEPT2020-V2-FINAL.pdf ...................................................
2 SYNOPSIS.....................................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Coronavirus-19 (COVID-19) ........................................................................
3.1.1 Coronavirus Biology ........................................................................
3.2  Host Nucleotide Synthesis .............................................................................
3.3  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.4  Brequinar........................................................................................................
3.5  Rationale for the Planned Trial ......................................................................
3.5.1 Brequinar Dose Selection.................................................................
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3.5.2    Risk/Benefit of Brequinar .............................................................
3.6  Risks Associated with Participation in the Clinical Study.............................
3.7  Possible Interactions with Concomitant Medical Treatments........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Stopping Criteria .............................................................................................
8.4.1 Individual Stopping Criteria.............................................................
8.4.2 Study-Level Stopping Criteria .........................................................
8.5 Concomitant Medication/Treatment ...............................................................
8.6 Treatment Compliance....................................................................................
8.7 Storage, Stability, Labeling and Packaging ....................................................
8.7.1 Storage and Stability ........................................................................
8.7.2 Labeling and Packaging ...................................................................
8.7.3 Blinding and Randomization............................................................
8.7.4 Unblinding/Expectedness.................................................................
8.7.5 Study Drug Accountability...............................................................
8.8 Prohibited Medications ...................................................................................
8.9 Study Adjustments Due to COVID-19............................................................
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9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board..............................................................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Non-Childbearing Potential.............................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Follow Up of Grade 3 or 4 Toxicities ...........................................................
10.2 Infection Follow Up ......................................................................................
10.3 Classification of Causality ............................................................................
10.4 Classification of Severity ..............................................................................
10.5 Serious Adverse Event (SAE) Reporting ....................................................
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.7 Pregnancies....................................................................................................
10.8 Safety Monitoring for Hematologic Toxicities.............................................
10.9 Data Monitoring Committee .........................................................................
10.9.1 DMC Safety Review Schedule.......................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Sample Size Considerations..........................................................................
11.5 Randomization ..............................................................................................
11.6 Pooling of Study Centers ..............................................................................
11.7 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
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12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: WHO Ordinal Scale.................................................................
CCB-CRISIS-02 Protocol v3.0 23SEPT2020...............................................................................
2 SYNOPSIS.....................................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Coronavirus-19 (COVID-19) ........................................................................
3.1.1 Coronavirus Biology ........................................................................
3.2  Host Nucleotide Synthesis .............................................................................
3.3  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.4  Brequinar........................................................................................................
3.5  Rationale for the Planned Trial ......................................................................
3.5.1 Brequinar Dose Selection.................................................................
3.5.2    Risk/Benefit of Brequinar .............................................................
3.6  Risks Associated with Participation in the Clinical Study.............................
3.7  Possible Interactions with Concomitant Medical Treatments........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
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7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Stopping Criteria .............................................................................................
8.4.1 Individual Stopping Criteria.............................................................
8.4.2 Study-Level Stopping Criteria .........................................................
8.5 Concomitant Medication/Treatment ...............................................................
8.6 Treatment Compliance....................................................................................
8.7 Storage, Stability, Labeling and Packaging ....................................................
8.7.1 Storage and Stability ........................................................................
8.7.2 Labeling and Packaging ...................................................................
8.7.3 Blinding and Randomization............................................................
8.7.4 Unblinding/Expectedness.................................................................
8.7.5 Study Drug Accountability...............................................................
8.8 Prohibited Medications ...................................................................................
8.9 Study Adjustments Due to COVID-19............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board..............................................................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Non-Childbearing Potential.............................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Follow Up of Grade 3 or 4 Toxicities ...........................................................
10.2 Infection Follow Up ......................................................................................
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10.3 Classification of Causality ............................................................................
10.4 Classification of Severity ..............................................................................
10.5 Serious Adverse Event (SAE) Reporting ....................................................
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.7 Pregnancies....................................................................................................
10.8 Safety Monitoring for Hematologic Toxicities.............................................
10.9 Data Monitoring Committee .........................................................................
10.9.1 DMC Safety Review Schedule.......................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Sample Size Considerations..........................................................................
11.5 Randomization ..............................................................................................
11.6 Pooling of Study Centers ..............................................................................
11.7 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: WHO Ordinal Scale.................................................................
CCB-CRISIS-02_Protocol v4.0 01OCT2020 ...............................................................................
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2 SYNOPSIS.....................................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Coronavirus-19 (COVID-19) ........................................................................
3.1.1 Coronavirus Biology ........................................................................
3.2  Host Nucleotide Synthesis .............................................................................
3.3  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.4  Brequinar........................................................................................................
3.5  Rationale for the Planned Trial ......................................................................
3.5.1 Brequinar Dose Selection.................................................................
3.5.2    Risk/Benefit of Brequinar .............................................................
3.6  Risks Associated with Participation in the Clinical Study.............................
3.7  Possible Interactions with Concomitant Medical Treatments........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Stopping Criteria .............................................................................................
8.4.1 Individual Stopping Criteria.............................................................
8.4.2 Study-Level Stopping Criteria .........................................................
8.5 Concomitant Medication/Treatment ...............................................................
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8.6 Treatment Compliance....................................................................................
8.7 Storage, Stability, Labeling and Packaging ....................................................
8.7.1 Storage and Stability ........................................................................
8.7.2 Labeling and Packaging ...................................................................
8.7.3 Blinding and Randomization............................................................
8.7.4 Unblinding/Expectedness.................................................................
8.7.5 Study Drug Accountability...............................................................
8.8 Prohibited Medications ...................................................................................
8.9 Study Adjustments Due to COVID-19............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board..............................................................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Non-Childbearing Potential.............................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Follow Up of Grade 3 or 4 Toxicities ...........................................................
10.2 Infection Follow Up ......................................................................................
10.3 Classification of Causality ............................................................................
10.4 Classification of Severity ..............................................................................
10.5 Serious Adverse Event (SAE) Reporting ....................................................
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.7 Pregnancies....................................................................................................
10.8 Safety Monitoring for Hematologic Toxicities.............................................
10.9 Data Monitoring Committee .........................................................................
10.9.1 DMC Safety Review Schedule.......................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Sample Size Considerations..........................................................................
11.5 Randomization ..............................................................................................
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11.6 Pooling of Study Centers ..............................................................................
11.7 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: WHO Ordinal Scale.................................................................
CCB-CRISIS-02 Protocol v5.0 19NOV2020 ...............................................................................
2 SYNOPSIS.....................................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Coronavirus-19 (COVID-19) ........................................................................
3.1.1 Coronavirus Biology ........................................................................
3.2  Host Nucleotide Synthesis .............................................................................
3.3  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.4  Brequinar........................................................................................................
3.5  Rationale for the Planned Trial ......................................................................
3.5.1 Brequinar Dose Selection.................................................................
3.5.2    Risk/Benefit of Brequinar .............................................................
3.6  Risks Associated with Participation in the Clinical Study.............................
3.7  Possible Interactions with Concomitant Medical Treatments........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
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4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Stopping Criteria .............................................................................................
8.4.1 Individual Stopping Criteria.............................................................
8.4.2 Study-Level Stopping Criteria .........................................................
8.5 Concomitant Medication/Treatment ...............................................................
8.6 Treatment Compliance....................................................................................
8.7 Storage, Stability, Labeling and Packaging ....................................................
8.7.1 Storage and Stability ........................................................................
8.7.2 Labeling and Packaging ...................................................................
8.7.3 Blinding and Randomization............................................................
8.7.4 Unblinding/Expectedness.................................................................
8.7.5 Study Drug Accountability...............................................................
8.8 Prohibited Medications ...................................................................................
8.9 Study Adjustments Due to COVID-19............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board..............................................................................
9.4 Schedule of Events..........................................................................................
241
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9.5 Study Conduct.................................................................................................
9.5.1 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Non-Childbearing Potential.............................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Follow Up of Grade 3 or 4 Toxicities ...........................................................
10.2 Infection Follow Up ......................................................................................
10.3 Classification of Causality ............................................................................
10.4 Classification of Severity ..............................................................................
10.5 Serious Adverse Event (SAE) Reporting ....................................................
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.7 Pregnancies....................................................................................................
10.8 Safety Monitoring for Hematologic Toxicities.............................................
10.9 Data Monitoring Committee .........................................................................
10.9.1 DMC Safety Review Schedule.......................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Sample Size Considerations..........................................................................
11.5 Randomization ..............................................................................................
11.6 Pooling of Study Centers ..............................................................................
11.7 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
252
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13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: WHO Ordinal Scale.................................................................
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PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 1 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
STUDY PROTOCOL 
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 No: CCB-CRISIS-02 
Version: 1.0 
 
Version Date:  20 August 2020 
 
 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
 
IND Number: 149291 
 
 
 
 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations. 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 2 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.1.1 Coronavirus Biology .................................................................................................... 16 
3.2 Host Nucleotide Synthesis ......................................................................................... 16 
3.3 Dihydroorotate dehydrogenase (DHODH) ................................................................ 16 
3.4 Brequinar .................................................................................................................... 17 
3.5 Rationale for the Planned Trial .................................................................................. 17 
3.5.1 Brequinar Dose Selection ............................................................................................. 18 
3.5.2 Risk/Benefit of Brequinar ............................................................................................ 18 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 19 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 19 
3.7.1 CYP Interactions .......................................................................................................... 19 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 19 
4 TRIAL OBJECTIVES ........................................................................................................ 20 
4.1 Primary Objective ...................................................................................................... 20 
4.2 Secondary Objectives ................................................................................................. 20 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 20 
5 TRIAL DESIGN ................................................................................................................. 21 
6 TRIAL ENDPOINTS.......................................................................................................... 22 
6.1 Primary Endpoint ....................................................................................................... 22 
6.2 Secondary Endpoints .................................................................................................. 22 
6.3 Exploratory Endpoints................................................................................................ 22 
7 TRIAL POPULATION ....................................................................................................... 23 
7.1 Number of Subjects .................................................................................................... 23 
7.2 Inclusion criteria ......................................................................................................... 23 
7.3 Exclusion Criteria ....................................................................................................... 23 
8 STUDY TREATMENTS .................................................................................................... 25 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
8.1 Description of Study Medications .............................................................................. 25 
8.1.1 Brequinar ...................................................................................................................... 25 
8.2 Treatment Administration .......................................................................................... 25 
8.2.1 Safety/Tolerability ........................................................................................................ 25 
8.3 Study Discontinuation ................................................................................................ 26 
8.4 Stopping Criteria ........................................................................................................ 26 
8.4.1 Individual Stopping Criteria ......................................................................................... 26 
8.4.2 Study-Level Stopping Criteria...................................................................................... 26 
8.5 Concomitant Medication/Treatment .......................................................................... 26 
8.6 Treatment Compliance ............................................................................................... 27 
8.7 Storage, Stability, Labeling and Packaging ............................................................... 27 
8.7.1 Storage and Stability .................................................................................................... 27 
8.7.2 Labeling and Packaging ............................................................................................... 27 
8.7.3 Blinding and Randomization ........................................................................................ 27 
8.7.4 Unblinding/Expectedness ............................................................................................. 27 
8.7.5 Study Drug Accountability ........................................................................................... 27 
8.8 Prohibited Medications .............................................................................................. 28 
8.9 Study Adjustments Due to COVID-19....................................................................... 28 
9 CONDUCT OF THE TRIAL.............................................................................................. 29 
9.1 Ethical and Regulatory Considerations ...................................................................... 29 
9.2 Informed Consent ....................................................................................................... 29 
9.3 Institutional Review Board......................................................................................... 30 
9.4 Schedule of Events ..................................................................................................... 31 
9.5 Study Conduct ............................................................................................................ 31 
9.5.1 Unscheduled Visits ....................................................................................................... 31 
9.6 Compliance with Study Procedures ........................................................................... 31 
9.7 Early Withdrawal from the Study .............................................................................. 32 
9.8 Early Termination of the Study .................................................................................. 32 
9.9 Non-Childbearing Potential........................................................................................ 32 
10 ADVERSE EVENT REPORTING..................................................................................... 33 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 4 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 34 
10.2 Infection Follow Up ................................................................................................... 34 
10.3 Classification of Causality ......................................................................................... 34 
10.4 Classification of Severity ........................................................................................... 35 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 35 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 36 
10.7 Pregnancies................................................................................................................. 37 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 37 
10.9 Data Monitoring Committee ...................................................................................... 38 
10.9.1 
DMC Safety Review Schedule ............................................................................... 39 
11 STATISTICAL CONSIDERATIONS................................................................................ 40 
11.1 Study Populations for Analysis .................................................................................. 40 
11.2 Safety Analyses .......................................................................................................... 40 
11.3 Efficacy Analyses ....................................................................................................... 40 
11.4 Sample Size Considerations ....................................................................................... 40 
11.5 Randomization ........................................................................................................... 40 
11.6 Pooling of Study Centers............................................................................................ 41 
11.7 Interim Analysis ......................................................................................................... 41 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 42 
12.1 Investigator’s Performance ........................................................................................ 42 
12.2 Confidentiality ............................................................................................................ 42 
12.3 Source Documentation ............................................................................................... 42 
12.4 Data Collection ........................................................................................................... 43 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 43 
12.6 Non-Protocol Research .............................................................................................. 44 
12.7 Publication .................................................................................................................. 44 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 45 
13.1 General ....................................................................................................................... 45 
13.2 Indemnity ................................................................................................................... 45 
13.3 Data Monitoring ......................................................................................................... 45 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 5 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
13.4 Audit ........................................................................................................................... 45 
13.5 Confidentiality ............................................................................................................ 46 
13.6 Finance ....................................................................................................................... 46 
14 REFERENCES ................................................................................................................... 47 
15 APPENDICES .................................................................................................................... 48 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events .................................................. 48 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 49 
15.3 Appendix C: WHO Ordinal Scale .............................................................................. 50 
 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
LIST OF FIGURES  
Figure 3-1. DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine synthesis; 
it is completely essential for the generation of UMP. ............................................... 16 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 7 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AML 
Acute myeloid leukemia 
ARDS 
Acute respiratory disease syndrome 
AST 
Aspartate amino transferase 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus-19 infection 
CRP 
c-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Curricula vitae 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DHODHi 
Dihydroorotate dehydrogenase inhibitor 
DMC 
Data Safety Monitoring Board 
ECMO 
Extra corporeal membrane oxygenation 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
EUA 
Emergency Use Authorization 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IMP 
Inosine-5’ phosphate 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEWS2 
National Early Warning System (NEWS) 2 Score 
RNA 
Ribonucleic Acid 
RdRp 
RNA-dependent RNA polymerase 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
SARS Coronavirus 2 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
UMP 
Uridine 5’-monophosphatase 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
2 
SYNOPSIS  
CCB-CRISIS-02 SYNOPSIS  
IND 
149291 
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  
Protocol Number 
CCB-CRISIS-02 
Rationale 
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.  
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) + 5 days 
of brequinar 100 mg or SOC + 5 days of placebo.  
Investigational product will be supplied as either brequinar 100 mg oral capsules 
or placebo capsules. The subjects are to self-administer one capsule on Study Days 
1 – 5.  
Treatment assignment will be randomized, double-blind. 
Primary 
Objectives 
● To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load 
for brequinar-treated subjects compared to placebo-treated subjects through 
Day 29. 
Secondary 
Objectives 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-
19 subjects as measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 10 of 50 
PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
● To reduce the percentage of subjects requiring hospital admission as an in-
patient for > 24 hours for brequinar subjects compared to subjects who received 
placebo; 
● To reduce mortality through Day 29 for brequinar subjects compared to 
subjects who received placebo. 
Exploratory 
Objectives 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
● To reduce disease severity as measured by the WHO Ordinal Scale score 
measured for the subset of subject with baseline WHO Ordinal Scale of 2 for 
brequinar subjects compared to subjects who received placebo.  
Design 
This will be a phase 2 randomized, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive SOC per relevant guidelines 
for treatment of out-patients with COVID-19 infection. In addition to SOC, 
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 procedures are presented in detail in the Schedule of Events. Study visits 
(virtual or in person) will take place at Screening and on Study Days 1, 8, 15, 22, 
and 29. 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 pO2, and 
complete a symptom assessment on Days 1, 4, 8, 12, 15, 22, and 29. 
Sample Size: 
Approximately 100 subjects will be randomized to 5 days of either SOC + 
brequinar 100 mg or SOC + placebo in a 1:1 ratio (approximately 50 subjects 
assigned to brequinar 100 mg and 50 subjects to placebo).  
Number of Sites: 
Approximately 15 
Study Period: 
An enrollment period of 3 months is expected. 
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 within 14 days of randomization. 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
4. Out-patient (not currently hospitalized or was hospitalized with duration < 
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, ansomia, dysgeusia, or other 
symptom commonly associated with COVID-19.  
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 for menstruating women and < 12 gm/dL for all 
other subjects 
6. Absolute neutrophil count < 1500 cells/mm3 
7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
8. AST and/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. 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
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).  
Treatment 
All subjects will receive standard of care (SOC) including symptomatic care. 
Subjects will be randomly assigned to SOC + brequinar 100 mg daily x 5 or SOC 
+ placebo daily x 5. Study encounters will be conducted remotely whenever 
possible. 
DMC 
A Data Monitoring Committee (DMC) will meet periodically to review the safety 
and scientific conduct of the study. At a minimum, the DMC is to review adverse 
events and safety laboratory assessments after the first 20 subjects complete Day 
8, and again after the first 40 subjects complete Day 8.  
Procedures 
Study procedures are outlined in the Schedule of Events. 
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
29. After Day 29, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug. 
Treatment-emergent adverse events will be those with an onset after the date and 
time of first treatment. 
Subjects who develop Grade 3 or 4 toxicities or SAEs are to be re-evaluated every 
2 days, as feasible, until the toxicity returns to Grade ≤ 2 severity. 
Stopping Criteria 
Individual Criteria:  
• Participants who develop a Grade 3 toxicity that is assessed by the 
investigator to be related to the study drug are to be permanently 
discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to 
study drug, are to be permanently discontinued from study treatment. 
Study-Level Stopping Criteria: 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse 
event or laboratory abnormality; 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or 
laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or 
laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per 
protocol. 
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking 
the database. All analyses of safety and efficacy for this study will be descriptive 
in nature and presented by group. Subject demographics and baseline 
characteristics will be summarized. Subject data listings will also be provided.  
Summaries for quantitative variables will include the mean, median, quartiles, 
standard error, minimum, and maximum. For qualitative variables, the summaries 
will include the number and percentage of subjects for each outcome, and the 95% 
CI, when appropriate.  Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.4 or 
higher). Safety and tolerability will be assessed in terms of AEs, SAEs, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after randomization will be tabulated by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term and system organ class, and by 
severity and relationship to study treatment. All laboratory results and other 
clinical measures will be summarized using appropriate descriptive statistics. 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2, 3 
(± 8 
hr) 
D4 
(± 8 
hrs) 
D5 
(± 8 
hrs) 
D8 
(± 1 
day) 
D12 
(± 1 
day) 
D15 
(± 1 
day) 
D22 
(±1 
day) 
Final Visit  
D29 
(± 2 days) 
Informed Consent (note Date and 
Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications 
(dose, route, duration or 
ongoing) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Medical history (relevant within 
one year or ongoing)/ History of 
current illness (date of symptom 
onset or change in baseline co-
morbidity thought to be due to 
COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported 
height and weight, date of birth, 
gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check 
for 
Physical 
Exam 
abnormalities 
(subject 
self-
reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Randomize subject and dispense 
Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, pO2. 
cSymptom Assessment will be using a checklist provided to the subject with symptoms such as sore throat, cough, GI 
symptoms (vomting, diarrhea), ansomia, dysgeusia, other (specify), etc. 
dSample Day 1 must be obtained prior to dosing. Viral load specimens will be saliva samples self-collected by the 
subject using an Oragene® collection system or similar. These samples are to be sent to CCLS for analysis. The 
viral load sample may also be used to perform viral cultures (sample can be split, no additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. 
Note that any visits/visit activities may be conducted via telephone, telemedicine, or digital media other than serum 
pregnancy test and chemistry/hematology sample collection. These labs may be collected at the clinical site or another 
designated out-patient facility/laboratory or collected via home visit. Arrangements for shipping viral load samples 
will be made by the study team. 
 


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STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
MEDICAL MONITOR 
Name:  
Norberto Soto, MD 
Title: 
Senior Medical Director 
Telephone No.: 
(609) 212-7892 
E-mail: 
Norberto.Soto@Covance.com 
 


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3 
INTRODUCTION 
3.1 
Coronavirus-19 (COVID-19) 
Beginning in December 2019, Chinese scientists isolated a novel coronavirus, severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) from patients with virus-infected pneumonia 
which was later designated as coronavirus disease 2019 (COVID-19) by the World Health 
Organisation (WHO) (Zhou et al., 2020 [2]; Phelan et al., 2020 [3]).  
Approximately 14% of those affected with this virus will develop severe disease requiring 
hospitalization and oxygen support; 5% will require admission to the intensive care unit (Handel 
et al., 2020 [4]). Severe cases may be complicated by acute respiratory disease syndrome (ARDS), 
sepsis and septic shock, and multi-organ failure, including acute kidney injury and cardiac injury. 
Risk factors for death include older age and co-morbid disease such as hypertension and diabetes 
(Zhou, et al., 2020 [2]). This means that most patients will be treated as out-patients. Reducing 
viral load in this environment is critically important for both the subjects themselves by preventing 
worsening of symptoms and possibly avoiding hospitalization, but also to reduce the transmission 
of the disease to others in the patients’ households and their communities. 
3.1.1 Coronavirus Biology 
Coronaviruses, like other RNA-based viruses, do not have the machinery to synthesize their own 
nucleotides and thus depend upon the host intracellular pool of nucleotides for viral replication. In 
essence, viruses steal the host RNA building blocks, and without these building blocks they are 
unable to replicate. The SARS-CoV-2 is a single-stranded (positive sense) RNA virus with a 
genome that is 29,811 nucleotides long, quite a lot larger than other RNA-based viruses (e.g. the 
hepatitis C genome comprises only 9600 nucleotides). The nucleotide composition is broken down 
as: 29.9% adenosines, 18.4% cytosines, 19.6% guanines, and 
32.1% uridines (Sah et al., 2020 [12]). 
3.2 
 Host Nucleotide Synthesis 
Host 
de 
novo 
pyrimidine 
synthesis 
generates 
uridine 
monophosphate (UMP) as the building block for all pyrimidine 
ribonucleotides and deoxyribonucleotides (Figure 3-1). There 
exists no salvage pathway for the synthesis of UMP, the 
fundamental building block of pyrimidines. Inhibition of 
enzymatic steps upstream of UMP (Figure 3-1) leads to a rapid 
and profound depletion of intracellular pyrimidines.  
3.3 
 Dihydroorotate dehydrogenase (DHODH) 
The enzyme dihydroorotate dehydrogenase (DHODH) catalyzes 
the 4th step of de novo pyrimidine synthesis and inhibition of 
DHODH completely halts all pyrimidine production. As shown in 
Figure 3-1, DHODH is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III 
 
Figure 
3-1. 
DHODH 
is 
a 
mitochondrial 
enzyme 
that 
catalyzes the 4th step of pyrimidine 
synthesis; it is completely essential 
for the generation of UMP.   


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of the electron-transport chain via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a clear therapeutic target for the inhibition of host pyrimidine synthesis. The chemical 
inhibition of DHODH in vitro or in vivo leads to the rapid depletion of UMP and subsequent 
depletion of downstream products thymine and cytosine. This forces a cell to rely on the salvage 
of extracellular pyrimidine nucleotides and this extracellular salvage is not capable of maintaining 
the cell’s normal nucleotide pool (Sykes et al., 2016) [1]).    
3.4 
 Brequinar 
Brequinar is an orally available and potent inhibitor of DHODH. Brequinar is one of more than 
300 quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, 
which was started after it was found that a compound of this class had antitumor activity. Brequinar 
was selected by DuPont for further development as a potential clinical drug because of its activity 
against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. 
In an indication such as treating SARS-CoV-2 infection, brequinar will act as a host-targeting 
antiviral. It is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH), 
the enzyme that catalyzes the fourth step in pyrimidine synthesis, namely the conversion of 
dihydroorotate (DHO) to orotate. DHODH inhibitors, including brequinar, inhibit de novo 
pyrimidine synthesis thereby leading to a depletion of a cell’s pool of uridine, cytidine and 
thymidine ribonucleotides and deoxyribonucleotides.  
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in 
human intestinal Caco-2 cells as well as in human primary intestinal organoids (Chen et al., 2019 
[6]). Treatment with teriflunomide, another DHODHi, has been effective in vitro and in vivo in a 
murine model of foot and mouth disease virus (Mei-Jian et al., 2019 [7]). DHODH inhibition 
(DHODHi) also inhibited the growth of dengue virus in vitro (Wang et al., 2011 [8]). DHODHi 
also showed antiviral effects against RNA viruses including influenza A, Zika, Ebola and 
coronavirus SARS-CoV-2 (Xiong et al., 2020 [11]). Brequinar has also been shown to inhibit the 
replication of Ebola virus, vesicular stomatitis virus and Zika virus in vitro (Luthra et al., 2018 
[9]). Brequinar inhibits the replication of human immunodeficiency virus (HIV) in vitro (Andersen 
et al., 2019 [10]). When considering brequinar as an antiviral for treatment of SARS-CoV-2, oral 
brequinar is highly bioavailable (>95%) and has good penetration of lung tissue with an average 
tissue:blood ratio of 0.5 following a single dose of brequinar in the rat. It is therefore expected to 
achieve a similar period of DHODH inhibition in lung tissue (Brequinar IB [5]). 
3.5 
 Rationale for the Planned Trial 
DHODH inhibition has been extensively studied as a potential therapeutic target in the treatment 
of RNA-based viruses. The inhibition of DHODH is effective in inhibiting viral replication in pre-
clinical models involving many RNA-based viruses with nanomolar potency and a high selectivity 
index (see the Brequinar IB [5], Section 5). In these pre-clinical models, the benefit of DHODH 
inhibition can be reversed by the supplementation of exogenous nucleotides, confirming that the 
on-target effect of host pyrimidine depletion is key to the anti-viral activity.  


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The CCB-CRISIS-02 trial will study standard of care (SOC) with 5 days of brequinar (DHODH 
inhibition) compared to SOC with 5 days of placebo treatment. Clear Creek Bio hypothesizes that 
a defined 5-day course of brequinar will inhibit the enzyme DHODH to a degree sufficient to result 
in the transient depletion of host pyrimidine nucleotides, thereby inhibiting viral replication. A 
recent publication demonstrated that inhibitors of DHODH could potentiate the activity of 
inhibitors of RNA-dependent RNA polymerase (RdRp) in the treatment of dengue virus, another 
single-stranded RNA virus similar to SARS-CoV-2 (Liu et al., 2020 [13]). This inhibition of viral 
replication may restore the balance in favor of the host immune system for the clearance of SARS-
CoV-2. 
Marketed DHODHi medications are available, including leflunomide or teriflunomide, however 
these are very weak inhibitors of DHODH with cellular potency ~500 times lower than brequinar. 
These low potency inhibitors of DHODH are not expected to have the ability to acutely lower the 
pool of intracellular pyrimidines to the degree that is required for decreasing the viral load 
associated with SARS-CoV-2 infection, making brequinar the better choice for acute SARS-CoV-
2 infection.  
The CRISIS2 study is a proof-of-concept study in patients with SARS-Cov-2 infection and will 
serve as a basis for future studies to determine the safety and effectiveness of brequinar in COVID-
19. 
3.5.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with 5 days of consecutive daily 
dosing suggest that 5 days of daily doses of 100 mg p.o. will be safe and well tolerated. A dose of 
brequinar 100 mg achieves plasma concentrations of approximately 1 uM (0.4 ug/ml) that should 
result in sufficient suppression of nucleotide synthesis. When given over 5 days, these plasma 
concentrations are achieved on a daily basis without accumulation, also assuring the safety of this 
regimen (see Brequinar IB [5]).  
3.5.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive safety and pharmacokinetic database exists with 
more than 1,000 patients treated with brequinar. Cancer patients (N = 806) have been exposed to 
this compound for treatment of a variety of solid tumors at various treatment regimens, doses, and 
routes including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 
5 every 4 weeks, and daily times 21 days for multiple courses. Lower doses than used in the cancer 
studies have also been utilized for patients with psoriasis and organ transplant. The maximum 
intravenous dose given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 
mg/m2 daily for 21 days. There has been limited testing of DHODHi to date in the clinic for 
infection with SARS-CoV-2. DHODHi therapy at relatively high doses in the context of trials for 
patients with cancer has the expected safety side-effects of mucositis and bone marrow 
suppression. Importantly, however, the prior clinical experience in 39 subjects who received daily 
brequinar for 5 consecutive days at or lower than 100 mg/day show no cases of mucositis and only 
1 (2.6%) episode of mild thrombocytopenia. Based on these data the 100 mg per day dose proposed 
for administration in this study should be within a safe and tolerable range as well as demonstrating 
the predicted antiviral effect.  


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The potential benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 5-
day period of brequinar dosing will suppress host de novo pyrimidine synthesis for this period thus 
decreasing viral load. Inhibition of DHODH is expected to reduce the ability of the virus to 
replicate and it is for this reason that brequinar will be administered to patients with COVID-19 in 
this study. 
 
3.6 
 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of high-dose brequinar in patients with 
refractory solid tumors, reversible myelosuppression, in particular thrombocytopenia, and 
mucositis have been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, 
fatigue, and leukopenia have been dose-limiting in trials utilizing other schedules of brequinar 
administration. However, these effects were self-limiting, transient, required treatment in few 
cases, and resolved following discontinuation of dosing. These adverse effects have been 
associated with higher doses of brequinar given via the intravenous route and for longer durations 
than the 100 mg dose and 5-day regimen proposed for this study.  
In addition to studying a higher risk population with symptomatic COVID-19, a comprehensive 
safety monitoring plan will be utilized in this study to assess the ongoing safety and well-being of 
participants (see Section 10.8).  
3.7 
 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in severely ill cancer patients including antibiotics, antifungals and other critical care 
medications. No formal interaction studies have been conducted for these medications, however, 
there have not been any reports of interactions with any medications during the clinical trials with 
more than 800 cancer patients.  
3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with 
medications commonly used in treating hematologic malignancies. The nonclinical studies 
performed to date have demonstrated there is no first-pass metabolism and there have been no 
apparent hepatotoxic effects in the clinical studies. Brequinar itself does not appear to be a 
substrate for metabolism by cytochrome P450 enzymes when tested under a variety of conditions. 
(See Brequinar IB [5]; nonclinical data on file with Clear Creek).  
3.8 
Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated by highly experienced clinicians familiar with the treatment of viral 
infections and their complications.  
 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load for brequinar-
treated subjects compared to placebo-treated subjects through Day 29. 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-19 subjects as 
measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with brequinar 
compared to subjects who received placebo;  
● To reduce the percentage of subjects requiring hospital admission as an inpatient for >24 hours 
for brequinar subjects compared to subjects who received placebo; 
• To improve survival status through Day 29 for brequinar subjects compared to subjects who 
received placebo. 
4.3 
EXPLORATORY OBJECTIVES 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical symptoms and pre-
existing non-COVID-19 symptoms returned to baseline; 
● To reduce disease severity as measured by the WHO Ordinal Scale score for the subset of 
subjects with baseline WHO Ordinal Scale of 2 for brequinar subjects compared to subjects 
who received placebo. 


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5 
TRIAL DESIGN 
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 per (SOC) 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 
procedures are presented in detail in the Schedule of Events (Appendix 15.1). Study visits (virtual 
or in person) will take place at Screening and on Study Days 1, 8, 15, 22, and 29. 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 pO2, and complete 
a symptom assessment checklist on Days 1, 4, 8, 12, 15, 22, and 29.   


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6 
TRIAL ENDPOINTS 
6.1 
Primary Endpoint 
Quantitative SARS-CoV-2 viral load through Day 29. 
6.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
Through Day 29: 
● Rates of AEs and SAEs including laboratory assessments; 
● Duration of viral shedding;  
• Percentage of subjects requiring admission as an inpatient for >24 hours. 
6.3 
Exploratory Endpoints 
● Time to viral clearance (two consecutive negative tests);  
● Time to resolution of new onset COVID-19-related clinical symptoms and pre-existing non-
COVID-19 symptoms returned to baseline; 
● Disease severity as measured by the WHO Ordinal Scale score for the subset of subjects with 
baseline WHO Ordinal Scale of 2; 
 


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7 
TRIAL POPULATION 
7.1 
Number of Subjects 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled in the 
study until approximately 100 subjects have completed the study. Subjects will be randomized to 
either standard of care plus brequinar 100 mg or standard of care plus placebo in a 1:1 ratio 
(approximately 50 subjects assigned to standard of care plus brequinar 100 mg and approximately 
50 subjects assigned to standard of care plus placebo).  
7.2 
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 within 
14 days of randomization. 
4. Out-patient (not currently hospitalized or was hospitalized with duration < 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. 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. 
8. Able to swallow capsules. 
7.3 
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 


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4. Platelets ≤150,000 cell/mm3 
5. Hemoglobin < 10 gm/dL for menstruating women and < 12 gm/dL for all other subjects 
6. Absolute neutrophil count < 1500 cells/mm3 
7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
8. AST and/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). 
 


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8 
STUDY TREATMENTS 
8.1 
Description of Study Medications 
8.1.1 Brequinar 
Brequinar and placebo will be supplied as 100 mg capsules. Dosing will be a single 5-day course 
of brequinar 100 mg capsules or placebo 100 mg capsules once daily for 5 doses.  
8.2 
Treatment Administration 
This will be a phase 2 randomized, placebo-controlled, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive standard of care (SOC) for COVID-19 
infection. Subjects will be randomly assigned in a 1:1 ratio to standard of care plus brequinar or 
standard of care plus placebo. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit. The NIH Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 
(July 2017) will be utilized for AE reporting. All appropriate treatment areas should have access to 
a copy of the criteria.  
Adverse events (AEs) commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure (IB) and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 cancer 
subjects treated once-weekly (DuP 785-012, see Brequinar IB [5]), the deaths of three patients 
were attributed to study drug toxicity (two to hemorrhage, one following acute renal failure). 
Severe toxicities grades (Grades 3 to 4) which typically led to discontinuation in this study 
included hematologic toxicities (anemia, thrombocytopenia, leukopenia, granulocytopenia), 
digestive system toxicity (nausea, vomiting, stomatitis, others including gastric hemorrhage) and 
mucositis.  
In three oncology studies with five consecutive days of intravenous (IV) brequinar dosing in 168 
subjects (Study 785-001 [14], 785-003 [15], and 785-005 [16]) there were no toxic deaths. For 
subjects from these three studies who were treated with a daily dose of 100 mg or below  (as will 
be dosed in CCB-CRISIS-02), AEs through 21 days showed that 2 of 39 subjects (5.1%) had a 
severe (Grades 3 or 4) AE related to study drug (1 subject each with hyperbilirubinemia and 
hyperglycemia), and no subjects discontinued from the study due to a study drug-related AE. The 
few study drug related AEs through 21 days at or below the 100 mg dose from these three studies 
included 2 subjects each with nausea, vomiting, and creatinine elevated and one subject each 
with thrombocytopenia and diarrhea. When only studies with oral dosing were considered at this 
dose level (Studies 785-022 [17], 785-031 [18] , and 785-034 [19]), the study drug related AEs 
through 21 days (each observed in one subject only) included diarrhea, headache, nausea, 
pruritus, abdominal pain, anorexia, chest pain, dry mouth, fatigue, keratosis, stomatitis, and 
vomiting. See brequinar IB [5]. 


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In most instances, brequinar-related toxicities were transient, clinically manageable, and reversible 
upon discontinuation of brequinar treatment. Any of these events reported with brequinar use can 
be serious in nature and may result in death.  
A 5-day course of oral brequinar administered once daily at a low level relative to those 
administered in the cancer studies is expected to be safe and well tolerated in the COVID-19 
population. 
8.3 
Study Discontinuation 
Subjects will remain in the study through at least Study Day 29 (or longer if needed to follow up 
study drug-related adverse events). Participants may discontinue from the study by withdrawing 
consent at any time or for any reason as presented in Section 9.7. 
8.4 
Stopping Criteria 
8.4.1 Individual Stopping Criteria 
• Participants who develop a Grade 3 toxicity that is assessed by the investigator to be related 
to the study drug are to be permanently discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to 
be permanently discontinued from study treatment. 
• Subjects who develop Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 
days, as feasible, until the toxicity returns to ≤ Grade 2 severity. 
8.4.2 Study-Level Stopping Criteria 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse event or 
laboratory abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or laboratory 
abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC, see Section 10.9), the DMC 
will determine whether to stop the study, amend the protocol, or continue the study per 
protocol. 
8.5 
Concomitant Medication/Treatment 
Record the name, dose, start/stop date, indication for use, route, and whether ongoing or stopped 
for medications/treatments taken within two weeks prior to study entry as well as any medications 
taken during the study are to be recorded. Prohibited medications are identified in Section 8.8.  


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8.6 
Treatment Compliance 
Compliance will be assessed by reviewing the subject’s medication diary and study records as 
appropriate. 
8.7 
Storage, Stability, Labeling and Packaging 
8.7.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.7.2 Labeling and Packaging  
The bulk drug and unit-dose containers will be labeled in accordance with national laws and 
regulations. 
8.7.3 Blinding and Randomization 
The trial will be conducted in double blinded, randomized manner with random assignment to 
standard of care plus brequinar or standard of care plus placebo. The brequinar and placebo 
capsules will be provided to each participating institution in pre-numbered bottles intended for 
individual subjects to be dispensed by the institution’s pharmacist or designated person. 
Randomization assignments will be provided by an independent statistician to the drug packaging 
company. The pharmacist/designated person will dispense the next number in sequence to the next 
patient who qualifies for the study at an individual site. 
8.7.4 Unblinding/Expectedness 
Contact the Covance Medical Monitor if it is necessary to break the blind for this blinded study 
due to an adverse event (AE). Each site will be provided with a sealed envelope containing 
individual sealed envelopes for subject numbers assigned to that site. Each individual subject 
number sealed envelope will have the treatment (brequinar or placebo) randomly assigned to that 
subject number. Do not open the outer envelope or the individual sealed envelope unless it has 
been agreed with the Medical Monitor and the Sponsor that unblinding is necessary for that 
particular AE. Unblinding must be documented in the study records. Envelope seals are to be 
checked to ensure they remain intact during drug accountability monitoring. 
If after a discussion with the Medical Monitor, the investigator or treating clinician believes the 
AE leading to unblinding to be related to the study drug, no further doses of drug should be 
administered to that subject.  
Expectedness will be determined by establishing whether an adverse event is among those 
identified in the protocol and the brequinar IB or are commonly associated with COVID-19 or 
similar severe viral illnesses and their complications.   
8.7.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 


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The Investigator must keep a record of all study medication received, administered, and discarded.  
It must be clear from the records whether the subject received study medication and what subject 
number was assigned to which subject. Adequate drug is to be dispensed for the number of subjects 
expected to be treated at each institution.  
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor.  
At the end of the study any unused study drug will be returned to the Sponsor for destruction or 
may be destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. Records may be electronic or paper and may be accessed remotely for 
monitoring/drug accountability purposes. 
Each subject will be provided with one bottle with five brequinar or five placebo capsules for the 
five days of dosing. 
8.8 
Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide). 
Treatment is prohibited with agents known to cause bone marrow suppression leading to 
thrombocytopenia.  
8.9 
Study Adjustments Due to COVID-19 
Due to the highly contagious nature of COVID-19, multiple adjustments and revised procedures 
are rapidly evolving regarding clinical trial management and study conduct. Reasonable 
procedures implemented by study staff to avoid spreading this disease are acceptable to Clear 
Creek with written permission. Examples include but are not limited to e-consent, telephone 
consent and study visits conducted by telemedicine, telephone or other digital media.  
Background standard of care is to be maintained in both treatment arms. The standard of care is 
expected to change as additional information, such as that from randomized controlled trials, 
emerges, and the Sponsor and the treating clinicians will need to address anticipated off-label use 
of any other drugs, devices, or interventions that might be used to manage COVID-19 (e.g. 
anticoagulants).  
The Sponsor and treating clinicians are to consider changes in SOC over time, for example, 
overlapping toxicities of brequinar and a SOC treatment expected to be widely used is to be 
considered. The availability of new standard of care treatment may change over time and vary 
from one clinical trial site to another. The Sponsor will discuss these issues with FDA should the 
need arise. 
 


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9 
CONDUCT OF THE TRIAL 
9.1 
Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) as revised in 
Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland (2000, Note of 
Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) (2013), and with 
the International Council on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and United States (US) FDA Regulations. 
9.2 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50),  
the FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public 
Health Emergency (March 2020, Updated April 16, 2020) [20], as well as local and national 
regulations. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the Institutional Review Board (IRB). Subjects and their relatives, if 
necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Product (IP), 
and the hazards involved, as well as the potential benefits that may come from treatment with this 
IP. The trial procedures will be explained in lay language and any questions will be answered. The 
subjects will be given an IRB-approved consent form. The subjects will be given appropriate time 
to consider their participation in the trial and have any questions answered prior to signing the 
consent form. If a subject agrees to participate, he/she will sign and date an informed consent form 
and be provided with a copy of the signed consent. All subjects who sign an informed consent 
form are to be recorded on the applicable screening log. If the subject is unable to consent for any 
reason, a designated family member or healthcare power of attorney or other person may consent 
per institutional policy.  
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the FDA and other relevant 
regulatory authorities. Subjects will be informed that they are free to refuse participation in this 
clinical investigation, and if they should participate, it will be made clear to them that they may 
withdraw from the trial at any time without prejudicing further medical care they may require. The 
subject will receive a copy of the consent form as well as an information sheet about the trial.  
Informed consent must be obtained from every subject prior to any study-specific procedures. 
Standard procedures carried out prior to completing the informed consent process but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
Documentation of consent will be subject to review by the Sponsor; if in writing, a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. Verbal consents will 
be documented by the study team as appropriate and agreed by the IRB. 


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Note that informed consent procedures have been affected by COVID-19, and the study staff may 
use any consent method that has been approved by the IRB (e.g., phone consent, verbal consent 
with witness, e-consent, etc.) of the local institution. In-person consent, written consent signatures 
and providing hard copies to the subject are examples of procedures that may be foregone under 
these circumstances. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 
A sample subject information sheet and consent form are available from Clear Creek.  The final 
version at each institution may differ depending on institutional requirements and standard 
formats. This protocol will not be amended for site specific changes as such changes are to be 
made to the site’s consent when required. 
9.3 
Institutional Review Board  
It is the responsibility of the Investigator to submit the protocol, consent form and information 
sheet to the IRB. An IB will be available for review by the IRB. The protocol and informed consent 
form (ICF) must be approved by the IRB prior to the recruitment of the first subject. The template 
consent form may be revised in accordance with site-specific requirements with Sponsor review 
and approval. A copy of the IRB written approval must be provided to the Sponsor and investigator 
before the trial may start at that institution. Written approval from the IRB is also required for 
substantial protocol amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating 
to the scientific documents in support of the trial.  Amendments are “substantial” when they are 
likely to have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures 
taken as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. On completion of the trial, the 
Investigator will inform the applicable IRB as per local IRB requirements that the trial has ended. 
If the study is terminated for any reason, the investigator will return all clinical supplies and study-
related equipment supplied by the Sponsor to the Sponsor unless otherwise specified.  


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9.4 
Schedule of Events 
Study activities will be conducted or supervised by experienced personnel throughout the study 
based on the Schedule of Events. The subjects may collect the saliva sample for viral load testing 
and perform other study activities such as body temperature, heart rate, respiratory rate, pO2, and 
symptom assessments themselves with appropriate training. Telemedicine visits such as phone 
calls or other remote media are to be utilized as much as possible. Subjects may need to come to 
an out-patient facility or be visited by a home health professional for some study assessments. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALK), 
alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
and calcium), lactate dehydrogenase (LDH). 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and 
platelet count. 
Viral load sampling is to be carried out on Days 1, 4, 8, 12, 15, 22, and 29. The subject is to self- 
collect saliva samples with appropriate training for this analysis. Samples may be banked for future 
retrospective analyses. 
Hospitalization status after enrollment is to be recorded as not hospitalized or admitted to hospital 
as an in-patient with admission > 24 hours.    
9.5 
Study Conduct 
The study visits are to be conducted as shown in the Schedule of Events, Appendix 15.1. 
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF.  
9.5.1 Unscheduled Visits 
Unscheduled visits and tests are permitted as needed to assess AEs/SAEs throughout the study. 
Unscheduled visits and tests are also permitted as needed to assess AEs/ SAEs with onset within 
two (2) weeks after the final study visit providing the AE is considered related to study drug 
9.6 
Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely 
as possible.  However, it is recognized in a clinical setting that protocol-specified timings may not 
occur exactly as specified in the protocol, particularly when conducted remotely by the subject. 
Provided that activities are carried out within the identified windows it will not be necessary to file 
a protocol deviation. Remote visits such as a telemedicine visit may be conducted to collect as 
much information as possible remotely. A home visit or return to the clinical site or an out-patient 
laboratory may be arranged for safety labs or other assessments, when required. Telemedicine or 


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other remote technique is to be utilized to ensure subject compliance when subject is performing 
self-collection of study assessments.  
9.7 
Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in the 
study.   
Subjects must discontinue study medication if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all scheduled evaluations even for subjects who discontinue study medication 
prior to completing the treatment period unless consent is withdrawn. 
9.8 
Early Termination of the Study 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any 
reason at the Sponsor’s request, the study may be terminated at that site or the entire study 
terminated after discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with 
the reasons for termination of the study. This will be conducted within 15 days of the decision to 
terminate the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
9.9 
Non-Childbearing Potential 
Women of non-childbearing potential are defined as those who have no uterus, ligation of the 
fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical 
removal of the ovaries. Documentation of surgical procedure or physical examination is required 
for subjects who have had a hysterectomy or tubal ligation. A woman is also presumed to be 
infertile due to natural causes if she has been amenorrheic for greater than 12 months and has an 
FSH greater than 40 IU/L. In the absence of such documentation, a negative serum pregnancy test  
is required for inclusion into the study. 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  
Events that occur prior to informed consent will be entered as medical history; AEs that occur after 
informed consent will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not judged by the 
Investigator or designated person to be related to study drug. All AEs will be documented in the 
subject's medical record and CRF. For any pre-existing condition or abnormal laboratory finding 
that changes in severity after dosing, this change should be recorded as an AE. New abnormal 
laboratory findings that are clinically significant are considered AEs. 
All adverse events will be collected from the time of informed consent through Day 29. After Day 
29, collect/record only Serious Adverse Events (SAEs) which are assessed by the Investigator or 
designated person to be related to study drug.  AE details are to be documented including start and 
stop date and times, whether continuous or intermittent, severity, any intervention utilized to 
correct the event (e.g., medication, surgery, or other therapy), outcome and the relationship to the 
study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, are Grades 3 or 4, or 
require therapy. 
If a death occurs during the SAE reporting period, the cause of death such as pneumonia, ARDS, 
or respiratory failure, is considered as the AE and the death is considered its outcome. Death should 
be considered an outcome, not an event. The event or condition leading to death should be recorded 
and reported as a single medical concept on the AE eCRF. Generally, only one such event should 
be reported. “Fatal” will be recorded as the outcome of this respective event; death due to an 
outcome of an AE will not be recorded as separate event. If the primary cause of death is disease 
progression, the cause of death should be clearly identified as COVID-19. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA). For example, record appendicitis, not appendectomy. 


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The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. The medical history section of the case report form will serve as the source document for 
baseline events.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. Adverse events occurring after signing consent are to be recorded in the eCRF using the AE 
form. 
3. Serious adverse events will be reported to the local IRB according to institutional policy. 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) will be used for 
adverse event reporting.   
10.1 Follow Up of Grade 3 or 4 Toxicities 
Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, as feasible, until the 
toxicity returns to Grade ≤ 2 severity. 
10.2 Infection Follow Up 
Any new infection that occurs on study regardless of infecting agent (i.e., viral or non-viral) should 
be captured. Additionally, the site of infection and source of culture (BAL, tracheal aspirate, 
sputum, blood, urine, etc.) should also be recorded. 
10.3 Classification of Causality 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the Investigator. 
10.4 Classification of Severity 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the criteria. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.5 Serious Adverse Event (SAE) Reporting 
The regulatory definition of an SAE is any untoward medical occurrence or effect that at any dose 
fulfills one or more of these criteria: 
• results in death; 
• is life threatening (at the time of the event); 
• requires in-patient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect; 
• or is an event considered medically serious by the Investigator. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. IB for an unauthorized investigational 
product or summary of product characteristics for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events which 
did not directly result in the SAE should be detailed in the description section on the SAE form 
and listed separately as AEs if necessary. For fatal SAEs, report the cause of death as an SAE with 
a fatal outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  


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• Routine treatment or monitoring of COVID-19 infection, not associated with any 
deterioration in condition;  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition; 
• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY EMAIL TO THE SAE REPORTING EMAIL USING THE FORM 
PROVIDED.  ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF 
WITHIN 48 HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address for reporting SAEs can be found below and at the 
front of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted 
to Covance Patient Safety until the event has subsided or, in case of permanent impairment, it 
stabilizes, and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL:  
SAEIntake@covance.com 
Medical Monitor: 
Norberto Soto, MD  
Telephone: 
(609) 212-7892 
Covance Physician/Medical Monitor 
Email: 
Norberto.Soto@Covance.com 
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
Telephone: 
M: (484) 686-0545 
VP, Clinical Operations 
Email: 
bpowers@clearcreekbio.com  
All SAEs will be reported to the IRB periodically, at the end of the study, or per local institutional 
guidelines.   
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Covance Physician and site Investigator. It is critical that all SAEs are 
reported within the 24-hour guideline so that the expectedness determination can be made. 
SUSARs require immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor will ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 


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IRB(s) within seven (7) calendar days of the date of first report to Covance Patient Safety / 
Sponsor. Follow-up information will be communicated to the relevant Regulatory Authority within 
an additional eight calendar days. 
All other SUSARs will be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first notification to Covance Patient 
Safety / Sponsor. 
The Sponsor or designee will also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
requested additional information on an expedited basis.   
10.7 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to Covance Patient Safety (by email 
to SAEIntake@covance.com) and to the IRB by the investigational staff within 1 working day of 
their knowledge of the event. The collection period for a pregnancy occurring in a subject or a 
subject’s partner will begin at the first dose of study drug and will continue through 90 days after 
the last dose of study drug. Monitoring of the subject or partner should continue until the 
conclusion of the pregnancy, if the subject or subject’s partner has consented to this. Monitoring 
of the baby should continue for 3 months after birth, if the subject or subject’s partner has 
consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation, if the subject has consented to this. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as (S)AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow 
the subject until the end of pregnancy, with the subject’s consent. This request and the subject’s 
response will be documented in the subject’s source document. 
10.8 Safety Monitoring for Hematologic Toxicities 
Myelosuppression is a known effect of DHODH inhibition that is associated with prolonged 
exposure and high doses. To reduce the risk of this effect with brequinar in COVID-19 subjects, 
the extensive brequinar safety database with over 1,000 patients has been evaluated to select a dose 


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level expected to be safe and well tolerated with regard to hematologic toxicity. In addition to 
enhancing safety by selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will be under the care of highly qualified medical personnel. Clinically 
significant out-of-range laboratory results will be reported as adverse events. 
In addition to real time assessments by the treating clinical team, the Covance Medical Monitor 
will assess the available hematology data on a periodic basis to identify any pathologic trends or 
safety issues. Any apparent increase in the expected rate or severity of hematologic safety events 
will be discussed with the Principal Investigators and the Sponsor. In addition, the Data Monitoring 
Committee (DMC) will assess available hematology data on a periodic basis to independently 
assess any pathologic trends or safety issues. If the rate or severity of hematologic toxicities 
appears to be above the expected rate or the severity appears worse than that expected, the trial 
enrollment will be suspended and no further subjects will be treated while a comprehensive data 
review is conducted. Depending on the outcome of the safety review the study may be stopped, 
the design adjusted, or the study may continue as designed. Individual and Study stopping rules 
are provided in Section 8.4. 
Safety laboratory results are to be initially assessed in real time by the Principal Investigator or 
designated person. Any study drug-related clinically significant out-of-range laboratories or study 
drug-related adverse events will be followed as needed until resolution or stable. 
The in-clinic assessments and telemedicine/phone call visits will specifically ask about possible 
hematologic toxicity including any evidence of the list below. Subjects will be provided with a list 
of the following events in lay terms and will be instructed to call the research team if any of these 
events occur. 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Any of these symptoms considered clinically significant will be recorded as an adverse event and 
must be followed until resolved or stable. 
10.9 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to provide independent oversight to this 
trial. The primary responsibility of the DMC will be to review the progress and conduct of the trial 
in order to maintain scientific rigor and to ensure the wellbeing of subjects participating in the 
trial. The specific responsibilities of the DMC will be detailed in a separate DMC charter. The 
DMC will include at a minimum at least one statistician and two clinicians who will perform 


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periodic data review to assess whether there are clinically significant differences between 
treatment arms that could affect participant safety.  Following such a review, the DMC Chair will 
advise the Sponsor that the study be stopped, the design changed, or that the study may continue 
per protocol. 
10.9.1 DMC Safety Review Schedule 
The DMC is to review adverse events and safety laboratory assessments after the first 20 subjects 
complete the Day 8 visit, and again after the first 40 subjects complete the Day 8 visit. 
 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses will be descriptive in nature and presented by group.   
Summaries for quantitative variables will include the mean, median, quartiles, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and 95% confidence interval (CI), when appropriate. Any 
statistical testing will be considered exploratory and descriptive. All computations will be 
performed using SAS® (Version 9.4 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 Study Populations for Analysis 
All safety analyses will be based on the ITT population, which is defined as all randomized 
subjects. As will be described in the SAP, efficacy analyses of changes in viral load will be based 
on the population of subjects with detectable viral load at baseline or similar qualification. Sample 
size may be adjusted if an inadequate number of subjects have detectable viral load at baseline. 
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, WHO Assessments, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data listings. The 
incidence of post-randomization adverse events will be tabulated by MedDRA preferred term and 
system organ class, and by severity and relationship to study treatment. All laboratory results and 
study assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will primarily be assessed via viral load changes. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this proof-of-concept study. The sample 
size of approximately 100 subjects planned to be entered in this trial is expected to be adequate to 
provide safety and efficacy information to advise future study design. 
11.5 Randomization 
A randomization scheme will be provided by an independent statistician to the drug packaging 
company to ensure subjects are randomly assigned to SOC + brequinar or SOC + placebo in a 1:1 
ratio.  


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11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 


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12 INVESTIGATOR RESPONSIBILITIES 
12.1 Investigator’s Performance 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement found in Section 15.2 to 
indicate commitment to comply with the contents. 
12.2 Confidentiality 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality 
will be maintained during all audits and inspections of the trial site and documentation. A unique 
number will be assigned to each subject at the start of the trial and this, with the subject’s initials, 
will be used to identify the subject. In some cases, a further step may be taken to assign “fake 
initials” to the subject, per individual site requirements. The subject’s number will be the site 
number followed by the number of this subject at this site and will be used as the unique identifier 
in the source records and on the eCRF, on all trial correspondence and in the trial database. The 
Investigator will keep a list of identification codes or initials used for each subject along with the 
unique number assigned. 
All information provided to the Investigator relevant to the investigational product (IP), as well as 
information obtained during the course of the trial will be regarded as confidential. The 
Investigator and members of his/her research team agree not to disclose or publish such 
information in any way to any third-party without prior written permission from the Sponsor which 
will not be unreasonably withheld, except as required by law, or as permitted by the Publications 
section of this protocol, Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 Source Documentation 
Investigators are to maintain adequate source documentation of the original study data, for 
example medication records, laboratory reports and pharmacy records as appropriate. The 
Investigator will allow inspections of the trial site and documentation by clinical research and audit 
personnel from the Sponsor, external auditors or representatives of regulatory authorities. The 
purpose of these inspections is to verify and corroborate the data collected on the eCRFs. In order 
to do this, direct access to the subjects' medical or clinic records is necessary. The Investigator will 
ensure that certain information is contained in the medical or clinic written or electronic records 
of the subject and that the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical 
and medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IP being 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
evaluated, the trial number assigned to that subject and a statement that consent was obtained; 
• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study. A signed copy should also be filed in the 
investigator file. 
12.4 Data Collection 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. 
In addition, suitably qualified and trained clinical research personnel of the Sponsor will visit the 
trial site at regular intervals during the trial for monitoring purposes and to assist the research staff 
with any queries. All queries and discrepancies relating to the data collection are to be resolved at 
the completion of the trial. Remote data capture is encouraged whenever possible. 
12.5 Case Report Forms, Investigator’s Site File and Record Retention 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will 
be reviewed against source documentation at each monitoring visit. All CRFs and supporting 
source documentation must be completed and available to the Sponsor in a timely manner. 
Changes or corrections due to data clarification and resolutions will be tracked by paper or 
electronically with an audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed 
for completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the 
IB, the protocol plus any amendments, all correspondence with the IRB including the approval for 
the trial to proceed, Regulatory Authority approval/ notification (if applicable) including a sample 
of an approved informed consent, IP accountability, Source Documents, investigator and staff 
curricula vitae (CVs,) trial documentation, and all trial correspondence. The original signed 
informed consent forms and the final report will be kept in the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a responsibility 
to retain essential documents for as long as is required by the Sponsor and applicable regulatory 
authorities. It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. Investigators will be asked to contact the Sponsor prior 
to the destruction of any data or removal to another site if this occurs prior to the Sponsor 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
notification that the documentation is no longer required. Any transfer of ownership of the data or 
of documents will be documented in writing. The new owner will assume responsibility for data 
retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
13 SPONSOR RESPONSIBILITIES 
13.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on GCP (CPMP/ICH/135/95, Jan.97) 
and US FDA Regulations. It is the Sponsor's responsibility to obtain appropriate regulatory 
approval to perform the trial (if applicable). The Sponsor should notify promptly all concerned 
investigator(s), IRB(s) and the Regulatory Authority of findings that could adversely affect the 
health of the patients/ subjects, impact on the conduct of the trial or alter the Regulatory 
Authority’s authorization to continue the trial. If it is necessary to change or deviate from the 
protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the relevant 
regulatory authority and relevant IRB of the new events, the measures taken and the plan for further 
action as soon as possible.  This will be by telephone in the first instance followed by a written 
report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all SUSARs to the relevant regulatory authority and IRBs.   
13.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site or 
will access the electronic health record (EHR) or conduct remote monitoring visits at regular 
intervals during the trial for monitoring purposes and to assist the research staff with any queries. 
CRFs and source documentation will be available for review during monitoring visits to the trial 
site. The function of this monitoring is to ensure compliance with the protocol, adherence to 
regulatory and GCP obligations, proper maintenance of records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. 
On-site visits are not required for any monitoring visits for this study.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed, and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 
13.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.   


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13.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
14 REFERENCES  
1. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 171-
186. 
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 
Published online March 9, 2020. https://doi.org/10.1016/S0140-6736(20)30566-3 
3. Phelan A, Katz R, and Gostin L. The novel coronavirus originating in Wuhan, China. 
Challenges for global health governance. Jama. 2020;323(8):709-710.   
4. Handel A, Mille J, Yang G, Fung I. If containment is not possible, how do we minimize 
mortality for COVID-19 and other emerging disease outbreaks. March 13, 2020. 
https://doi.org/10.1101/2020.03.13.20034892. 
5. Brequinar Investigator’s Brochure 
6. Chen S, Ding S, Yin Y, Xu L, Li P, Peppelenbosch MP, et al. Suppression of pyrimidine 
biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. 
Antiviral Res. 2019 Jul;167:35–44.  
7. Mei-Jiao G, Shi-Fang L, Yan-Yan C, Jun-Jun S, Yue-Feng S, Ting-Ting R, et al. 
Antiviral effects of selected IMPDH and DHODH inhibitors against foot and mouth 
disease virus. Biomed Pharmacother. 2019 Oct;118:109305.  
8. Wang QY, Bushell S, Qing M, Xu HY, Bonavia A, Nunes S, et al. Inhibition of Dengue 
Virus through Suppression of Host Pyrimidine Biosynthesis. 2011 Jun 9;85(13):6548–56.  
9. Luthra P, Naidoo J, Pietzsch CA, De S, Khadka S, Anantpadma M, et al. Inhibiting 
pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside 
pools and activation of innate immune responses. Antiviral Res. 2018 Oct;158:288–302.  
10. Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, et al. Novel Antiviral 
Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine. 
Viruses. 2019 Oct 18;11(10).  
11. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang, Y, et al. Novel and potent inhibitors 
targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-
spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-
CoV-2. 
12. Sah R, Rodriguez-Morales AJ, Jha R, Chu DKW, Gu H, Peiris M, et al. Complete Genome 
Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Isolated in Nepal. Microbiol 
Resour Announc. 2020 Mar 12;9(11). 
13. Liu Q, Gupta A, Okesli-Armlovich A, Qiao W, Fischer C, Smith M, et al. Enhancing the 
Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with 
Modulators of Pyrimidine Metabolism. bioRxiv. 2020 Jan 1;2020.03.24.992230. 
14. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
15. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
16. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
18. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
20. FDA Guidance “COVID-19: Developing Drugs and Biological Products for the Treatment 
or Prevention (https://www.fda.gov/media/137926/download) 
 


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15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2, 3 
(± 8 
hr) 
D4 
(± 8 
hrs) 
D5 
(± 8 
hrs) 
D8 
(± 1 
day) 
D12 
(± 1 
day) 
D15 
(± 1 
day) 
D22 
(±1 
day) 
Final Visit  
D29 
(± 2 days) 
Informed Consent (note Date and 
Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications 
(dose, route, duration or 
ongoing) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Medical history (relevant within 
one year or ongoing)/ History of 
current illness (date of symptom 
onset or change in baseline co-
morbidity thought to be due to 
COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported 
height and weight, date of birth, 
gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check 
for 
Physical 
Exam 
abnormalities 
(subject 
self-
reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Randomize subject and dispense 
Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, pO2. 
cSymptom Assessment will be using a checklist provided to the subject with symptoms such as sore throat, cough, GI 
symptoms (vomiting, diarrhea), anosmia, dysgeusia, other (specify), etc. 
dSample Day 1 must be obtained prior to dosing. Viral load specimens will be saliva samples self-collected by the 
subject using an Oragene® collection system or similar. These samples are to be sent to CCLS for analysis. The 
viral load sample may also be used to perform viral cultures (sample can be split, no additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. 
Note that any visits/visit activities may be conducted via telephone, telemedicine, or digital media other than serum 
pregnancy test and chemistry/hematology sample collection. These labs may be collected at the clinical site or another 
designated out-patient facility/laboratory or collected via home visit. Arrangements for shipping viral load samples 
will be made by the study team. 
 


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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-02 
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.  
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all 
of its provisions.  It is further agreed that the details of this trial and all information provided to 
me by Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be 
revealed for any reason without written authorization from Clear Creek Bio, Inc. except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms, and all materials provided for the conduct of the trial 
are the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that 
Clear Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as 
for submission to government regulatory agencies, required internal reports, and presentations 
without violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in 
accordance with current Good Clinical Practice Guidelines, to all data generated by this trial and 
the source documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: ____________________________________ 
 
Signature: ____________________________________________ Date: __________________ 
 
 
 


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PROTOCOL VERSION 1.0 DATE: 20 August 2020 
 
15.3 Appendix C: WHO Ordinal Scale 
 
WHO clinical progression scale 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
STUDY PROTOCOL 
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 No: CCB-CRISIS-02 
Version: 2.0 
 
Version Date:  15 September 2020 
 
 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
 
IND Number: 149291 
 
 
 
 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein may 
be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in accordance with 
the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration of Helsinki (1964, 
1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations and locally applicable 
regulations. 
 


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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.1.1 Coronavirus Biology .................................................................................................... 16 
3.2 Host Nucleotide Synthesis ......................................................................................... 16 
3.3 Dihydroorotate dehydrogenase (DHODH) ................................................................ 16 
3.4 Brequinar .................................................................................................................... 17 
3.5 Rationale for the Planned Trial .................................................................................. 17 
3.5.1 Brequinar Dose Selection ............................................................................................. 18 
3.5.2 Risk/Benefit of Brequinar ............................................................................................ 18 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 19 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 19 
3.7.1 CYP Interactions .......................................................................................................... 19 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 19 
4 TRIAL OBJECTIVES ........................................................................................................ 20 
4.1 Primary Objective ...................................................................................................... 20 
4.2 Secondary Objectives ................................................................................................. 20 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 20 
5 TRIAL DESIGN ................................................................................................................. 21 
6 TRIAL ENDPOINTS.......................................................................................................... 22 
6.1 Primary Endpoint ....................................................................................................... 22 
6.2 Secondary Endpoints .................................................................................................. 22 
6.3 Exploratory Endpoints................................................................................................ 22 
7 TRIAL POPULATION ....................................................................................................... 23 
7.1 Number of Subjects .................................................................................................... 23 
7.2 Inclusion criteria ......................................................................................................... 23 
7.3 Exclusion Criteria ....................................................................................................... 23 
8 STUDY TREATMENTS .................................................................................................... 25 


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Clear Creek Bio, Inc. 
CONFIDENTIAL 
8.1 Description of Study Medications .............................................................................. 25 
8.1.1 Brequinar ...................................................................................................................... 25 
8.2 Treatment Administration .......................................................................................... 25 
8.2.1 Safety/Tolerability ........................................................................................................ 25 
8.3 Study Discontinuation ................................................................................................ 26 
8.4 Stopping Criteria ........................................................................................................ 26 
8.4.1 Individual Stopping Criteria ......................................................................................... 26 
8.4.2 Study-Level Stopping Criteria...................................................................................... 26 
8.5 Concomitant Medication/Treatment .......................................................................... 26 
8.6 Treatment Compliance ............................................................................................... 26 
8.7 Storage, Stability, Labeling and Packaging ............................................................... 27 
8.7.1 Storage and Stability .................................................................................................... 27 
8.7.2 Labeling and Packaging ............................................................................................... 27 
8.7.3 Blinding and Randomization ........................................................................................ 27 
8.7.4 Unblinding/Expectedness ............................................................................................. 27 
8.7.5 Study Drug Accountability ........................................................................................... 27 
8.8 Prohibited Medications .............................................................................................. 28 
8.9 Study Adjustments Due to COVID-19....................................................................... 28 
9 CONDUCT OF THE TRIAL.............................................................................................. 29 
9.1 Ethical and Regulatory Considerations ...................................................................... 29 
9.2 Informed Consent ....................................................................................................... 29 
9.3 Institutional Review Board......................................................................................... 30 
9.4 Schedule of Events ..................................................................................................... 30 
9.5 Study Conduct ............................................................................................................ 31 
9.5.1 Unscheduled Visits ....................................................................................................... 31 
9.6 Compliance with Study Procedures ........................................................................... 32 
9.7 Early Withdrawal from the Study .............................................................................. 32 
9.8 Early Termination of the Study .................................................................................. 32 
9.9 Non-Childbearing Potential........................................................................................ 33 
10 ADVERSE EVENT REPORTING..................................................................................... 34 


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Clear Creek Bio, Inc. 
CONFIDENTIAL 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 35 
10.2 Infection Follow Up ................................................................................................... 35 
10.3 Classification of Causality ......................................................................................... 35 
10.4 Classification of Severity ........................................................................................... 36 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 36 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 37 
10.7 Pregnancies................................................................................................................. 38 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 38 
10.9 Data Monitoring Committee ...................................................................................... 39 
10.9.1 
DMC Safety Review Schedule ............................................................................... 40 
11 STATISTICAL CONSIDERATIONS................................................................................ 41 
11.1 Study Populations for Analysis .................................................................................. 41 
11.2 Safety Analyses .......................................................................................................... 41 
11.3 Efficacy Analyses ....................................................................................................... 41 
11.4 Sample Size Considerations ....................................................................................... 41 
11.5 Randomization ........................................................................................................... 41 
11.6 Pooling of Study Centers............................................................................................ 42 
11.7 Interim Analysis ......................................................................................................... 42 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 43 
12.1 Investigator’s Performance ........................................................................................ 43 
12.2 Confidentiality ............................................................................................................ 43 
12.3 Source Documentation ............................................................................................... 43 
12.4 Data Collection ........................................................................................................... 44 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 44 
12.6 Non-Protocol Research .............................................................................................. 45 
12.7 Publication .................................................................................................................. 45 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 46 
13.1 General ....................................................................................................................... 46 
13.2 Indemnity ................................................................................................................... 46 
13.3 Data Monitoring ......................................................................................................... 46 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
13.4 Audit ........................................................................................................................... 46 
13.5 Confidentiality ............................................................................................................ 47 
13.6 Finance ....................................................................................................................... 47 
14 REFERENCES ................................................................................................................... 48 
15 APPENDICES .................................................................................................................... 49 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events .................................................. 49 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 50 
15.3 Appendix C: WHO Ordinal Scale .............................................................................. 51 
 
 
 
 


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Clear Creek Bio, Inc. 
CONFIDENTIAL 
LIST OF FIGURES  
Figure 3-1. DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine synthesis; it 
is completely essential for the generation of UMP. ................................................... 16 


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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AML 
Acute myeloid leukemia 
ARDS 
Acute respiratory disease syndrome 
AST 
Aspartate amino transferase 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus-19 infection 
CRP 
c-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Curricula vitae 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DHODHi 
Dihydroorotate dehydrogenase inhibitor 
DMC 
Data Safety Monitoring Board 
ECMO 
Extra corporeal membrane oxygenation 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
EUA 
Emergency Use Authorization 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IMP 
Inosine-5’ phosphate 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEWS2 
National Early Warning System (NEWS) 2 Score 
RNA 
Ribonucleic Acid 
RdRp 
RNA-dependent RNA polymerase 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
SARS Coronavirus 2 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
SpO2 
Peripheral capillary oxygen saturation 


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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
Abbreviation 
Definition 
UMP 
Uridine 5’-monophosphatase 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
2 
SYNOPSIS  
CCB-CRISIS-02 SYNOPSIS  
IND 
149291 
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  
Protocol Number 
CCB-CRISIS-02 
Rationale 
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.  
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) + 5 days 
of brequinar 100 mg or SOC + 5 days of placebo.  
Investigational product will be supplied as either brequinar 100 mg oral capsules 
or placebo capsules. The subjects are to self-administer one capsule on Study Days 
1 – 5.  
Treatment assignment will be randomized, double-blind. 
Primary 
Objectives 
● To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load 
for brequinar-treated subjects compared to placebo-treated subjects through 
Day 29. 
Secondary 
Objectives 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-
19 subjects as measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  


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CONFIDENTIAL 
● To reduce the percentage of subjects requiring hospital admission as an in-
patient for > 24 hours for brequinar subjects compared to subjects who received 
placebo; 
● To reduce all-cause mortality through Day 29 for brequinar subjects compared 
to subjects who received placebo. 
Exploratory 
Objectives 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in 
the WHO Ordinal Scale score measured for the subset of subjects with baseline 
WHO Ordinal Scale of 2 for brequinar subjects compared to subjects who 
received placebo.  
Design 
This will be a phase 2 randomized, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive SOC per relevant guidelines 
for treatment of out-patients with COVID-19 infection. In addition to SOC, 
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 procedures are presented in detail in the Schedule of Events. Study visits 
(virtual or in person) will take place at Screening and on Study Days 1, 8, 15, 22, 
and 29. 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 on Days 1, 4, 8, 12, 15, 22, and 29. A home health 
nurse will visit the subject at Screening and on study Days 1, 8, 15, 22, and 29. 
Telemedicine visits will be conducted by site staff on study Days 4 and 12. 
Sample Size: 
Approximately 100 subjects will be randomized to 5 days of either SOC + 
brequinar 100 mg or SOC + placebo in a 1:1 ratio (approximately 50 subjects 
assigned to brequinar 100 mg and 50 subjects to placebo).  
Number of Sites: 
Approximately 15 
Study Period: 
An enrollment period of 3 months is expected. 
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.  


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CONFIDENTIAL 
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 within 14 days of first dose. 
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.  
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 and/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 


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CONFIDENTIAL 
10. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks 
of first dose. 
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).  
Treatment 
All subjects will receive standard of care (SOC) including symptomatic care. 
Subjects will be randomly assigned to SOC + brequinar 100 mg daily x 5 or SOC 
+ placebo daily x 5. Study encounters will be conducted remotely whenever 
possible. 
DMC 
A Data Monitoring Committee (DMC) will meet periodically to review the safety 
and scientific conduct of the study. At a minimum, the DMC is to review adverse 
events and safety laboratory assessments after the first 20 subjects complete Day 
8, and again after the first 40 subjects complete Day 8.  
Procedures 
Study procedures are outlined in the Schedule of Events. 
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of first dose through Day 29. After 
Day 29, collect/record only Serious Adverse Events (SAEs) or those judged by the 
Investigator or designated person to be related to study drug. Treatment-emergent 
adverse events will be those with an onset after the date and time of first treatment. 
Subjects who develop Grade 3 or 4 toxicities or SAEs are to be re-evaluated every 
2 days, as feasible, until the toxicity returns to Grade ≤ 2 severity. 
Stopping Criteria 
Individual Criteria:  
• Participants who develop a Grade 3 toxicity that is assessed by the 
investigator to be related to the study drug are to be permanently 
discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to 
study drug, are to be permanently discontinued from study treatment. 
Study-Level Stopping Criteria: 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse 
event or laboratory abnormality; 


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• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or 
laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or 
laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per 
protocol. 
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking 
the database. All analyses of safety and efficacy for this study will be descriptive 
in nature and presented by group. Subject demographics and baseline 
characteristics will be summarized. Subject data listings will also be provided.  
Summaries for quantitative variables will include the mean, median, quartiles, 
standard error, minimum, and maximum. For qualitative variables, the summaries 
will include the number and percentage of subjects for each outcome, and the 95% 
CI, when appropriate.  Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.4 or 
higher). Safety and tolerability will be assessed in terms of AEs, SAEs, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures 
will be summarized using appropriate descriptive statistics. 
 
 
 


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CONFIDENTIAL 
CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
 
Procedures 
Screen 
(days 
-14 to -1) 
D1 
D2, 3 
(± 8 
hrs) 
D4 
(± 8 
hrs) 
D5 
(± 8 
hrs) 
D8 
(± 1 
day) 
D12 
(± 1 
day) 
D15 
(± 1 
day) 
D22 
(±1 
day) 
Final 
Visit  
D29 
(± 2 days) 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, SpO2. Subject will be provided with a thermometer and 
pulse oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health 
nurse. Vital signs parameters will be observed and recorded by study staff via telemedicine or during a visit by the home 
health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms 
(vomiting, diarrhea), anosmia, dysgeusia, other (specify), etc. Severity Mild, Moderate, or Severe will be collected. 
dRT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-
2 result. Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be 
obtained prior to dosing. Viral load specimens after Screening will be saliva samples self-collected by the subject using 
an Oragene® collection system or similar. The home health nurse will train the subject and observe sample collection 
on Day 1. These samples are to be sent to CCLS for analysis. The viral load sample may also be used to perform viral 
cultures (sample can be split by the central laboratory, no additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any 
visits/visit activities may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and 
chemistry/hematology sample collection. These labs may be collected at the clinical site or another designated out-patient 
facility/laboratory or collected via home visit. Arrangements for shipping viral load samples will be made by the study 
team. 


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CONFIDENTIAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
MEDICAL MONITOR 
Name:  
Norberto Soto, MD 
Title: 
Senior Medical Director 
Telephone No.: 
(609) 212-7892 
E-mail: 
Norberto.Soto@Covance.com 
 


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CONFIDENTIAL 
3 
INTRODUCTION 
3.1 
Coronavirus-19 (COVID-19) 
Beginning in December 2019, Chinese scientists isolated a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) from patients with virus-infected pneumonia which was later 
designated as coronavirus disease 2019 (COVID-19) by the World Health Organisation (WHO) (Zhou 
et al., 2020 [2]; Phelan et al., 2020 [3]).  
Approximately 14% of those affected with this virus will develop severe disease requiring 
hospitalization and oxygen support; 5% will require admission to the intensive care unit (Handel et 
al., 2020 [4]). Severe cases may be complicated by acute respiratory disease syndrome (ARDS), sepsis 
and septic shock, and multi-organ failure, including acute kidney injury and cardiac injury. Risk 
factors for death include older age and co-morbid disease such as hypertension and diabetes (Zhou, et 
al., 2020 [2]). This means that most patients will be treated as out-patients. Reducing viral load in this 
environment is critically important for both the subjects themselves by preventing worsening of 
symptoms and possibly avoiding hospitalization, but also to reduce the transmission of the disease to 
others in the patients’ households and their communities. 
3.1.1 Coronavirus Biology 
Coronaviruses, like other RNA-based viruses, do not have the machinery to synthesize their own 
nucleotides and thus depend upon the host intracellular pool of nucleotides for viral replication. In 
essence, viruses steal the host RNA building blocks, and without these building blocks they are unable 
to replicate. The SARS-CoV-2 is a single-stranded (positive sense) RNA virus with a genome that is 
29,811 nucleotides long, quite a lot larger than other RNA-based viruses (e.g. the hepatitis C genome 
comprises only 9600 nucleotides). The nucleotide composition is broken down as: 29.9% adenosines, 
18.4% cytosines, 19.6% guanines, and 32.1% uridines (Sah et al., 
2020 [12]). 
3.2 
 Host Nucleotide Synthesis 
Host de novo pyrimidine synthesis generates uridine monophosphate 
(UMP) as the building block for all pyrimidine ribonucleotides and 
deoxyribonucleotides (Figure 3-1). There exists no salvage pathway 
for the synthesis of UMP, the fundamental building block of 
pyrimidines. Inhibition of enzymatic steps upstream of UMP (Figure 
3-1) leads to a rapid and profound depletion of intracellular 
pyrimidines.  
3.3 
 Dihydroorotate dehydrogenase (DHODH) 
The enzyme dihydroorotate dehydrogenase (DHODH) catalyzes the 
4th step of de novo pyrimidine synthesis and inhibition of DHODH 
completely halts all pyrimidine production. As shown in Figure 3-1, 
DHODH is located on the inner mitochondrial membrane and 
transfers electrons between DHO and complex III of the electron-
 
Figure 
3-1. 
DHODH 
is 
a 
mitochondrial 
enzyme 
that 
catalyzes the 4th step of pyrimidine 
synthesis; it is completely essential 
for the generation of UMP.   


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transport chain via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a clear therapeutic target for the inhibition of host pyrimidine synthesis. The chemical 
inhibition of DHODH in vitro or in vivo leads to the rapid depletion of UMP and subsequent depletion 
of downstream products thymine and cytosine. This forces a cell to rely on the salvage of extracellular 
pyrimidine nucleotides and this extracellular salvage is not capable of maintaining the cell’s normal 
nucleotide pool (Sykes et al., 2016) [1]).  
  
3.4 
 Brequinar 
Brequinar is an orally available and potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity against 
experimental tumors and because its water solubility made it relatively straightforward to formulate. 
In an indication such as treating SARS-CoV-2 infection, brequinar will act as a host-targeting antiviral. 
It is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH), the enzyme 
that catalyzes the fourth step in pyrimidine synthesis, namely the conversion of dihydroorotate (DHO) 
to orotate. DHODH inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby 
leading to a depletion of a cell’s pool of uridine, cytidine and thymidine ribonucleotides and 
deoxyribonucleotides.  
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in human 
intestinal Caco-2 cells as well as in human primary intestinal organoids (Chen et al., 2019 [6]). 
Treatment with teriflunomide, another DHODHi, has been effective in vitro and in vivo in a murine 
model of foot and mouth disease virus (Mei-Jian et al., 2019 [7]). DHODH inhibition (DHODHi) also 
inhibited the growth of dengue virus in vitro (Wang et al., 2011 [8]). DHODHi also showed antiviral 
effects against RNA viruses including influenza A, Zika, Ebola and coronavirus SARS-CoV-2 (Xiong 
et al., 2020 [11]). Brequinar has also been shown to inhibit the replication of Ebola virus, vesicular 
stomatitis virus and Zika virus in vitro (Luthra et al., 2018 [9]). Brequinar inhibits the replication of 
human immunodeficiency virus (HIV) in vitro (Andersen et al., 2019 [10]). When considering 
brequinar as an antiviral for treatment of SARS-CoV-2, oral brequinar is highly bioavailable (>95%) 
and has good penetration of lung tissue with an average tissue:blood ratio of 0.5 following a single 
dose of brequinar in the rat. It is therefore expected to achieve a similar period of DHODH inhibition 
in lung tissue (Brequinar IB [5]). 
3.5 
 Rationale for the Planned Trial 
DHODH inhibition has been extensively studied as a potential therapeutic target in the treatment of 
RNA-based viruses. The inhibition of DHODH is effective in inhibiting viral replication in pre-clinical 
models involving many RNA-based viruses with nanomolar potency and a high selectivity index (see 
the Brequinar IB [5], Section 5). In these pre-clinical models, the benefit of DHODH inhibition can 
be reversed by the supplementation of exogenous nucleotides, confirming that the on-target effect of 
host pyrimidine depletion is key to the anti-viral activity.  


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The CCB-CRISIS-02 trial will study standard of care (SOC) with 5 days of brequinar (DHODH 
inhibition) compared to SOC with 5 days of placebo treatment. Clear Creek Bio hypothesizes that a 
defined 5-day course of brequinar will inhibit the enzyme DHODH to a degree sufficient to result in 
the transient depletion of host pyrimidine nucleotides, thereby inhibiting viral replication. A recent 
publication demonstrated that inhibitors of DHODH could potentiate the activity of inhibitors of RNA-
dependent RNA polymerase (RdRp) in the treatment of dengue virus, another single-stranded RNA 
virus similar to SARS-CoV-2 (Liu et al., 2020 [13]). This inhibition of viral replication may restore 
the balance in favor of the host immune system for the clearance of SARS-CoV-2. 
Marketed DHODHi medications are available, including leflunomide or teriflunomide, however these 
are very weak inhibitors of DHODH with cellular potency ~500 times lower than brequinar. These 
low potency inhibitors of DHODH are not expected to have the ability to acutely lower the pool of 
intracellular pyrimidines to the degree that is required for decreasing the viral load associated with 
SARS-CoV-2 infection, making brequinar the better choice for acute SARS-CoV-2 infection.  
The CRISIS2 study is a proof-of-concept study in patients with SARS-Cov-2 infection and will serve 
as a basis for future studies to determine the safety and effectiveness of brequinar in COVID-19. 
3.5.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with 5 days of consecutive daily 
dosing suggest that 5 days of daily doses of 100 mg p.o. will be safe and well tolerated. A dose of 
brequinar 100 mg achieves plasma concentrations of approximately 1 uM (0.4 ug/ml) that should result 
in sufficient suppression of nucleotide synthesis. When given over 5 days, these plasma concentrations 
are achieved on a daily basis without accumulation, also assuring the safety of this regimen (see 
Brequinar IB [5]).  
3.5.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive safety and pharmacokinetic database exists with 
more than 1,000 patients treated with brequinar. Cancer patients (N = 806) have been exposed to this 
compound for treatment of a variety of solid tumors at various treatment regimens, doses, and routes 
including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 
weeks, and daily times 21 days for multiple courses. Lower doses than used in the cancer studies have 
also been utilized for patients with psoriasis and organ transplant. The maximum intravenous dose 
given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. 
There has been limited testing of DHODHi to date in the clinic for infection with SARS-CoV-2. 
DHODHi therapy at relatively high doses in the context of trials for patients with cancer has the 
expected safety side-effects of mucositis and bone marrow suppression. Importantly, however, the 
prior clinical experience in 39 subjects who received daily brequinar for 5 consecutive days at or lower 
than 100 mg/day show no cases of mucositis and only 1 (2.6%) episode of mild thrombocytopenia. 
Based on these data the 100 mg per day dose proposed for administration in this study should be within 
a safe and tolerable range as well as demonstrating the predicted antiviral effect.  
The potential benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 5-day 
period of brequinar dosing will suppress host de novo pyrimidine synthesis for this period thus 
decreasing viral load. Inhibition of DHODH is expected to reduce the ability of the virus to replicate 


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CONFIDENTIAL 
and it is for this reason that brequinar will be administered to patients with COVID-19 in this study.
 
 
3.6 
 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of high-dose brequinar in patients with 
refractory solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis 
have been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of brequinar administration. 
However, these effects were self-limiting, transient, required treatment in few cases, and resolved 
following discontinuation of dosing. These adverse effects have been associated with higher doses of 
brequinar given via the intravenous route and for longer durations than the 100 mg dose and 5-day 
regimen proposed for this study.  
In addition to studying a higher risk population with symptomatic COVID-19, a comprehensive safety 
monitoring plan will be utilized in this study to assess the ongoing safety and well-being of participants 
(see Section 10.8).  
3.7 
 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in severely ill cancer patients including antibiotics, antifungals and other critical care 
medications. No formal interaction studies have been conducted for these medications, however, there 
have not been any reports of interactions with any medications during the clinical trials with more than 
800 cancer patients.  
3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with medications 
commonly used in treating hematologic malignancies. The nonclinical studies performed to date have 
demonstrated there is no first-pass metabolism and there have been no apparent hepatotoxic effects in 
the clinical studies. Brequinar itself does not appear to be a substrate for metabolism by cytochrome 
P450 enzymes when tested under a variety of conditions. (See Brequinar IB [5]; nonclinical data on 
file with Clear Creek).  
3.8 
Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated by highly experienced clinicians familiar with the treatment of viral 
infections and their complications.  
 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load for brequinar-treated 
subjects compared to placebo-treated subjects through Day 29. 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-19 subjects as 
measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with brequinar compared 
to subjects who received placebo;  
● To reduce the percentage of subjects requiring hospital admission as an inpatient for >24 hours for 
brequinar subjects compared to subjects who received placebo; 
• To reduce all-cause mortality through Day 29 for brequinar subjects compared to subjects who 
received placebo. 
4.3 
EXPLORATORY OBJECTIVES 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical symptoms and pre-
existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in the WHO Ordinal 
Scale score for the subset of subjects with baseline WHO Ordinal Scale of 2 for brequinar subjects 
compared to subjects who received placebo. 


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CONFIDENTIAL 
5 
TRIAL DESIGN 
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 per (SOC) 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 procedures 
are presented in detail in the Schedule of Events (Appendix 15.1). Study visits (virtual or in person) 
will take place at Screening and on Study Days 1, 8, 15, 22, and 29. 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 Days 1, 4, 8, 12, 15, 22, and 29.   


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CONFIDENTIAL 
6 
TRIAL ENDPOINTS 
6.1 
Primary Endpoint 
Quantitative SARS-CoV-2 viral load through Day 29. 
6.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
Through Day 29: 
● Rates of AEs and SAEs including laboratory assessments; 
● Duration of viral shedding;  
• Percentage of subjects requiring admission as an inpatient for >24 hours. 
• All-cause mortality. 
6.3 
Exploratory Endpoints 
Through Day 29: 
● Time to viral clearance (two consecutive negative tests);  
● Time to resolution of new onset COVID-19-related clinical symptoms and pre-existing non-
COVID-19 symptoms returned to baseline; 
● Time to clinical improvement measured by a favorable shift in WHO Ordinal Scale score for the 
subset of subjects with baseline WHO Ordinal Scale of 2. 
 


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7 
TRIAL POPULATION 
7.1 
Number of Subjects 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 100 subjects have completed the study. Subjects will be randomized to either 
standard of care plus brequinar 100 mg or standard of care plus placebo in a 1:1 ratio (approximately 
50 subjects assigned to standard of care plus brequinar 100 mg and approximately 50 subjects assigned 
to standard of care plus placebo).  
7.2 
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 within 14 days 
of first dose. 
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. 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. 
8. Able to swallow capsules. 
7.3 
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 


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5. Hemoglobin < 10 gm/dL  
6. Absolute neutrophil count < 1500 cells/mm3 
7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
8. AST and/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 first dose. 
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). 
 


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8 
STUDY TREATMENTS 
8.1 
Description of Study Medications 
8.1.1 Brequinar 
Brequinar and placebo will be supplied as 100 mg capsules. Dosing will be a single 5-day course of 
brequinar 100 mg capsules or placebo 100 mg capsules once daily for 5 doses.  
8.2 
Treatment Administration 
This will be a phase 2 randomized, placebo-controlled, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive standard of care (SOC) for COVID-19 infection. 
Subjects will be randomly assigned in a 1:1 ratio to standard of care plus brequinar or standard of care 
plus placebo. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit. The NIH Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) 
will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
criteria.  
Adverse events (AEs) commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure (IB) and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 cancer subjects 
treated once-weekly (DuP 785-012, see Brequinar IB [5]), the deaths of three patients were attributed 
to study drug toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades 
(Grades 3 to 4) which typically led to discontinuation in this study included hematologic toxicities 
(anemia, thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, 
vomiting, stomatitis, others including gastric hemorrhage) and mucositis.  
In three oncology studies with five consecutive days of intravenous (IV) brequinar dosing in 168 
subjects (Study 785-001 [14], 785-003 [15], and 785-005 [16]) there were no toxic deaths. For 
subjects from these three studies who were treated with a daily dose of 100 mg or below  (as will be 
dosed in CCB-CRISIS-02), AEs through 21 days showed that 2 of 39 subjects (5.1%) had a severe 
(Grades 3 or 4) AE related to study drug (1 subject each with hyperbilirubinemia and 
hyperglycemia), and no subjects discontinued from the study due to a study drug-related AE. The 
few study drug related AEs through 21 days at or below the 100 mg dose from these three studies 
included 2 subjects each with nausea, vomiting, and creatinine elevated and one subject each with 
thrombocytopenia and diarrhea. When only studies with oral dosing were considered at this dose 
level (Studies 785-022 [17], 785-031 [18] , and 785-034 [19]), the study drug related AEs through 
21 days (each observed in one subject only) included diarrhea, headache, nausea, pruritus, 
abdominal pain, anorexia, chest pain, dry mouth, fatigue, keratosis, stomatitis, and vomiting. See 
brequinar IB [5]. 


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In most instances, brequinar-related toxicities were transient, clinically manageable, and reversible 
upon discontinuation of brequinar treatment. Any of these events reported with brequinar use can be 
serious in nature and may result in death.  
A 5-day course of oral brequinar administered once daily at a low level relative to those administered 
in the cancer studies is expected to be safe and well tolerated in the COVID-19 population. 
8.3 
Study Discontinuation 
Subjects will remain in the study through at least Study Day 29 (or longer if needed to follow up study 
drug-related adverse events). Participants may discontinue from the study by withdrawing consent at 
any time or for any reason as presented in Section 9.7. 
8.4 
Stopping Criteria 
8.4.1 Individual Stopping Criteria 
• Participants who develop a Grade 3 toxicity that is assessed by the investigator to be related to 
the study drug are to be permanently discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be 
permanently discontinued from study treatment. 
• Subjects who develop Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, 
as feasible, until the toxicity returns to ≤ Grade 2 severity. 
8.4.2 Study-Level Stopping Criteria 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse event or laboratory 
abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC, see Section 10.9), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per protocol. 
8.5 
Concomitant Medication/Treatment 
Record the name, dose, start/stop date, indication for use, route, and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications taken 
during the study are to be recorded. Prohibited medications are identified in Section 8.8.  
8.6 
Treatment Compliance 
Compliance will be assessed by reviewing the subject’s medication diary and study records as 
appropriate. 


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8.7 
Storage, Stability, Labeling and Packaging 
8.7.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.7.2 Labeling and Packaging  
The bulk drug and unit-dose containers will be labeled in accordance with national laws and 
regulations. 
8.7.3 Blinding and Randomization 
The trial will be conducted in double blinded, randomized manner with random assignment to standard 
of care plus brequinar or standard of care plus placebo. The brequinar and placebo capsules will be 
provided to each participating institution in pre-numbered bottles intended for individual subjects to 
be dispensed by the institution’s pharmacist or designated person. Randomization assignments will be 
provided by an independent statistician to the drug packaging company. The pharmacist/designated 
person will dispense the next number in sequence to the next patient who qualifies for the study at an 
individual site. 
8.7.4 Unblinding/Expectedness 
Contact the Covance Medical Monitor if it is necessary to break the blind for this blinded study due 
to an adverse event (AE). Each site will be provided with a sealed envelope containing individual 
sealed envelopes for subject numbers assigned to that site. Each individual subject number sealed 
envelope will have the treatment (brequinar or placebo) randomly assigned to that subject number. Do 
not open the outer envelope or the individual sealed envelope unless it has been agreed with the 
Medical Monitor and the Sponsor that unblinding is necessary for that particular AE. Unblinding must 
be documented in the study records. Envelope seals are to be checked to ensure they remain intact 
during drug accountability monitoring. 
If after a discussion with the Medical Monitor, the investigator or treating clinician believes the AE 
leading to unblinding to be related to the study drug, no further doses of drug should be administered 
to that subject.  
Expectedness will be determined by establishing whether an adverse event is among those identified 
in the protocol and the brequinar IB or are commonly associated with COVID-19 or similar severe 
viral illnesses and their complications.   
8.7.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, administered, and discarded.  It 
must be clear from the records whether the subject received study medication and what subject number 
was assigned to which subject. Adequate drug is to be dispensed for the number of subjects expected 
to be treated at each institution.  


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The pharmacist/staff member responsible for drug accountability is to document the date and time of 
dispensing and for what subject the study drug was intended (i.e., record subject initials and birth date 
or other unique identifier). A pharmacy manual will be provided by the Sponsor.  
At the end of the study any unused study drug will be returned to the Sponsor for destruction or may 
be destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours and 
with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. Records may be electronic or paper and may be accessed remotely for monitoring/drug 
accountability purposes. 
Each subject will be provided with one bottle with five brequinar or five placebo capsules for the five 
days of dosing. 
8.8 
Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide). 
Treatment is prohibited with agents known to cause bone marrow suppression leading to 
thrombocytopenia.  
8.9 
Study Adjustments Due to COVID-19 
Due to the highly contagious nature of COVID-19, multiple adjustments and revised procedures are 
rapidly evolving regarding clinical trial management and study conduct. Reasonable procedures 
implemented by study staff to avoid spreading this disease are acceptable to Clear Creek with written 
permission. Examples include but are not limited to e-consent, telephone consent and study visits 
conducted by telemedicine, telephone or other digital media.  
Background standard of care is to be maintained in both treatment arms. The standard of care is 
expected to change as additional information, such as that from randomized controlled trials, emerges, 
and the Sponsor and the treating clinicians will need to address anticipated off-label use of any other 
drugs, devices, or interventions that might be used to manage COVID-19 (e.g. anticoagulants).  
The Sponsor and treating clinicians are to consider changes in SOC over time, for example, 
overlapping toxicities of brequinar and a SOC treatment expected to be widely used is to be 
considered. The availability of new standard of care treatment may change over time and vary from 
one clinical trial site to another. The Sponsor will discuss these issues with FDA should the need arise. 
 


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9 
CONDUCT OF THE TRIAL 
9.1 
Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) as revised in Tokyo 
(1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland (2000, Note of Clarification 
2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) (2013), and with the International 
Council on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and United States (US) FDA Regulations. 
9.2 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50),  the 
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health 
Emergency (March 2020, Updated April 16, 2020) [20], as well as local and national regulations. 
Information should be given in both oral and written form whenever possible and deemed appropriate 
by the Institutional Review Board (IRB). Subjects and their relatives, if necessary, must be given 
ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, expected 
duration and purpose of the trial, the administration of the Investigational Product (IP), and the hazards 
involved, as well as the potential benefits that may come from treatment with this IP. The trial 
procedures will be explained in lay language and any questions will be answered. The subjects will be 
given an IRB-approved consent form. The subjects will be given appropriate time to consider their 
participation in the trial and have any questions answered prior to signing the consent form. If a subject 
agrees to participate, he/she will sign and date an informed consent form and be provided with a copy 
of the signed consent. All subjects who sign an informed consent form are to be recorded on the 
applicable screening log. If the subject is unable to consent for any reason, a designated family member 
or healthcare power of attorney or other person may consent per institutional policy.  
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the FDA and other relevant regulatory 
authorities. Subjects will be informed that they are free to refuse participation in this clinical 
investigation, and if they should participate, it will be made clear to them that they may withdraw from 
the trial at any time without prejudicing further medical care they may require. The subject will receive 
a copy of the consent form as well as an information sheet about the trial.  
Informed consent must be obtained from every subject prior to any study-specific procedures. 
Standard procedures carried out prior to completing the informed consent process but within the time 
constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
Documentation of consent will be subject to review by the Sponsor; if in writing, a copy will be given 
to the subject and a copy will be filed with the subject’s medical notes. Verbal consents will be 
documented by the study team as appropriate and agreed by the IRB. 
Note that informed consent procedures have been affected by COVID-19, and the study staff may use 
any consent method that has been approved by the IRB (e.g., phone consent, verbal consent with 


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witness, e-consent, etc.) of the local institution. In-person consent, written consent signatures and 
providing hard copies to the subject are examples of procedures that may be foregone under these 
circumstances. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she meets 
the subject selection criteria. 
A sample subject information sheet and consent form are available from Clear Creek.  The final 
version at each institution may differ depending on institutional requirements and standard formats. 
This protocol will not be amended for site specific changes as such changes are to be made to the site’s 
consent when required. 
9.3 
Institutional Review Board  
It is the responsibility of the Investigator to submit the protocol, consent form and information sheet 
to the IRB. An IB will be available for review by the IRB. The protocol and informed consent form 
(ICF) must be approved by the IRB prior to the recruitment of the first subject. The template consent 
form may be revised in accordance with site-specific requirements with Sponsor review and approval. 
A copy of the IRB written approval must be provided to the Sponsor and investigator before the trial 
may start at that institution. Written approval from the IRB is also required for substantial protocol 
amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating to 
the scientific documents in support of the trial.  Amendments are “substantial” when they are likely to 
have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures taken 
as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the trial. On completion of the trial, the Investigator 
will inform the applicable IRB as per local IRB requirements that the trial has ended. If the study is 
terminated for any reason, the investigator will return all clinical supplies and study-related equipment 
supplied by the Sponsor to the Sponsor unless otherwise specified.  
9.4 
Schedule of Events 
Study activities will be conducted or supervised by experienced personnel throughout the study based 
on the Schedule of Events. The subjects may collect the saliva sample for viral load testing and perform 
other study activities such as body temperature, heart rate, respiratory rate, SpO2, and symptom 


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assessments themselves with appropriate training. Equipment will be provided to the subject for study 
purposes including a pulse oximeter with heart rate monitoring capability and a thermometer. 
Telemedicine visits such as phone calls or other remote media are to be utilized as much as possible. 
Subjects may need to come to an out-patient facility or be visited by a home health professional for 
some study assessments. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALK), 
alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, and 
calcium), lactate dehydrogenase (LDH). 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and 
platelet count. 
Viral load sampling is to be carried out on Days 1, 4, 8, 12, 15, 22, and 29. The subject is to self- 
collect saliva samples with appropriate training for this analysis. Samples may be banked for future 
analyses. If the subject cannot provide documentation of the previous positive COVID-19 test, the site 
may perform an additional RT-PCR test. The subject must have a documented positive result to be 
eligible for the study. 
Hospitalization status after enrollment is to be recorded as not hospitalized or admitted to hospital as 
an in-patient with admission > 24 hours.    
As much of the study as possible will be conducted via telemedicine remote from the site (e.g., consent, 
medical history, concomitant medications may be collected remotely). Subjects will be visited at home 
(or place of residence) by a home health nurse at Screening and on study Days 1, 8, 15, 22, and 29. 
On study Days 4 and 12 the vital signs collection will be observed via telemedicine by the study site 
staff. Subjects will be provided with a pulse oximeter and thermometer during the Screening in-home 
visit, as well as being trained on the use of these devices during that visit. Training will also be 
provided by the home health nurse for the saliva collection required for viral load testing. Assessments 
will be recorded by the home nurse during home visits and by the site staff during telemedicine visits. 
These data will be entered in the eCRF by the site staff or as determined by the study team. 
9.5 
Study Conduct 
The study visits are to be conducted as shown in the Schedule of Events, Appendix 15.1. 
Study completion or the reason for study discontinuation will be recorded in the source document and 
the eCRF.  
9.5.1 Unscheduled Visits 
Unscheduled visits and tests are permitted as needed to assess AEs/SAEs throughout the study. 
Unscheduled visits and tests are also permitted as needed to assess AEs/ SAEs with onset within two 
(2) weeks after the final study visit providing the AE is considered related to study drug 


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9.6 
Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely as 
possible.  However, it is recognized in a clinical setting that protocol-specified timings may not occur 
exactly as specified in the protocol, particularly when conducted remotely by the subject. Provided 
that activities are carried out within the identified windows it will not be necessary to file a protocol 
deviation. Remote visits such as a telemedicine visit may be conducted to collect as much information 
as possible remotely. A home visit or return to the clinical site or an out-patient laboratory may be 
arranged for safety labs or other assessments, when required. Telemedicine or other remote technique 
is to be utilized to ensure subject compliance when subject is performing self-collection of study 
assessments.  
9.7 
Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after discussion 
with the other party if it is believed it would be unsafe for the subject to continue in the study.   
Subjects must discontinue study medication if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all scheduled evaluations even for subjects who discontinue study medication prior to 
completing the treatment period unless consent is withdrawn. 
9.8 
Early Termination of the Study 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any reason 
at the Sponsor’s request, the study may be terminated at that site or the entire study terminated after 
discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with the 
reasons for termination of the study. This will be conducted within 15 days of the decision to terminate 
the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 


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9.9 
Non-Childbearing Potential 
Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian 
tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the 
ovaries. Documentation of surgical procedure or physical examination is required for subjects who 
have had a hysterectomy or tubal ligation. A woman is also presumed to be infertile due to natural 
causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L. 
In the absence of such documentation, a negative serum pregnancy test is required for inclusion into 
the study. 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the medicinal product, whether or not 
considered related to the medicinal product.  
Events that occur prior to first dose will be entered as medical history; events that occur after first dose 
will be entered as adverse events (AEs) on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not judged by the 
Investigator or designated person to be related to study drug. All AEs will be documented in the 
subject's medical record and CRF. For any pre-existing condition or abnormal laboratory finding that 
changes in severity after dosing, this change should be recorded as an AE. New abnormal laboratory 
findings that are clinically significant are considered AEs. 
Adverse events will be collected from the time of first dose through Day 29. After Day 29, 
collect/record only Serious Adverse Events (SAEs) which are assessed by the Investigator or 
designated person to be related to study drug.  AE details are to be documented including start and 
stop date and times, whether continuous or intermittent, severity, any intervention utilized to correct 
the event (e.g., medication, surgery, or other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor by 
the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution or 
until they are considered stable or for at least 30 days after discontinuation of study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, are Grades 3 or 4, or require 
therapy. 
If a death occurs during the SAE reporting period, the cause of death such as pneumonia, ARDS, or 
respiratory failure, is considered as the AE and the death is considered its outcome. Death should be 
considered an outcome, not an event. The event or condition leading to death should be recorded and 
reported as a single medical concept on the AE eCRF. Generally, only one such event should be 
reported. “Fatal” will be recorded as the outcome of this respective event; death due to an outcome of 
an AE will not be recorded as separate event. If the primary cause of death is disease progression, the 
cause of death should be clearly identified as COVID-19. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered as 
the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim text 
to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA). For example, record appendicitis, not appendectomy. 
The following guidelines will be followed for the recording and reporting of adverse and serious 


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adverse events. 
1. The medical history section of the case report form will serve as the source document for baseline 
events.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start date 
of the baseline event. 
2. Adverse events occurring after first dose are to be recorded in the eCRF using the AE form. 
3. Serious adverse events will be reported to the local IRB according to institutional policy. 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) will be used for adverse 
event reporting.   
10.1 Follow Up of Grade 3 or 4 Toxicities 
Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, as feasible, until the toxicity 
returns to Grade ≤ 2 severity. 
10.2 Infection Follow Up 
Any new infection that occurs on study regardless of infecting agent (i.e., viral or non-viral) should be 
captured. Additionally, the site of infection and source of culture (BAL, tracheal aspirate, sputum, 
blood, urine, etc.) should also be recorded. 
10.3 Classification of Causality 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the Investigator. 
10.4 Classification of Severity 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.5 Serious Adverse Event (SAE) Reporting 
The regulatory definition of an SAE is any untoward medical occurrence or effect that at any dose 
fulfills one or more of these criteria: 
• results in death; 
• is life threatening (at the time of the event); 
• requires in-patient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect; 
• or is an event considered medically serious by the Investigator. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the Investigator, 
at immediate risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. IB for an unauthorized investigational product 
or summary of product characteristics for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events which did 
not directly result in the SAE should be detailed in the description section on the SAE form and listed 
separately as AEs if necessary. For fatal SAEs, report the cause of death as an SAE with a fatal 
outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  


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• Routine treatment or monitoring of COVID-19 infection, not associated with any 
deterioration in condition;  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition; 
• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 24 
HOURS) BY EMAIL TO THE SAE REPORTING EMAIL USING THE FORM PROVIDED.  
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF WITHIN 48 
HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address for reporting SAEs can be found below and at the front 
of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted to 
Covance Patient Safety until the event has subsided or, in case of permanent impairment, it stabilizes, 
and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL:  
SAEIntake@covance.com 
Medical Monitor: 
Norberto Soto, MD  
Telephone: 
(609) 212-7892 
Covance Physician/Medical Monitor 
Email: 
Norberto.Soto@Covance.com 
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
Telephone: 
M: (484) 686-0545 
VP, Clinical Operations 
Email: 
bpowers@clearcreekbio.com  
All SAEs will be reported to the IRB periodically, at the end of the study, or per local institutional 
guidelines.   
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the study 
drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and IRB 
by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness will be 
judged by the Covance Physician and site Investigator. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require immediate 
attention and expedited reporting to relevant regulatory authorities. 
The Sponsor will ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 


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IRB(s) within seven (7) calendar days of the date of first report to Covance Patient Safety / Sponsor. 
Follow-up information will be communicated to the relevant Regulatory Authority within an 
additional eight calendar days. 
All other SUSARs will be reported to the Regulatory Authority and to the IRB(s) concerned as soon 
as possible within a maximum of fifteen calendar days of first notification to Covance Patient Safety 
/ Sponsor. 
The Sponsor or designee will also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
requested additional information on an expedited basis.   
10.7 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to Covance Patient Safety (by email to 
SAEIntake@covance.com) and to the IRB by the investigational staff within 1 working day of their 
knowledge of the event. The collection period for a pregnancy occurring in a subject or a subject’s 
partner will begin at the first dose of study drug and will continue through 90 days after the last dose 
of study drug. Monitoring of the subject or partner should continue until the conclusion of the 
pregnancy, if the subject or subject’s partner has consented to this. Monitoring of the baby should 
continue for 3 months after birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or designee 
will discontinue the pregnant subject from the treatment aspects of the study, continue to follow her 
per protocol for safety outcomes only, and advise her to seek prenatal care and counseling from her 
primary care provider. Data on fetal outcome and breast-feeding will be collected for regulatory 
reporting and drug safety evaluation, if the subject has consented to this. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as (S)AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow the 
subject until the end of pregnancy, with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. 
10.8 Safety Monitoring for Hematologic Toxicities 
Myelosuppression is a known effect of DHODH inhibition that is associated with prolonged exposure 
and high doses. To reduce the risk of this effect with brequinar in COVID-19 subjects, the extensive 
brequinar safety database with over 1,000 patients has been evaluated to select a dose level expected 
to be safe and well tolerated with regard to hematologic toxicity. In addition to enhancing safety by 


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selecting a relatively brief 5-day exposure and a low brequinar dose, all subjects in the clinical trial 
will be under the care of highly qualified medical personnel. Clinically significant out-of-range 
laboratory results will be reported as adverse events. 
In addition to real time assessments by the treating clinical team, the Covance Medical Monitor will 
assess the available hematology data on a periodic basis to identify any pathologic trends or safety 
issues. Any apparent increase in the expected rate or severity of hematologic safety events will be 
discussed with the Principal Investigators and the Sponsor. In addition, the Data Monitoring 
Committee (DMC) will assess available hematology data on a periodic basis to independently assess 
any pathologic trends or safety issues. If the rate or severity of hematologic toxicities appears to be 
above the expected rate or the severity appears worse than that expected, the trial enrollment will be 
suspended and no further subjects will be treated while a comprehensive data review is conducted. 
Depending on the outcome of the safety review the study may be stopped, the design adjusted, or the 
study may continue as designed. Individual and Study stopping rules are provided in Section 8.4. 
Safety laboratory results are to be initially assessed in real time by the Principal Investigator or 
designated person. Any study drug-related clinically significant out-of-range laboratories or study 
drug-related adverse events will be followed as needed until resolution or stable. 
The in-clinic assessments and telemedicine/phone call visits will specifically ask about possible 
hematologic toxicity including any evidence of the list below. Subjects will be provided with a list of 
the following events in lay terms and will be instructed to call the research team if any of these events 
occur. 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Any of these symptoms considered clinically significant will be recorded as an adverse event and must 
be followed until resolved or stable. 
10.9 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to provide independent oversight to this 
trial. The primary responsibility of the DMC will be to review the progress and conduct of the trial in 
order to maintain scientific rigor and to ensure the wellbeing of subjects participating in the trial. The 
specific responsibilities of the DMC will be detailed in a separate DMC charter. The DMC will include 
at a minimum at least one statistician and two clinicians who will perform periodic data review to 
assess whether there are clinically significant differences between treatment arms that could affect 


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participant safety.  Following such a review, the DMC Chair will advise the Sponsor that the study be 
stopped, the design changed, or that the study may continue per protocol. 
10.9.1 DMC Safety Review Schedule 
The DMC is to review adverse events and safety laboratory assessments after the first 20 subjects 
complete the Day 8 visit, and again after the first 40 subjects complete the Day 8 visit. 
 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. All 
analyses will be descriptive in nature and presented by group.   
Summaries for quantitative variables will include the mean, median, quartiles, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and 95% confidence interval (CI), when appropriate. Any 
statistical testing will be considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.4 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. Subject 
data listings will also be provided. The following sections will briefly summarize of the planned 
statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 Study Populations for Analysis 
All safety analyses will be based on the ITT population, which is defined as all randomized subjects. 
As will be described in the SAP, efficacy analyses of changes in viral load will be based on the 
population of subjects with detectable viral load at baseline or similar qualification. Sample size may 
be adjusted if an inadequate number of subjects have detectable viral load at baseline. 
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, WHO Assessments, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data listings. The 
incidence of post-first dose (treatment-emergent) adverse events will be tabulated by MedDRA 
preferred term and system organ class, and by severity and relationship to study treatment. All 
laboratory results and study assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will primarily be assessed via viral load changes. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this proof-of-concept study. The sample size of 
approximately 100 subjects planned to be entered in this trial is expected to be adequate to provide 
safety and efficacy information to advise future study design. 
11.5 Randomization 
A randomization scheme will be provided by an independent statistician to the drug packaging 
company to ensure subjects are randomly assigned to SOC + brequinar or SOC + placebo in a 1:1 
ratio.  


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11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 


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12 INVESTIGATOR RESPONSIBILITIES 
12.1 Investigator’s Performance 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement found in Section 15.2 to 
indicate commitment to comply with the contents. 
12.2 Confidentiality 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality will 
be maintained during all audits and inspections of the trial site and documentation. A unique number 
will be assigned to each subject at the start of the trial and this, with the subject’s initials, will be used 
to identify the subject. In some cases, a further step may be taken to assign “fake initials” to the subject, 
per individual site requirements. The subject’s number will be the site number followed by the number 
of this subject at this site and will be used as the unique identifier in the source records and on the 
eCRF, on all trial correspondence and in the trial database. The Investigator will keep a list of 
identification codes or initials used for each subject along with the unique number assigned. 
All information provided to the Investigator relevant to the investigational product (IP), as well as 
information obtained during the course of the trial will be regarded as confidential. The Investigator 
and members of his/her research team agree not to disclose or publish such information in any way to 
any third-party without prior written permission from the Sponsor which will not be unreasonably 
withheld, except as required by law, or as permitted by the Publications section of this protocol, 
Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 Source Documentation 
Investigators are to maintain adequate source documentation of the original study data, for example 
medication records, laboratory reports and pharmacy records as appropriate. The Investigator will 
allow inspections of the trial site and documentation by clinical research and audit personnel from the 
Sponsor, external auditors or representatives of regulatory authorities. The purpose of these 
inspections is to verify and corroborate the data collected on the eCRFs. In order to do this, direct 
access to the subjects' medical or clinic records is necessary. The Investigator will ensure that certain 
information is contained in the medical or clinic written or electronic records of the subject and that 
the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IP being evaluated, 
the trial number assigned to that subject and a statement that consent was obtained; 


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• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each subject 
during the clinical phase of the study. A signed copy should also be filed in the investigator file. 
12.4 Data Collection 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. In 
addition, suitably qualified and trained clinical research personnel of the Sponsor will visit the trial 
site at regular intervals during the trial for monitoring purposes and to assist the research staff with 
any queries. All queries and discrepancies relating to the data collection are to be resolved at the 
completion of the trial. Remote data capture is encouraged whenever possible. 
12.5 Case Report Forms, Investigator’s Site File and Record Retention 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will be 
reviewed against source documentation at each monitoring visit. All CRFs and supporting source 
documentation must be completed and available to the Sponsor in a timely manner. Changes or 
corrections due to data clarification and resolutions will be tracked by paper or electronically with an 
audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed for 
completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the IB, 
the protocol plus any amendments, all correspondence with the IRB including the approval for the 
trial to proceed, Regulatory Authority approval/ notification (if applicable) including a sample of an 
approved informed consent, IP accountability, Source Documents, investigator and staff curricula 
vitae (CVs,) trial documentation, and all trial correspondence. The original signed informed consent 
forms and the final report will be kept in the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of time 
permitted by the hospital, institution or private practice. The Investigator has a responsibility to retain 
essential documents for as long as is required by the Sponsor and applicable regulatory authorities. It 
is the responsibility of the Sponsor to inform the Investigator as to when these documents no longer 
need to be retained. Investigators will be asked to contact the Sponsor prior to the destruction of any 
data or removal to another site if this occurs prior to the Sponsor notification that the documentation 
is no longer required. Any transfer of ownership of the data or of documents will be documented in 
writing. The new owner will assume responsibility for data retention and archiving. 


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Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials and 
intends to publish the results of this trial. All publications resulting from the clinical trial must be in a 
form that does not reveal technical information that the Sponsor considers confidential or proprietary.  
A copy of any abstract, presentation or manuscript proposed for publication must be submitted to the 
Sponsor for review at least 30 days before its submission for any meeting or journal. In addition, if 
deemed necessary by the Sponsor for protection of proprietary information prior to patent filing, the 
Investigator agrees to a further delay of 60 days before any presentation or publication is submitted. 
The Sponsor reserves the right to include the report of this trial in any regulatory documentation or 
submission or in any informational materials prepared for the medical profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of the 
following criteria: Investigator must participate in the review of and content of the protocol; review 
and comment on the study results; participate in the writing, reviewing and commenting of the 
manuscript; and approve the final manuscript for submission. 
 


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13 SPONSOR RESPONSIBILITIES 
13.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on GCP (CPMP/ICH/135/95, Jan.97) and 
US FDA Regulations. It is the Sponsor's responsibility to obtain appropriate regulatory approval to 
perform the trial (if applicable). The Sponsor should notify promptly all concerned investigator(s), 
IRB(s) and the Regulatory Authority of findings that could adversely affect the health of the patients/ 
subjects, impact on the conduct of the trial or alter the Regulatory Authority’s authorization to continue 
the trial. If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to 
the subjects the Sponsor will notify the relevant regulatory authority and relevant IRB of the new 
events, the measures taken and the plan for further action as soon as possible.  This will be by telephone 
in the first instance followed by a written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  If 
the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be conducted 
within 15 days of the decision to terminate the trial.  The Sponsor will report in an expeditious manner 
all SUSARs to the relevant regulatory authority and IRBs.   
13.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result of 
participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site or will 
access the electronic health record (EHR) or conduct remote monitoring visits at regular intervals 
during the trial for monitoring purposes and to assist the research staff with any queries. CRFs and 
source documentation will be available for review during monitoring visits to the trial site. The 
function of this monitoring is to ensure compliance with the protocol, adherence to regulatory and 
GCP obligations, proper maintenance of records including IP accountability records, correct 
administration of IP including storage conditions and accurate reporting of AEs. On-site visits are not 
required for any monitoring visits for this study.   
Once the data from the case report forms have been entered onto the database, they will be reviewed, 
and the data verified against the subject’s source data. Any discrepancies will be tracked by paper or 
electronically with an electronic audit trail. 
13.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place while 
the trial is being conducted or up to several years later.   


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13.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


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14 REFERENCES  
1. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 171-186. 
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Published 
online March 9, 2020. https://doi.org/10.1016/S0140-6736(20)30566-3 
3. Phelan A, Katz R, and Gostin L. The novel coronavirus originating in Wuhan, China. 
Challenges for global health governance. Jama. 2020;323(8):709-710.   
4. Handel A, Mille J, Yang G, Fung I. If containment is not possible, how do we minimize 
mortality for COVID-19 and other emerging disease outbreaks. March 13, 2020. 
https://doi.org/10.1101/2020.03.13.20034892. 
5. Brequinar Investigator’s Brochure 
6. Chen S, Ding S, Yin Y, Xu L, Li P, Peppelenbosch MP, et al. Suppression of pyrimidine 
biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral 
Res. 2019 Jul;167:35–44.  
7. Mei-Jiao G, Shi-Fang L, Yan-Yan C, Jun-Jun S, Yue-Feng S, Ting-Ting R, et al. Antiviral 
effects of selected IMPDH and DHODH inhibitors against foot and mouth disease virus. 
Biomed Pharmacother. 2019 Oct;118:109305.  
8. Wang QY, Bushell S, Qing M, Xu HY, Bonavia A, Nunes S, et al. Inhibition of Dengue 
Virus through Suppression of Host Pyrimidine Biosynthesis. 2011 Jun 9;85(13):6548–56.  
9. Luthra P, Naidoo J, Pietzsch CA, De S, Khadka S, Anantpadma M, et al. Inhibiting 
pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside 
pools and activation of innate immune responses. Antiviral Res. 2018 Oct;158:288–302.  
10. Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, et al. Novel Antiviral Activities 
of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine. Viruses. 2019 Oct 
18;11(10).  
11. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang, Y, et al. Novel and potent inhibitors 
targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-
spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. 
12. Sah R, Rodriguez-Morales AJ, Jha R, Chu DKW, Gu H, Peiris M, et al. Complete Genome 
Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Isolated in Nepal. Microbiol 
Resour Announc. 2020 Mar 12;9(11). 
13. Liu Q, Gupta A, Okesli-Armlovich A, Qiao W, Fischer C, Smith M, et al. Enhancing the 
Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with 
Modulators of Pyrimidine Metabolism. bioRxiv. 2020 Jan 1;2020.03.24.992230. 
14. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
15. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
16. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
18. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
20. FDA Guidance “COVID-19: Developing Drugs and Biological Products for the Treatment or 
Prevention (https://www.fda.gov/media/137926/download) 
 


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15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
Procedures 
Screen 
(days  
-14 to -1) 
D1 
D2, 3 
(± 8 
hrs) 
D4 
(± 8 
hrs) 
D5 
(± 8 
hrs) 
D8 
(± 1 
day) 
D12 
(± 1 
day) 
D15 
(± 1 
day) 
D22 
(±1 
day) 
Final 
Visit  
D29 
(± 2 days) 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, and SpO2. Subject will be provided with a thermometer 
and pulse oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health 
nurse. Vital signs parameters will be observed and recorded by study staff via telemedicine or during a visit by the home 
health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms 
(vomiting, diarrhea), anosmia, dysgeusia, other (specify), etc. Severity Mild, Moderate, or Severe will be collected. 
d RT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-
2 result. Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be 
obtained prior to dosing. Viral load specimens after Screening will be saliva samples self-collected by the subject using an 
Oragene® collection system or similar. The home health nurse will train the subject and observe sample collection on Day 
1. These samples are to be sent to CCLS for analysis. The viral load sample may also be used to perform viral cultures 
(sample can be split by the central laboratory, no additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. 
Note that any visits/visit activities may be conducted via telephone, telemedicine, or digital media other than serum 
pregnancy test and chemistry/hematology sample collection. These labs may be collected at the clinical site or another 
designated out-patient facility/laboratory or collected via home visit. Arrangements for shipping viral load samples will be 
made by the study team. 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-02 
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.  
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all of 
its provisions.  It is further agreed that the details of this trial and all information provided to me by 
Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be revealed for 
any reason without written authorization from Clear Creek Bio, Inc. except to those who are to 
participate in the conduct of the trial. 
I agree that all data, the case report forms, and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that Clear 
Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as for 
submission to government regulatory agencies, required internal reports, and presentations without 
violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in accordance 
with current Good Clinical Practice Guidelines, to all data generated by this trial and the source 
documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: ____________________________________ 
 
Signature: ____________________________________________ Date: __________________ 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 51 of 51 
PROTOCOL VERSION 2.0 DATE: 15 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
15.3 Appendix C: WHO Ordinal Scale 
 
Patient State 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized: moderate disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized: severe disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Dead 
10 
 
WHO clinical progression scale 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
Page 1 of 51 
PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
STUDY PROTOCOL 
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 No: CCB-CRISIS-02 
Version: 3.0 
Version Date:  23 September 2020 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 149291 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein may 
be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in accordance with 
the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration of Helsinki (1964, 
1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations and locally applicable 
regulations. 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.1.1 Coronavirus Biology .................................................................................................... 16 
3.2 Host Nucleotide Synthesis ......................................................................................... 16 
3.3 Dihydroorotate dehydrogenase (DHODH) ................................................................ 16 
3.4 Brequinar .................................................................................................................... 17 
3.5 Rationale for the Planned Trial .................................................................................. 17 
3.5.1 Brequinar Dose Selection ............................................................................................. 18 
3.5.2 Risk/Benefit of Brequinar ............................................................................................ 18 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 19 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 19 
3.7.1 CYP Interactions .......................................................................................................... 19 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 19 
4 TRIAL OBJECTIVES ........................................................................................................ 20 
4.1 Primary Objective ...................................................................................................... 20 
4.2 Secondary Objectives ................................................................................................. 20 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 20 
5 TRIAL DESIGN ................................................................................................................. 21 
6 TRIAL ENDPOINTS.......................................................................................................... 22 
6.1 Primary Endpoint ....................................................................................................... 22 
6.2 Secondary Endpoints .................................................................................................. 22 
6.3 Exploratory Endpoints................................................................................................ 22 
7 TRIAL POPULATION ....................................................................................................... 23 
7.1 Number of Subjects .................................................................................................... 23 
7.2 Inclusion criteria ......................................................................................................... 23 
7.3 Exclusion Criteria ....................................................................................................... 23 
8 STUDY TREATMENTS .................................................................................................... 25 


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Clear Creek Bio, Inc. 
CONFIDENTIAL 
8.1 Description of Study Medications .............................................................................. 25 
8.1.1 Brequinar ...................................................................................................................... 25 
8.2 Treatment Administration .......................................................................................... 25 
8.2.1 Safety/Tolerability ........................................................................................................ 25 
8.3 Study Discontinuation ................................................................................................ 26 
8.4 Stopping Criteria ........................................................................................................ 26 
8.4.1 Individual Stopping Criteria ......................................................................................... 26 
8.4.2 Study-Level Stopping Criteria...................................................................................... 26 
8.5 Concomitant Medication/Treatment .......................................................................... 26 
8.6 Treatment Compliance ............................................................................................... 26 
8.7 Storage, Stability, Labeling and Packaging ............................................................... 27 
8.7.1 Storage and Stability .................................................................................................... 27 
8.7.2 Labeling and Packaging ............................................................................................... 27 
8.7.3 Blinding and Randomization ........................................................................................ 27 
8.7.4 Unblinding/Expectedness ............................................................................................. 27 
8.7.5 Study Drug Accountability ........................................................................................... 27 
8.8 Prohibited Medications .............................................................................................. 28 
8.9 Study Adjustments Due to COVID-19....................................................................... 28 
9 CONDUCT OF THE TRIAL.............................................................................................. 29 
9.1 Ethical and Regulatory Considerations ...................................................................... 29 
9.2 Informed Consent ....................................................................................................... 29 
9.3 Institutional Review Board......................................................................................... 30 
9.4 Schedule of Events ..................................................................................................... 30 
9.5 Study Conduct ............................................................................................................ 31 
9.5.1 Unscheduled Visits ....................................................................................................... 32 
9.6 Compliance with Study Procedures ........................................................................... 32 
9.7 Early Withdrawal from the Study .............................................................................. 32 
9.8 Early Termination of the Study .................................................................................. 32 
9.9 Non-Childbearing Potential........................................................................................ 33 
10 ADVERSE EVENT REPORTING..................................................................................... 34 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 35 
10.2 Infection Follow Up ................................................................................................... 35 
10.3 Classification of Causality ......................................................................................... 35 
10.4 Classification of Severity ........................................................................................... 36 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 36 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 37 
10.7 Pregnancies................................................................................................................. 38 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 38 
10.9 Data Monitoring Committee ...................................................................................... 39 
10.9.1 
DMC Safety Review Schedule ............................................................................... 40 
11 STATISTICAL CONSIDERATIONS................................................................................ 41 
11.1 Study Populations for Analysis .................................................................................. 41 
11.2 Safety Analyses .......................................................................................................... 41 
11.3 Efficacy Analyses ....................................................................................................... 41 
11.4 Sample Size Considerations ....................................................................................... 41 
11.5 Randomization ........................................................................................................... 41 
11.6 Pooling of Study Centers............................................................................................ 42 
11.7 Interim Analysis ......................................................................................................... 42 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 43 
12.1 Investigator’s Performance ........................................................................................ 43 
12.2 Confidentiality ............................................................................................................ 43 
12.3 Source Documentation ............................................................................................... 43 
12.4 Data Collection ........................................................................................................... 44 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 44 
12.6 Non-Protocol Research .............................................................................................. 45 
12.7 Publication .................................................................................................................. 45 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 46 
13.1 General ....................................................................................................................... 46 
13.2 Indemnity ................................................................................................................... 46 
13.3 Data Monitoring ......................................................................................................... 46 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
13.4 Audit ........................................................................................................................... 46 
13.5 Confidentiality ............................................................................................................ 47 
13.6 Finance ....................................................................................................................... 47 
14 REFERENCES ................................................................................................................... 48 
15 APPENDICES .................................................................................................................... 49 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events .................................................. 49 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 50 
15.3 Appendix C: WHO Ordinal Scale .............................................................................. 51 
 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
LIST OF FIGURES 
Figure 3-1.  
DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine synthesis; 
it is completely essential for the generation of UMP. ................................................. 16 
  


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AML 
Acute myeloid leukemia 
ARDS 
Acute respiratory disease syndrome 
AST 
Aspartate amino transferase 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus-19 infection 
CRP 
c-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Curricula vitae 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DHODHi 
Dihydroorotate dehydrogenase inhibitor 
DMC 
Data Safety Monitoring Board 
ECMO 
Extra corporeal membrane oxygenation 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
EUA 
Emergency Use Authorization 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IMP 
Inosine-5’ phosphate 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEWS2 
National Early Warning System (NEWS) 2 Score 
RNA 
Ribonucleic Acid 
RdRp 
RNA-dependent RNA polymerase 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
SARS Coronavirus 2 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
SpO2 
Peripheral capillary oxygen saturation 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
Abbreviation 
Definition 
UMP 
Uridine 5’-monophosphatase 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
2 
SYNOPSIS  
CCB-CRISIS-02 SYNOPSIS  
IND 
149291 
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  
Protocol Number 
CCB-CRISIS-02 
Rationale 
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.  
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) + 5 days 
of brequinar 100 mg or SOC + 5 days of placebo.  
Investigational product will be supplied as either brequinar 100 mg oral capsules 
or placebo capsules. The subjects are to self-administer one capsule on Study Days 
1 – 5.  
Treatment assignment will be randomized, double-blind. 
Primary 
Objectives 
● To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load 
for brequinar-treated subjects compared to placebo-treated subjects through 
Day 29. 
Secondary 
Objectives 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-
19 subjects as measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
● To reduce the percentage of subjects requiring hospital admission as an in-
patient for > 24 hours for brequinar subjects compared to subjects who received 
placebo; 
● To reduce all-cause mortality through Day 29 for brequinar subjects compared 
to subjects who received placebo. 
Exploratory 
Objectives 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in 
the WHO Ordinal Scale score measured for the subset of subjects with baseline 
WHO Ordinal Scale of 2 for brequinar subjects compared to subjects who 
received placebo.  
Design 
This will be a phase 2 randomized, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive SOC per relevant guidelines 
for treatment of out-patients with COVID-19 infection. In addition to SOC, 
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 procedures are presented in detail in the Schedule of Events. Study visits 
(virtual or in person) will take place at Screening and on Study Days 1 - 8, 12, 15, 
22, and 29. 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 telephone, 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 with the site via 
telemedicine on Days 1, 4, 8, 12, 15, 22, and 29. The site will also have a telephone 
call with the subject on Study Days 2, 3, 5, 6, and 7 for changes in concomitant 
medications and assessment of adverse events, especially those that may indicate 
thrombocytopenia and mucositis. A home health nurse will visit the subject at 
Screening and on study Days 1, 8, 15, and 29. Telemedicine only visits will be 
conducted by site staff on study Days 4, 12, and 22. 
Sample Size: 
Approximately 100 subjects will be randomized to 5 days of either SOC + 
brequinar 100 mg or SOC + placebo in a 1:1 ratio (approximately 50 subjects 
assigned to brequinar 100 mg and 50 subjects to placebo).  
Number of Sites: 
Approximately 15 
Study Period: 
An enrollment period of 3 months is expected. 


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PROTOCOL VERSION 3.0 DATE: 23 SEPT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
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 within 14 days of first dose. 
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.  
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 


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CONFIDENTIAL 
8. AST and/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 first dose. 
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).  
Treatment 
All subjects will receive standard of care (SOC) including symptomatic care. 
Subjects will be randomly assigned to SOC + brequinar 100 mg daily x 5 or SOC 
+ placebo daily x 5. Study encounters will be conducted remotely whenever 
possible. 
DMC 
A Data Monitoring Committee (DMC) will meet periodically to review the safety 
and scientific conduct of the study. At a minimum, the DMC is to review adverse 
events and safety laboratory assessments after the first 20 subjects complete Day 
8, and again after the first 40 subjects complete Day 8.  
Procedures 
Study procedures are outlined in the Schedule of Events. 
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of first dose through Day 29. After 
Day 29, collect/record only Serious Adverse Events (SAEs) or those judged by the 
Investigator or designated person to be related to study drug. Treatment-emergent 
adverse events will be those with an onset after the date and time of first treatment. 
Subjects who develop Grade 3 or 4 toxicities or SAEs are to be re-evaluated every 
2 days, as feasible, until the toxicity returns to Grade ≤ 2 severity. 
During assessment for adverse events, investigators and site staff are to elicit from 
the subject any signs or symptoms of mucositis or thrombocytopenia, e.g.: 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 


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CONFIDENTIAL 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Stopping Criteria 
Individual Criteria:  
• Participants who develop a Grade 3 toxicity that is assessed by the 
investigator to be related to the study drug are to be permanently 
discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to 
study drug, are to be permanently discontinued from study treatment. 
Study-Level Stopping Criteria: 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse 
event or laboratory abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or 
laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or 
laboratory abnormality.  
All adverse events will be reviewed by the DMC during their reviews. Following 
assessment by the Data Monitoring Committee (DMC), the DMC will determine 
whether to stop the study, amend the protocol, or continue the study per protocol.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking 
the database. All analyses of safety and efficacy for this study will be descriptive 
in nature and presented by group. Subject demographics and baseline 
characteristics will be summarized. Subject data listings will also be provided.  
Summaries for quantitative variables will include the mean, median, quartiles, 
standard error, minimum, and maximum. For qualitative variables, the summaries 
will include the number and percentage of subjects for each outcome, and the 95% 
CI, when appropriate.  Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.4 or 
higher). Safety and tolerability will be assessed in terms of AEs, SAEs, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures 
will be summarized using appropriate descriptive statistics. 


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CONFIDENTIAL 
CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
Procedures 
Screen 
(days 
-14 to -1) 
HH+TMf 
D1 
HH
+ 
TM 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6, 
7 
(± 8 
hrs) 
TC 
D8 
(± 1 
day) 
HH+
TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 
day) 
HH+
TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 days) 
HH+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
D5 
only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, SpO2. Subject will be provided with a thermometer and pulse 
oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health nurse. Vital signs 
parameters will be observed and recorded by study staff via telemedicine or during a visit by the home health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms (vomiting, 
diarrhea), anosmia, dysgeusia, other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. 
dRT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-2 result. 
Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. 
Viral load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or 
similar. The home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS 
for analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no 
additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home 
visit. Arrangements for shipping viral load samples will be made by the study team. 
fHH = Home Health in-person visit; TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 


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CONFIDENTIAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
MEDICAL MONITOR 
Name:  
Norberto Soto, MD 
Title: 
Senior Medical Director 
Telephone No.: 
(609) 212-7892 
E-mail: 
Norberto.Soto@Covance.com 
 


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3 
INTRODUCTION 
3.1 
Coronavirus-19 (COVID-19) 
Beginning in December 2019, Chinese scientists isolated a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) from patients with virus-infected pneumonia which was later 
designated as coronavirus disease 2019 (COVID-19) by the World Health Organisation (WHO) (Zhou 
et al., 2020 [2]; Phelan et al., 2020 [3]).  
Approximately 14% of those affected with this virus will develop severe disease requiring 
hospitalization and oxygen support; 5% will require admission to the intensive care unit (Handel et 
al., 2020 [4]). Severe cases may be complicated by acute respiratory disease syndrome (ARDS), sepsis 
and septic shock, and multi-organ failure, including acute kidney injury and cardiac injury. Risk 
factors for death include older age and co-morbid disease such as hypertension and diabetes (Zhou, et 
al., 2020 [2]). This means that most patients will be treated as out-patients. Reducing viral load in this 
environment is critically important for both the subjects themselves by preventing worsening of 
symptoms and possibly avoiding hospitalization, but also to reduce the transmission of the disease to 
others in the patients’ households and their communities. 
3.1.1 Coronavirus Biology 
Coronaviruses, like other RNA-based viruses, do not have the machinery to synthesize their own 
nucleotides and thus depend upon the host intracellular pool of nucleotides for viral replication. In 
essence, viruses steal the host RNA building blocks, and without these building blocks they are unable 
to replicate. The SARS-CoV-2 is a single-stranded (positive sense) RNA virus with a genome that is 
29,811 nucleotides long, quite a lot larger than other RNA-based viruses (e.g. the hepatitis C genome 
comprises only 9600 nucleotides). The nucleotide composition is broken down as: 29.9% adenosines, 
18.4% cytosines, 19.6% guanines, and 32.1% uridines (Sah et al., 
2020 [12]). 
3.2 
 Host Nucleotide Synthesis 
Host de novo pyrimidine synthesis generates uridine monophosphate 
(UMP) as the building block for all pyrimidine ribonucleotides and 
deoxyribonucleotides (Figure 3-1). There exists no salvage pathway 
for the synthesis of UMP, the fundamental building block of 
pyrimidines. Inhibition of enzymatic steps upstream of UMP (Figure 
3-1) leads to a rapid and profound depletion of intracellular 
pyrimidines.  
3.3 
 Dihydroorotate dehydrogenase (DHODH) 
The enzyme dihydroorotate dehydrogenase (DHODH) catalyzes the 
4th step of de novo pyrimidine synthesis and inhibition of DHODH 
completely halts all pyrimidine production. As shown in Figure 3-1, 
DHODH is located on the inner mitochondrial membrane and 
transfers electrons between DHO and complex III of the electron-
 
Figure 
3-1. 
DHODH 
is 
a 
mitochondrial 
enzyme 
that 
catalyzes the 4th step of pyrimidine 
synthesis; it is completely essential 
for the generation of UMP.   


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transport chain via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a clear therapeutic target for the inhibition of host pyrimidine synthesis. The chemical 
inhibition of DHODH in vitro or in vivo leads to the rapid depletion of UMP and subsequent depletion 
of downstream products thymine and cytosine. This forces a cell to rely on the salvage of extracellular 
pyrimidine nucleotides and this extracellular salvage is not capable of maintaining the cell’s normal 
nucleotide pool (Sykes et al., 2016) [1]).  
  
3.4 
 Brequinar 
Brequinar is an orally available and potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity against 
experimental tumors and because its water solubility made it relatively straightforward to formulate. 
In an indication such as treating SARS-CoV-2 infection, brequinar will act as a host-targeting antiviral. 
It is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH), the enzyme 
that catalyzes the fourth step in pyrimidine synthesis, namely the conversion of dihydroorotate (DHO) 
to orotate. DHODH inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby 
leading to a depletion of a cell’s pool of uridine, cytidine and thymidine ribonucleotides and 
deoxyribonucleotides.  
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in human 
intestinal Caco-2 cells as well as in human primary intestinal organoids (Chen et al., 2019 [6]). 
Treatment with teriflunomide, another DHODHi, has been effective in vitro and in vivo in a murine 
model of foot and mouth disease virus (Mei-Jian et al., 2019 [7]). DHODH inhibition (DHODHi) also 
inhibited the growth of dengue virus in vitro (Wang et al., 2011 [8]). DHODHi also showed antiviral 
effects against RNA viruses including influenza A, Zika, Ebola and coronavirus SARS-CoV-2 (Xiong 
et al., 2020 [11]). Brequinar has also been shown to inhibit the replication of Ebola virus, vesicular 
stomatitis virus and Zika virus in vitro (Luthra et al., 2018 [9]). Brequinar inhibits the replication of 
human immunodeficiency virus (HIV) in vitro (Andersen et al., 2019 [10]). When considering 
brequinar as an antiviral for treatment of SARS-CoV-2, oral brequinar is highly bioavailable (>95%) 
and has good penetration of lung tissue with an average tissue:blood ratio of 0.5 following a single 
dose of brequinar in the rat. It is therefore expected to achieve a similar period of DHODH inhibition 
in lung tissue (Brequinar IB [5]). 
3.5 
 Rationale for the Planned Trial 
DHODH inhibition has been extensively studied as a potential therapeutic target in the treatment of 
RNA-based viruses. The inhibition of DHODH is effective in inhibiting viral replication in pre-clinical 
models involving many RNA-based viruses with nanomolar potency and a high selectivity index (see 
the Brequinar IB [5], Section 5). In these pre-clinical models, the benefit of DHODH inhibition can 
be reversed by the supplementation of exogenous nucleotides, confirming that the on-target effect of 
host pyrimidine depletion is key to the anti-viral activity.  


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The CCB-CRISIS-02 trial will study standard of care (SOC) with 5 days of brequinar (DHODH 
inhibition) compared to SOC with 5 days of placebo treatment. Clear Creek Bio hypothesizes that a 
defined 5-day course of brequinar will inhibit the enzyme DHODH to a degree sufficient to result in 
the transient depletion of host pyrimidine nucleotides, thereby inhibiting viral replication. A recent 
publication demonstrated that inhibitors of DHODH could potentiate the activity of inhibitors of RNA-
dependent RNA polymerase (RdRp) in the treatment of dengue virus, another single-stranded RNA 
virus similar to SARS-CoV-2 (Liu et al., 2020 [13]). This inhibition of viral replication may restore 
the balance in favor of the host immune system for the clearance of SARS-CoV-2. 
Marketed DHODHi medications are available, including leflunomide or teriflunomide, however these 
are very weak inhibitors of DHODH with cellular potency ~500 times lower than brequinar. These 
low potency inhibitors of DHODH are not expected to have the ability to acutely lower the pool of 
intracellular pyrimidines to the degree that is required for decreasing the viral load associated with 
SARS-CoV-2 infection, making brequinar the better choice for acute SARS-CoV-2 infection.  
The CRISIS2 study is a proof-of-concept study in patients with SARS-Cov-2 infection and will serve 
as a basis for future studies to determine the safety and effectiveness of brequinar in COVID-19. 
3.5.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with 5 days of consecutive daily 
dosing suggest that 5 days of daily doses of 100 mg p.o. will be safe and well tolerated. A dose of 
brequinar 100 mg achieves plasma concentrations of approximately 1 uM (0.4 ug/ml) that should result 
in sufficient suppression of nucleotide synthesis. When given over 5 days, these plasma concentrations 
are achieved on a daily basis without accumulation, also assuring the safety of this regimen (see 
Brequinar IB [5]).  
3.5.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive safety and pharmacokinetic database exists with 
more than 1,000 patients treated with brequinar. Cancer patients (N = 806) have been exposed to this 
compound for treatment of a variety of solid tumors at various treatment regimens, doses, and routes 
including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 
weeks, and daily times 21 days for multiple courses. Lower doses than used in the cancer studies have 
also been utilized for patients with psoriasis and organ transplant. The maximum intravenous dose 
given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. 
There has been limited testing of DHODHi to date in the clinic for infection with SARS-CoV-2. 
DHODHi therapy at relatively high doses in the context of trials for patients with cancer has the 
expected safety side-effects of mucositis and bone marrow suppression. Importantly, however, the 
prior clinical experience in 39 subjects who received daily brequinar for 5 consecutive days at or lower 
than 100 mg/day show no cases of mucositis and only 1 (2.6%) episode of mild thrombocytopenia. 
Based on these data the 100 mg per day dose proposed for administration in this study should be within 
a safe and tolerable range as well as demonstrating the predicted antiviral effect.  
The potential benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 5-day 
period of brequinar dosing will suppress host de novo pyrimidine synthesis for this period thus 
decreasing viral load. Inhibition of DHODH is expected to reduce the ability of the virus to replicate 


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and it is for this reason that brequinar will be administered to patients with COVID-19 in this study.
 
 
3.6 
 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of high-dose brequinar in patients with 
refractory solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis 
have been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of brequinar administration. 
However, these effects were self-limiting, transient, required treatment in few cases, and resolved 
following discontinuation of dosing. These adverse effects have been associated with higher doses of 
brequinar given via the intravenous route and for longer durations than the 100 mg dose and 5-day 
regimen proposed for this study.  
In addition to studying a higher risk population with symptomatic COVID-19, a comprehensive safety 
monitoring plan will be utilized in this study to assess the ongoing safety and well-being of participants 
(see Section 10.8).  
3.7 
 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in severely ill cancer patients including antibiotics, antifungals and other critical care 
medications. No formal interaction studies have been conducted for these medications, however, there 
have not been any reports of interactions with any medications during the clinical trials with more than 
800 cancer patients.  
3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with medications 
commonly used in treating hematologic malignancies. The nonclinical studies performed to date have 
demonstrated there is no first-pass metabolism and there have been no apparent hepatotoxic effects in 
the clinical studies. Brequinar itself does not appear to be a substrate for metabolism by cytochrome 
P450 enzymes when tested under a variety of conditions. (See Brequinar IB [5]; nonclinical data on 
file with Clear Creek).  
3.8 
Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated by highly experienced clinicians familiar with the treatment of viral 
infections and their complications.  
 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load for brequinar-treated 
subjects compared to placebo-treated subjects through Day 29. 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-19 subjects as 
measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with brequinar compared 
to subjects who received placebo;  
● To reduce the percentage of subjects requiring hospital admission as an inpatient for >24 hours for 
brequinar subjects compared to subjects who received placebo; 
• To reduce all-cause mortality through Day 29 for brequinar subjects compared to subjects who 
received placebo. 
4.3 
EXPLORATORY OBJECTIVES 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical symptoms and pre-
existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in the WHO Ordinal 
Scale score for the subset of subjects with baseline WHO Ordinal Scale of 2 for brequinar subjects 
compared to subjects who received placebo. 


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5 
TRIAL DESIGN 
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 per (SOC) 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 procedures 
are presented in detail in the Schedule of Events (Appendix 15.1). Study visits (virtual or in person) 
will take place at Screening and on Study Days 1 - 8, 12, 15, 22, and 29. 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 telephone, 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 with the site via telemedicine on Days 1, 4, 8, 12, 15, 22, and 29. The 
site will also have a telephone call with the subject on Study Days 2, 3, 5, 6, and 7 for changes in 
concomitant medications and assessment of adverse events, especially those that may indicate 
thrombocytopenia (see Section 10.8) and mucositis. A home health nurse will visit the subject at 
Screening and on study Days 1, 8, 15, and 29. Telemedicine only visits will be conducted by site staff 
on study Days 4, 12, and 22. 


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6 
TRIAL ENDPOINTS 
6.1 
Primary Endpoint 
Quantitative SARS-CoV-2 viral load through Day 29. 
6.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
Through Day 29: 
● Rates of AEs and SAEs including laboratory assessments; 
● Duration of viral shedding;  
• Percentage of subjects requiring admission as an inpatient for >24 hours. 
• All-cause mortality. 
6.3 
Exploratory Endpoints 
Through Day 29: 
● Time to viral clearance (two consecutive negative tests);  
● Time to resolution of new onset COVID-19-related clinical symptoms and pre-existing non-
COVID-19 symptoms returned to baseline; 
● Time to clinical improvement measured by a favorable shift in WHO Ordinal Scale score for the 
subset of subjects with baseline WHO Ordinal Scale of 2. 
 


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CONFIDENTIAL 
7 
TRIAL POPULATION 
7.1 
Number of Subjects 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 100 subjects have completed the study. Subjects will be randomized to either 
standard of care plus brequinar 100 mg or standard of care plus placebo in a 1:1 ratio (approximately 
50 subjects assigned to standard of care plus brequinar 100 mg and approximately 50 subjects assigned 
to standard of care plus placebo).  
7.2 
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 within 14 days 
of first dose. 
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. 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. 
8. Able to swallow capsules. 
7.3 
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 


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5. Hemoglobin < 10 gm/dL  
6. Absolute neutrophil count < 1500 cells/mm3 
7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
8. AST and/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 first dose. 
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). 
 


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8 
STUDY TREATMENTS 
8.1 
Description of Study Medications 
8.1.1 Brequinar 
Brequinar and placebo will be supplied as 100 mg capsules. Dosing will be a single 5-day course of 
brequinar 100 mg capsules or placebo 100 mg capsules once daily for 5 doses.  
8.2 
Treatment Administration 
This will be a phase 2 randomized, placebo-controlled, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive standard of care (SOC) for COVID-19 infection. 
Subjects will be randomly assigned in a 1:1 ratio to standard of care plus brequinar or standard of care 
plus placebo. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit. The NIH Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) 
will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
criteria.  
Adverse events (AEs) commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure (IB) and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 cancer subjects 
treated once-weekly (DuP 785-012, see Brequinar IB [5]), the deaths of three patients were attributed 
to study drug toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades 
(Grades 3 to 4) which typically led to discontinuation in this study included hematologic toxicities 
(anemia, thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, 
vomiting, stomatitis, others including gastric hemorrhage) and mucositis.  
In three oncology studies with five consecutive days of intravenous (IV) brequinar dosing in 168 
subjects (Study 785-001 [14], 785-003 [15], and 785-005 [16]) there were no toxic deaths. For 
subjects from these three studies who were treated with a daily dose of 100 mg or below  (as will be 
dosed in CCB-CRISIS-02), AEs through 21 days showed that 2 of 39 subjects (5.1%) had a severe 
(Grades 3 or 4) AE related to study drug (1 subject each with hyperbilirubinemia and 
hyperglycemia), and no subjects discontinued from the study due to a study drug-related AE. The 
few study drug related AEs through 21 days at or below the 100 mg dose from these three studies 
included 2 subjects each with nausea, vomiting, and creatinine elevated and one subject each with 
thrombocytopenia and diarrhea. When only studies with oral dosing were considered at this dose 
level (Studies 785-022 [17], 785-031 [18] , and 785-034 [19]), the study drug related AEs through 
21 days (each observed in one subject only) included diarrhea, headache, nausea, pruritus, 
abdominal pain, anorexia, chest pain, dry mouth, fatigue, keratosis, stomatitis, and vomiting. See 
brequinar IB [5]. 


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In most instances, brequinar-related toxicities were transient, clinically manageable, and reversible 
upon discontinuation of brequinar treatment. Any of these events reported with brequinar use can be 
serious in nature and may result in death.  
A 5-day course of oral brequinar administered once daily at a low level relative to those administered 
in the cancer studies is expected to be safe and well tolerated in the COVID-19 population. 
8.3 
Study Discontinuation 
Subjects will remain in the study through at least Study Day 29 (or longer if needed to follow up study 
drug-related adverse events). Participants may discontinue from the study by withdrawing consent at 
any time or for any reason as presented in Section 9.7. 
8.4 
Stopping Criteria 
8.4.1 Individual Stopping Criteria 
• Participants who develop a Grade 3 toxicity that is assessed by the investigator to be related to 
the study drug are to be permanently discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be 
permanently discontinued from study treatment. 
• Subjects who develop Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, 
as feasible, until the toxicity returns to ≤ Grade 2 severity. 
8.4.2 Study-Level Stopping Criteria 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse event or laboratory 
abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC, see Section 10.9), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per protocol. 
8.5 
Concomitant Medication/Treatment 
Record the name, dose, start/stop date, indication for use, route, and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications taken 
during the study are to be recorded. Prohibited medications are identified in Section 8.8.  
8.6 
Treatment Compliance 
Compliance will be assessed by reviewing the subject’s medication diary and study records as 
appropriate. 


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8.7 
Storage, Stability, Labeling and Packaging 
8.7.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.7.2 Labeling and Packaging  
The bulk drug and unit-dose containers will be labeled in accordance with national laws and 
regulations. 
8.7.3 Blinding and Randomization 
The trial will be conducted in double blinded, randomized manner with random assignment to standard 
of care plus brequinar or standard of care plus placebo. The brequinar and placebo capsules will be 
provided to each participating institution in pre-numbered bottles intended for individual subjects to 
be dispensed by the institution’s pharmacist or designated person. Randomization assignments will be 
provided by an independent statistician to the drug packaging company. The pharmacist/designated 
person will dispense the next number in sequence to the next patient who qualifies for the study at an 
individual site. 
8.7.4 Unblinding/Expectedness 
Contact the Covance Medical Monitor if it is necessary to break the blind for this blinded study due 
to an adverse event (AE). Each site will be provided with a sealed envelope containing individual 
sealed envelopes for subject numbers assigned to that site. Each individual subject number sealed 
envelope will have the treatment (brequinar or placebo) randomly assigned to that subject number. Do 
not open the outer envelope or the individual sealed envelope unless it has been agreed with the 
Medical Monitor and the Sponsor that unblinding is necessary for that particular AE. Unblinding must 
be documented in the study records. Envelope seals are to be checked to ensure they remain intact 
during drug accountability monitoring. 
If after a discussion with the Medical Monitor, the investigator or treating clinician believes the AE 
leading to unblinding to be related to the study drug, no further doses of drug should be administered 
to that subject.  
Expectedness will be determined by establishing whether an adverse event is among those identified 
in the protocol and the brequinar IB or are commonly associated with COVID-19 or similar severe 
viral illnesses and their complications.   
8.7.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, administered, and discarded.  It 
must be clear from the records whether the subject received study medication and what subject number 
was assigned to which subject. Adequate drug is to be dispensed for the number of subjects expected 
to be treated at each institution.  


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The pharmacist/staff member responsible for drug accountability is to document the date and time of 
dispensing and for what subject the study drug was intended (i.e., record subject initials and birth date 
or other unique identifier). A pharmacy manual will be provided by the Sponsor.  
At the end of the study any unused study drug will be returned to the Sponsor for destruction or may 
be destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours and 
with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. Records may be electronic or paper and may be accessed remotely for monitoring/drug 
accountability purposes. 
Each subject will be provided with one bottle with five brequinar or five placebo capsules for the five 
days of dosing. 
8.8 
Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide). 
Treatment is prohibited with agents known to cause bone marrow suppression leading to 
thrombocytopenia.  
8.9 
Study Adjustments Due to COVID-19 
Due to the highly contagious nature of COVID-19, multiple adjustments and revised procedures are 
rapidly evolving regarding clinical trial management and study conduct. Reasonable procedures 
implemented by study staff to avoid spreading this disease are acceptable to Clear Creek with written 
permission. Examples include but are not limited to e-consent, telephone consent and study visits 
conducted by telemedicine, telephone or other digital media.  
Background standard of care is to be maintained in both treatment arms. The standard of care is 
expected to change as additional information, such as that from randomized controlled trials, emerges, 
and the Sponsor and the treating clinicians will need to address anticipated off-label use of any other 
drugs, devices, or interventions that might be used to manage COVID-19 (e.g. anticoagulants).  
The Sponsor and treating clinicians are to consider changes in SOC over time, for example, 
overlapping toxicities of brequinar and a SOC treatment expected to be widely used is to be 
considered. The availability of new standard of care treatment may change over time and vary from 
one clinical trial site to another. The Sponsor will discuss these issues with FDA should the need arise. 
 


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9 
CONDUCT OF THE TRIAL 
9.1 
Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) as revised in Tokyo 
(1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland (2000, Note of Clarification 
2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) (2013), and with the International 
Council on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and United States (US) FDA Regulations. 
9.2 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50),  the 
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health 
Emergency (March 2020, Updated April 16, 2020) [20], as well as local and national regulations. 
Information should be given in both oral and written form whenever possible and deemed appropriate 
by the Institutional Review Board (IRB). Subjects and their relatives, if necessary, must be given 
ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, expected 
duration and purpose of the trial, the administration of the Investigational Product (IP), and the hazards 
involved, as well as the potential benefits that may come from treatment with this IP. The trial 
procedures will be explained in lay language and any questions will be answered. The subjects will be 
given an IRB-approved consent form. The subjects will be given appropriate time to consider their 
participation in the trial and have any questions answered prior to signing the consent form. If a subject 
agrees to participate, he/she will sign and date an informed consent form and be provided with a copy 
of the signed consent. All subjects who sign an informed consent form are to be recorded on the 
applicable screening log. If the subject is unable to consent for any reason, a designated family member 
or healthcare power of attorney or other person may consent per institutional policy.  
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the FDA and other relevant regulatory 
authorities. Subjects will be informed that they are free to refuse participation in this clinical 
investigation, and if they should participate, it will be made clear to them that they may withdraw from 
the trial at any time without prejudicing further medical care they may require. The subject will receive 
a copy of the consent form as well as an information sheet about the trial.  
Informed consent must be obtained from every subject prior to any study-specific procedures. 
Standard procedures carried out prior to completing the informed consent process but within the time 
constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
Documentation of consent will be subject to review by the Sponsor; if in writing, a copy will be given 
to the subject and a copy will be filed with the subject’s medical notes. Verbal consents will be 
documented by the study team as appropriate and agreed by the IRB. 
Note that informed consent procedures have been affected by COVID-19, and the study staff may use 
any consent method that has been approved by the IRB (e.g., phone consent, verbal consent with 


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witness, e-consent, etc.) of the local institution. In-person consent, written consent signatures and 
providing hard copies to the subject are examples of procedures that may be foregone under these 
circumstances. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she meets 
the subject selection criteria. 
A sample subject information sheet and consent form are available from Clear Creek.  The final 
version at each institution may differ depending on institutional requirements and standard formats. 
This protocol will not be amended for site specific changes as such changes are to be made to the site’s 
consent when required. 
9.3 
Institutional Review Board  
It is the responsibility of the Investigator to submit the protocol, consent form and information sheet 
to the IRB. An IB will be available for review by the IRB. The protocol and informed consent form 
(ICF) must be approved by the IRB prior to the recruitment of the first subject. The template consent 
form may be revised in accordance with site-specific requirements with Sponsor review and approval. 
A copy of the IRB written approval must be provided to the Sponsor and investigator before the trial 
may start at that institution. Written approval from the IRB is also required for substantial protocol 
amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating to 
the scientific documents in support of the trial.  Amendments are “substantial” when they are likely to 
have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures taken 
as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the trial. On completion of the trial, the Investigator 
will inform the applicable IRB as per local IRB requirements that the trial has ended. If the study is 
terminated for any reason, the investigator will return all clinical supplies and study-related equipment 
supplied by the Sponsor to the Sponsor unless otherwise specified.  
9.4 
Schedule of Events 
Study activities will be conducted or supervised by experienced personnel throughout the study based 
on the Schedule of Events. The subjects may collect the saliva sample for viral load testing and perform 
other study activities such as body temperature, heart rate, respiratory rate, SpO2, and symptom 


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assessments themselves with appropriate training. Equipment will be provided to the subject for study 
purposes including a pulse oximeter with heart rate monitoring capability and a thermometer. 
Telemedicine visits such as phone calls or other remote media are to be utilized as much as possible. 
Subjects may need to come to an out-patient facility or be visited by a home health professional for 
some study assessments. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALK), 
alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, and 
calcium), lactate dehydrogenase (LDH). 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and 
platelet count. 
Viral load sampling is to be carried out on Days 1, 4, 8, 12, 15, 22, and 29. The subject is to self- 
collect saliva samples with appropriate training for this analysis. Samples may be banked for future 
analyses. If the subject cannot provide documentation of the previous positive COVID-19 test, the site 
may perform an additional RT-PCR test as part of the Screening visit. The subject must have a 
documented positive result to be eligible for the study. 
Safety laboratory results (chemistry and hematology) are to be reviewed by investigator or designated 
site personnel within 48 hours of receipt of results. 
Hospitalization status after enrollment is to be recorded as not hospitalized or admitted to hospital as 
an in-patient with admission > 24 hours.    
As much of the study as possible will be conducted via telemedicine remote from the site (e.g., consent, 
medical history, concomitant medications may be collected remotely). Subjects will be visited at home 
(or place of residence) by a home health nurse at Screening and on study Days 1, 8, 15, and 29. On 
study Days 4, 12, and 22 the vital signs and saliva collections will be observed via telemedicine by the 
study site staff. Site staff will have a telephone call with subjects on study days 2, 3, 5, 6, and 7 to 
assess changes in concomitant medications and to assess adverse events, especially those that may 
indicate thrombocytopenia, e.g., unusual bruising, epistaxis, gingival bleeding, etc., and mucositis. 
Subjects will be provided with a pulse oximeter and thermometer during the Screening in-home visit, 
as well as being trained on the use of these devices during that visit. Training will also be provided by 
the home health nurse for the saliva collection required for viral load testing. Assessments will be 
recorded by the home nurse during home visits and by the site staff during telemedicine visits. These 
data will be entered in the eCRF by the site staff or as determined by the study team. 
9.5 
Study Conduct 
The study visits are to be conducted as shown in the Schedule of Events, Appendix 15.1. 
Study completion or the reason for study discontinuation will be recorded in the source document and 
the eCRF.  


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9.5.1 Unscheduled Visits 
Unscheduled visits and tests are permitted as needed to assess AEs/SAEs throughout the study. 
Unscheduled visits and tests are also permitted as needed to assess AEs/ SAEs with onset within two 
(2) weeks after the final study visit providing the AE is considered related to study drug 
9.6 
Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely as 
possible.  However, it is recognized in a clinical setting that protocol-specified timings may not occur 
exactly as specified in the protocol, particularly when conducted remotely by the subject. Provided 
that activities are carried out within the identified windows it will not be necessary to file a protocol 
deviation. Remote visits such as a telemedicine visit may be conducted to collect as much information 
as possible remotely. A home visit or return to the clinical site or an out-patient laboratory may be 
arranged for safety labs or other assessments, when required. Telemedicine or other remote technique 
is to be utilized to ensure subject compliance when subject is performing self-collection of study 
assessments.  
9.7 
Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after discussion 
with the other party if it is believed it would be unsafe for the subject to continue in the study.   
Subjects must discontinue study medication if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all scheduled evaluations even for subjects who discontinue study medication prior to 
completing the treatment period unless consent is withdrawn. 
9.8 
Early Termination of the Study 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any reason 
at the Sponsor’s request, the study may be terminated at that site or the entire study terminated after 
discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with the 
reasons for termination of the study. This will be conducted within 15 days of the decision to terminate 
the study.  


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If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
9.9 
Non-Childbearing Potential 
Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian 
tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the 
ovaries. Documentation of surgical procedure or physical examination is required for subjects who 
have had a hysterectomy or tubal ligation. A woman is also presumed to be infertile due to natural 
causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L. 
In the absence of such documentation, a negative serum pregnancy test is required for inclusion into 
the study. 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the medicinal product, whether or not 
considered related to the medicinal product.  
Events that occur prior to first dose will be entered as medical history; events that occur after first dose 
will be entered as adverse events (AEs) on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not judged by the 
Investigator or designated person to be related to study drug. All AEs will be documented in the 
subject's medical record and CRF. For any pre-existing condition or abnormal laboratory finding that 
changes in severity after dosing, this change should be recorded as an AE. New abnormal laboratory 
findings that are clinically significant are considered AEs. Investigators and site staff are to elicit from 
the subject and note any signs or symptoms of mucositis and thrombocytopenia (see Section 10.8). 
Adverse events will be collected from the time of first dose through Day 29. After Day 29, 
collect/record only Serious Adverse Events (SAEs) which are assessed by the Investigator or 
designated person to be related to study drug.  AE details are to be documented including start and 
stop date and times, whether continuous or intermittent, severity, any intervention utilized to correct 
the event (e.g., medication, surgery, or other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor by 
the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution or 
until they are considered stable or for at least 30 days after discontinuation of study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, are Grades 3 or 4, or require 
therapy. 
If a death occurs during the SAE reporting period, the cause of death such as pneumonia, ARDS, or 
respiratory failure, is considered as the AE and the death is considered its outcome. Death should be 
considered an outcome, not an event. The event or condition leading to death should be recorded and 
reported as a single medical concept on the AE eCRF. Generally, only one such event should be 
reported. “Fatal” will be recorded as the outcome of this respective event; death due to an outcome of 
an AE will not be recorded as separate event. If the primary cause of death is disease progression, the 
cause of death should be clearly identified as COVID-19. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered as 
the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim text 
to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA). For example, record appendicitis, not appendectomy. 


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The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. The medical history section of the case report form will serve as the source document for baseline 
events.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start date 
of the baseline event. 
2. Adverse events occurring after first dose are to be recorded in the eCRF using the AE form. 
3. Serious adverse events will be reported to the local IRB according to institutional policy. 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) will be used for adverse 
event reporting.   
10.1 Follow Up of Grade 3 or 4 Toxicities 
Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, as feasible, until the toxicity 
returns to Grade ≤ 2 severity. 
10.2 Infection Follow Up 
Any new infection that occurs on study regardless of infecting agent (i.e., viral or non-viral) should be 
captured. Additionally, the site of infection and source of culture (BAL, tracheal aspirate, sputum, 
blood, urine, etc.) should also be recorded. 
10.3 Classification of Causality 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the Investigator. 
10.4 Classification of Severity 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.5 Serious Adverse Event (SAE) Reporting 
The regulatory definition of an SAE is any untoward medical occurrence or effect that at any dose 
fulfills one or more of these criteria: 
• results in death; 
• is life threatening (at the time of the event); 
• requires in-patient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect; 
• or is an event considered medically serious by the Investigator. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the Investigator, 
at immediate risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. IB for an unauthorized investigational product 
or summary of product characteristics for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events which did 
not directly result in the SAE should be detailed in the description section on the SAE form and listed 
separately as AEs if necessary. For fatal SAEs, report the cause of death as an SAE with a fatal 
outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  


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• Routine treatment or monitoring of COVID-19 infection, not associated with any 
deterioration in condition;  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition; 
• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 24 
HOURS) BY EMAIL TO THE SAE REPORTING EMAIL USING THE FORM PROVIDED.  
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF WITHIN 48 
HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address for reporting SAEs can be found below and at the front 
of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted to 
Covance Patient Safety until the event has subsided or, in case of permanent impairment, it stabilizes, 
and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL:  
SAEIntake@covance.com 
Medical Monitor: 
Norberto Soto, MD  
Telephone: 
(609) 212-7892 
Covance Physician/Medical Monitor 
Email: 
Norberto.Soto@Covance.com 
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
Telephone: 
M: (484) 686-0545 
VP, Clinical Operations 
Email: 
bpowers@clearcreekbio.com  
All SAEs will be reported to the IRB periodically, at the end of the study, or per local institutional 
guidelines.   
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the study 
drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and IRB 
by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness will be 
judged by the Covance Physician and site Investigator. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require immediate 
attention and expedited reporting to relevant regulatory authorities. 
The Sponsor will ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 


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IRB(s) within seven (7) calendar days of the date of first report to Covance Patient Safety / Sponsor. 
Follow-up information will be communicated to the relevant Regulatory Authority within an 
additional eight calendar days. 
All other SUSARs will be reported to the Regulatory Authority and to the IRB(s) concerned as soon 
as possible within a maximum of fifteen calendar days of first notification to Covance Patient Safety 
/ Sponsor. 
The Sponsor or designee will also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
requested additional information on an expedited basis.   
10.7 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to Covance Patient Safety (by email to 
SAEIntake@covance.com) and to the IRB by the investigational staff within 1 working day of their 
knowledge of the event. The collection period for a pregnancy occurring in a subject or a subject’s 
partner will begin at the first dose of study drug and will continue through 90 days after the last dose 
of study drug. Monitoring of the subject or partner should continue until the conclusion of the 
pregnancy, if the subject or subject’s partner has consented to this. Monitoring of the baby should 
continue for 3 months after birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or designee 
will discontinue the pregnant subject from the treatment aspects of the study, continue to follow her 
per protocol for safety outcomes only, and advise her to seek prenatal care and counseling from her 
primary care provider. Data on fetal outcome and breast-feeding will be collected for regulatory 
reporting and drug safety evaluation, if the subject has consented to this. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as (S)AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow the 
subject until the end of pregnancy, with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. 
10.8 Safety Monitoring for Hematologic Toxicities 
Myelosuppression is a known effect of DHODH inhibition that is associated with prolonged exposure 
and high doses. To reduce the risk of this effect with brequinar in COVID-19 subjects, the extensive 
brequinar safety database with over 1,000 patients has been evaluated to select a dose level expected 
to be safe and well tolerated with regard to hematologic toxicity. In addition to enhancing safety by 


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selecting a relatively brief 5-day exposure and a low brequinar dose, all subjects in the clinical trial 
will be under the care of highly qualified medical personnel. Clinically significant out-of-range 
laboratory results will be reported as adverse events. 
In addition to real time assessments by the treating clinical team, the Covance Medical Monitor will 
assess the available hematology data on a periodic basis to identify any pathologic trends or safety 
issues. Any apparent increase in the expected rate or severity of hematologic safety events will be 
discussed with the Principal Investigators and the Sponsor. In addition, the Data Monitoring 
Committee (DMC) will assess available hematology data on a periodic basis to independently assess 
any pathologic trends or safety issues. If the rate or severity of hematologic toxicities appears to be 
above the expected rate or the severity appears worse than that expected, the trial enrollment will be 
suspended and no further subjects will be treated while a comprehensive data review is conducted. 
Depending on the outcome of the safety review the study may be stopped, the design adjusted, or the 
study may continue as designed. Individual and Study stopping rules are provided in Section 8.4. 
Safety laboratory results are to be initially assessed in real time by the Principal Investigator or 
designated person. Any study drug-related clinically significant out-of-range laboratories or study 
drug-related adverse events will be followed as needed until resolution or stable. 
The in-clinic assessments and telemedicine/phone call visits will specifically ask about possible 
hematologic toxicity including any evidence of the list below. Subjects will be provided with a list of 
the following events in lay terms and will be instructed to call the research team if any of these events 
occur. 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Any of these symptoms considered clinically significant will be recorded as an adverse event and must 
be followed until resolved or stable. 
10.9 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to provide independent oversight to this 
trial. The primary responsibility of the DMC will be to review the progress and conduct of the trial in 
order to maintain scientific rigor and to ensure the wellbeing of subjects participating in the trial. The 
specific responsibilities of the DMC will be detailed in a separate DMC charter. The DMC will include 
at a minimum at least one statistician and two clinicians who will perform periodic data review to 
assess whether there are clinically significant differences between treatment arms that could affect 
participant safety.  All adverse events will be reviewed by the DMC during their reviews. Following 


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such a review, the DMC Chair will advise the Sponsor that the study be stopped, the design changed, 
or that the study may continue per protocol. 
10.9.1 DMC Safety Review Schedule 
The DMC is to review adverse events and safety laboratory assessments after the first 20 subjects 
complete the Day 8 visit, and again after the first 40 subjects complete the Day 8 visit. 
 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. All 
analyses will be descriptive in nature and presented by group.   
Summaries for quantitative variables will include the mean, median, quartiles, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and 95% confidence interval (CI), when appropriate. Any 
statistical testing will be considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.4 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. Subject 
data listings will also be provided. The following sections will briefly summarize of the planned 
statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 Study Populations for Analysis 
All safety analyses will be based on the ITT population, which is defined as all randomized subjects. 
As will be described in the SAP, efficacy analyses of changes in viral load will be based on the 
population of subjects with detectable viral load at baseline or similar qualification. Sample size may 
be adjusted if an inadequate number of subjects have detectable viral load at baseline. 
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, WHO Assessments, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data listings. The 
incidence of post-first dose (treatment-emergent) adverse events will be tabulated by MedDRA 
preferred term and system organ class, and by severity and relationship to study treatment. All 
laboratory results and study assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will primarily be assessed via viral load changes. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this proof-of-concept study. The sample size of 
approximately 100 subjects planned to be entered in this trial is expected to be adequate to provide 
safety and efficacy information to advise future study design. 
11.5 Randomization 
A randomization scheme will be provided by an independent statistician to the drug packaging 
company to ensure subjects are randomly assigned to SOC + brequinar or SOC + placebo in a 1:1 
ratio.  


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CONFIDENTIAL 
11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 


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CONFIDENTIAL 
12 INVESTIGATOR RESPONSIBILITIES 
12.1 Investigator’s Performance 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement found in Section 15.2 to 
indicate commitment to comply with the contents. 
12.2 Confidentiality 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality will 
be maintained during all audits and inspections of the trial site and documentation. A unique number 
will be assigned to each subject at the start of the trial and this, with the subject’s initials, will be used 
to identify the subject. In some cases, a further step may be taken to assign “fake initials” to the subject, 
per individual site requirements. The subject’s number will be the site number followed by the number 
of this subject at this site and will be used as the unique identifier in the source records and on the 
eCRF, on all trial correspondence and in the trial database. The Investigator will keep a list of 
identification codes or initials used for each subject along with the unique number assigned. 
All information provided to the Investigator relevant to the investigational product (IP), as well as 
information obtained during the course of the trial will be regarded as confidential. The Investigator 
and members of his/her research team agree not to disclose or publish such information in any way to 
any third-party without prior written permission from the Sponsor which will not be unreasonably 
withheld, except as required by law, or as permitted by the Publications section of this protocol, 
Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 Source Documentation 
Investigators are to maintain adequate source documentation of the original study data, for example 
medication records, laboratory reports and pharmacy records as appropriate. The Investigator will 
allow inspections of the trial site and documentation by clinical research and audit personnel from the 
Sponsor, external auditors or representatives of regulatory authorities. The purpose of these 
inspections is to verify and corroborate the data collected on the eCRFs. In order to do this, direct 
access to the subjects' medical or clinic records is necessary. The Investigator will ensure that certain 
information is contained in the medical or clinic written or electronic records of the subject and that 
the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IP being evaluated, 
the trial number assigned to that subject and a statement that consent was obtained; 


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CONFIDENTIAL 
• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each subject 
during the clinical phase of the study. A signed copy should also be filed in the investigator file. 
12.4 Data Collection 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. In 
addition, suitably qualified and trained clinical research personnel of the Sponsor will visit the trial 
site at regular intervals during the trial for monitoring purposes and to assist the research staff with 
any queries. All queries and discrepancies relating to the data collection are to be resolved at the 
completion of the trial. Remote data capture is encouraged whenever possible. 
12.5 Case Report Forms, Investigator’s Site File and Record Retention 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will be 
reviewed against source documentation at each monitoring visit. All CRFs and supporting source 
documentation must be completed and available to the Sponsor in a timely manner. Changes or 
corrections due to data clarification and resolutions will be tracked by paper or electronically with an 
audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed for 
completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the IB, 
the protocol plus any amendments, all correspondence with the IRB including the approval for the 
trial to proceed, Regulatory Authority approval/ notification (if applicable) including a sample of an 
approved informed consent, IP accountability, Source Documents, investigator and staff curricula 
vitae (CVs,) trial documentation, and all trial correspondence. The original signed informed consent 
forms and the final report will be kept in the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of time 
permitted by the hospital, institution or private practice. The Investigator has a responsibility to retain 
essential documents for as long as is required by the Sponsor and applicable regulatory authorities. It 
is the responsibility of the Sponsor to inform the Investigator as to when these documents no longer 
need to be retained. Investigators will be asked to contact the Sponsor prior to the destruction of any 
data or removal to another site if this occurs prior to the Sponsor notification that the documentation 
is no longer required. Any transfer of ownership of the data or of documents will be documented in 
writing. The new owner will assume responsibility for data retention and archiving. 


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Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials and 
intends to publish the results of this trial. All publications resulting from the clinical trial must be in a 
form that does not reveal technical information that the Sponsor considers confidential or proprietary.  
A copy of any abstract, presentation or manuscript proposed for publication must be submitted to the 
Sponsor for review at least 30 days before its submission for any meeting or journal. In addition, if 
deemed necessary by the Sponsor for protection of proprietary information prior to patent filing, the 
Investigator agrees to a further delay of 60 days before any presentation or publication is submitted. 
The Sponsor reserves the right to include the report of this trial in any regulatory documentation or 
submission or in any informational materials prepared for the medical profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of the 
following criteria: Investigator must participate in the review of and content of the protocol; review 
and comment on the study results; participate in the writing, reviewing and commenting of the 
manuscript; and approve the final manuscript for submission. 
 


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CONFIDENTIAL 
13 SPONSOR RESPONSIBILITIES 
13.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on GCP (CPMP/ICH/135/95, Jan.97) and 
US FDA Regulations. It is the Sponsor's responsibility to obtain appropriate regulatory approval to 
perform the trial (if applicable). The Sponsor should notify promptly all concerned investigator(s), 
IRB(s) and the Regulatory Authority of findings that could adversely affect the health of the patients/ 
subjects, impact on the conduct of the trial or alter the Regulatory Authority’s authorization to continue 
the trial. If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to 
the subjects the Sponsor will notify the relevant regulatory authority and relevant IRB of the new 
events, the measures taken and the plan for further action as soon as possible.  This will be by telephone 
in the first instance followed by a written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  If 
the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be conducted 
within 15 days of the decision to terminate the trial.  The Sponsor will report in an expeditious manner 
all SUSARs to the relevant regulatory authority and IRBs.   
13.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result of 
participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site or will 
access the electronic health record (EHR) or conduct remote monitoring visits at regular intervals 
during the trial for monitoring purposes and to assist the research staff with any queries. CRFs and 
source documentation will be available for review during monitoring visits to the trial site. The 
function of this monitoring is to ensure compliance with the protocol, adherence to regulatory and 
GCP obligations, proper maintenance of records including IP accountability records, correct 
administration of IP including storage conditions and accurate reporting of AEs. On-site visits are not 
required for any monitoring visits for this study.   
Once the data from the case report forms have been entered onto the database, they will be reviewed, 
and the data verified against the subject’s source data. Any discrepancies will be tracked by paper or 
electronically with an electronic audit trail. 
13.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place while 
the trial is being conducted or up to several years later.   


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13.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


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CONFIDENTIAL 
14 REFERENCES  
1. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 171-186. 
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Published 
online March 9, 2020. https://doi.org/10.1016/S0140-6736(20)30566-3 
3. Phelan A, Katz R, and Gostin L. The novel coronavirus originating in Wuhan, China. 
Challenges for global health governance. Jama. 2020;323(8):709-710.   
4. Handel A, Mille J, Yang G, Fung I. If containment is not possible, how do we minimize 
mortality for COVID-19 and other emerging disease outbreaks. March 13, 2020. 
https://doi.org/10.1101/2020.03.13.20034892. 
5. Brequinar Investigator’s Brochure 
6. Chen S, Ding S, Yin Y, Xu L, Li P, Peppelenbosch MP, et al. Suppression of pyrimidine 
biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral 
Res. 2019 Jul;167:35–44.  
7. Mei-Jiao G, Shi-Fang L, Yan-Yan C, Jun-Jun S, Yue-Feng S, Ting-Ting R, et al. Antiviral 
effects of selected IMPDH and DHODH inhibitors against foot and mouth disease virus. 
Biomed Pharmacother. 2019 Oct;118:109305.  
8. Wang QY, Bushell S, Qing M, Xu HY, Bonavia A, Nunes S, et al. Inhibition of Dengue 
Virus through Suppression of Host Pyrimidine Biosynthesis. 2011 Jun 9;85(13):6548–56.  
9. Luthra P, Naidoo J, Pietzsch CA, De S, Khadka S, Anantpadma M, et al. Inhibiting 
pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside 
pools and activation of innate immune responses. Antiviral Res. 2018 Oct;158:288–302.  
10. Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, et al. Novel Antiviral Activities 
of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine. Viruses. 2019 Oct 
18;11(10).  
11. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang, Y, et al. Novel and potent inhibitors 
targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-
spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. 
12. Sah R, Rodriguez-Morales AJ, Jha R, Chu DKW, Gu H, Peiris M, et al. Complete Genome 
Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Isolated in Nepal. Microbiol 
Resour Announc. 2020 Mar 12;9(11). 
13. Liu Q, Gupta A, Okesli-Armlovich A, Qiao W, Fischer C, Smith M, et al. Enhancing the 
Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with 
Modulators of Pyrimidine Metabolism. bioRxiv. 2020 Jan 1;2020.03.24.992230. 
14. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
15. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
16. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
18. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
20. FDA Guidance “COVID-19: Developing Drugs and Biological Products for the Treatment or 
Prevention (https://www.fda.gov/media/137926/download) 
 


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CONFIDENTIAL 
15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
 
Procedures 
Screen 
(days  
-14 to -1) 
HH+TMf 
D1 
HH+
TM 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6,
7 
(± 8 
hrs) 
TC 
D8 
(± 1 
day) 
HH+
TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 
day) 
HH+
TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 days) 
HH+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
D5 
Only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, and SpO2. Subject will be provided with a thermometer and pulse 
oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health nurse. Vital signs 
parameters will be observed and recorded by study staff via telemedicine or during a visit by the home health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms (vomiting, 
diarrhea), anosmia, dysgeusia, other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. 
d RT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-2 result. 
Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. 
Viral load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or 
similar. The home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS 
for analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no 
additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home 
visit. Arrangements for shipping viral load samples will be made by the study team. 
fHH = Home Health in-person visit; TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
 
 
 


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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-02 
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.  
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all of 
its provisions.  It is further agreed that the details of this trial and all information provided to me by 
Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be revealed for 
any reason without written authorization from Clear Creek Bio, Inc. except to those who are to 
participate in the conduct of the trial. 
I agree that all data, the case report forms, and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that Clear 
Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as for 
submission to government regulatory agencies, required internal reports, and presentations without 
violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in accordance 
with current Good Clinical Practice Guidelines, to all data generated by this trial and the source 
documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: ____________________________________ 
 
Signature: ____________________________________________ Date: __________________ 
 
 
 


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15.3 Appendix C: WHO Ordinal Scale 
 
Patient State 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized: moderate disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized: severe disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Dead 
10 
 
WHO clinical progression scale 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
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CONFIDENTIAL 
STUDY PROTOCOL 
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 No: CCB-CRISIS-02 
Version: 4.0 
Version Date:  01 October 2020 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 149291 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein may 
be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in accordance with 
the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration of Helsinki (1964, 
1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations and locally applicable 
regulations. 


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TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.1.1 Coronavirus Biology .................................................................................................... 16 
3.2 Host Nucleotide Synthesis ......................................................................................... 16 
3.3 Dihydroorotate dehydrogenase (DHODH) ................................................................ 17 
3.4 Brequinar .................................................................................................................... 17 
3.5 Rationale for the Planned Trial .................................................................................. 18 
3.5.1 Brequinar Dose Selection ............................................................................................. 19 
3.5.2 Risk/Benefit of Brequinar ............................................................................................ 19 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 19 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 20 
3.7.1 CYP Interactions .......................................................................................................... 20 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 20 
4 TRIAL OBJECTIVES ........................................................................................................ 21 
4.1 Primary Objective ...................................................................................................... 21 
4.2 Secondary Objectives ................................................................................................. 21 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 21 
5 TRIAL DESIGN ................................................................................................................. 22 
6 TRIAL ENDPOINTS.......................................................................................................... 23 
6.1 Primary Endpoint ....................................................................................................... 23 
6.2 Secondary Endpoints .................................................................................................. 23 
6.3 Exploratory Endpoints................................................................................................ 23 
7 TRIAL POPULATION ....................................................................................................... 24 
7.1 Number of Subjects .................................................................................................... 24 
7.2 Inclusion criteria ......................................................................................................... 24 
7.3 Exclusion Criteria ....................................................................................................... 24 
8 STUDY TREATMENTS .................................................................................................... 26 


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8.1 Description of Study Medications .............................................................................. 26 
8.1.1 Brequinar ...................................................................................................................... 26 
8.2 Treatment Administration .......................................................................................... 26 
8.2.1 Safety/Tolerability ........................................................................................................ 26 
8.3 Study Discontinuation ................................................................................................ 27 
8.4 Stopping Criteria ........................................................................................................ 27 
8.4.1 Individual Stopping Criteria ......................................................................................... 27 
8.4.2 Study-Level Stopping Criteria...................................................................................... 27 
8.5 Concomitant Medication/Treatment .......................................................................... 27 
8.6 Treatment Compliance ............................................................................................... 27 
8.7 Storage, Stability, Labeling and Packaging ............................................................... 28 
8.7.1 Storage and Stability .................................................................................................... 28 
8.7.2 Labeling and Packaging ............................................................................................... 28 
8.7.3 Blinding and Randomization ........................................................................................ 28 
8.7.4 Unblinding/Expectedness ............................................................................................. 28 
8.7.5 Study Drug Accountability ........................................................................................... 28 
8.8 Prohibited Medications .............................................................................................. 29 
8.9 Study Adjustments Due to COVID-19....................................................................... 29 
9 CONDUCT OF THE TRIAL.............................................................................................. 30 
9.1 Ethical and Regulatory Considerations ...................................................................... 30 
9.2 Informed Consent ....................................................................................................... 30 
9.3 Institutional Review Board......................................................................................... 31 
9.4 Schedule of Events ..................................................................................................... 31 
9.5 Study Conduct ............................................................................................................ 32 
9.5.1 Unscheduled Visits ....................................................................................................... 33 
9.6 Compliance with Study Procedures ........................................................................... 33 
9.7 Early Withdrawal from the Study .............................................................................. 33 
9.8 Early Termination of the Study .................................................................................. 33 
9.9 Non-Childbearing Potential........................................................................................ 34 
10 ADVERSE EVENT REPORTING..................................................................................... 35 


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10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 36 
10.2 Infection Follow Up ................................................................................................... 36 
10.3 Classification of Causality ......................................................................................... 36 
10.4 Classification of Severity ........................................................................................... 37 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 37 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 38 
10.7 Pregnancies................................................................................................................. 39 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 39 
10.9 Data Monitoring Committee ...................................................................................... 40 
10.9.1 
DMC Safety Review Schedule ............................................................................... 41 
11 STATISTICAL CONSIDERATIONS................................................................................ 42 
11.1 Study Populations for Analysis .................................................................................. 42 
11.2 Safety Analyses .......................................................................................................... 42 
11.3 Efficacy Analyses ....................................................................................................... 42 
11.4 Sample Size Considerations ....................................................................................... 42 
11.5 Randomization ........................................................................................................... 42 
11.6 Pooling of Study Centers............................................................................................ 43 
11.7 Interim Analysis ......................................................................................................... 43 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 44 
12.1 Investigator’s Performance ........................................................................................ 44 
12.2 Confidentiality ............................................................................................................ 44 
12.3 Source Documentation ............................................................................................... 44 
12.4 Data Collection ........................................................................................................... 45 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 45 
12.6 Non-Protocol Research .............................................................................................. 46 
12.7 Publication .................................................................................................................. 46 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 47 
13.1 General ....................................................................................................................... 47 
13.2 Indemnity ................................................................................................................... 47 
13.3 Data Monitoring ......................................................................................................... 47 


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13.4 Audit ........................................................................................................................... 47 
13.5 Confidentiality ............................................................................................................ 48 
13.6 Finance ....................................................................................................................... 48 
14 REFERENCES ................................................................................................................... 49 
15 APPENDICES .................................................................................................................... 50 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events .................................................. 50 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 51 
15.3 Appendix C: WHO Ordinal Scale .............................................................................. 52 
 
 
 
 


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LIST OF FIGURES 
Figure 3-1. 
DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine synthesis; 
it is completely essential for the generation of UMP. ................................................. 17 
 
 
  


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CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AML 
Acute myeloid leukemia 
ARDS 
Acute respiratory disease syndrome 
AST 
Aspartate amino transferase 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus-19 infection 
CRP 
c-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Curricula vitae 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DHODHi 
Dihydroorotate dehydrogenase inhibitor 
DMC 
Data Safety Monitoring Board 
ECMO 
Extra corporeal membrane oxygenation 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
EUA 
Emergency Use Authorization 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IMP 
Inosine-5’ phosphate 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEWS2 
National Early Warning System (NEWS) 2 Score 
RNA 
Ribonucleic Acid 
RdRp 
RNA-dependent RNA polymerase 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
SARS Coronavirus 2 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
SpO2 
Peripheral capillary oxygen saturation 


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Abbreviation 
Definition 
UMP 
Uridine 5’-monophosphatase 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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CONFIDENTIAL 
2 
SYNOPSIS  
CCB-CRISIS-02 SYNOPSIS  
IND 
149291 
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  
Protocol Number 
CCB-CRISIS-02 
Rationale 
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.  
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) + 5 days 
of brequinar 100 mg or SOC + 5 days of placebo.  
Investigational product will be supplied as either brequinar 100 mg oral capsules 
or placebo capsules. The subjects are to self-administer one capsule on Study Days 
1 – 5.  
Treatment assignment will be randomized, double-blind. 
Primary 
Objectives 
● To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load 
for brequinar-treated subjects compared to placebo-treated subjects through 
Day 29. 
Secondary 
Objectives 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-
19 subjects as measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  


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● To reduce the percentage of subjects requiring hospital admission as an in-
patient for > 24 hours for brequinar subjects compared to subjects who received 
placebo; 
● To reduce all-cause mortality through Day 29 for brequinar subjects compared 
to subjects who received placebo. 
Exploratory 
Objectives 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in 
the WHO Ordinal Scale score measured for the subset of subjects with baseline 
WHO Ordinal Scale of 2 for brequinar subjects compared to subjects who 
received placebo.  
Design 
This will be a phase 2 randomized, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive SOC per relevant guidelines 
for treatment of out-patients with COVID-19 infection. In addition to SOC, 
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 procedures are presented in detail in the Schedule of Events. Study visits 
(virtual or in person) will take place at Screening and on Study Days 1 - 8, 12, 15, 
22, and 29. 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 telephone, 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 with the site via 
telemedicine on Days 1, 4, 8, 12, 15, 22, and 29. The site will also have a telephone 
call with the subject on Study Days 2, 3, 5, 6, and 7 for changes in concomitant 
medications and assessment of adverse events, especially those that may indicate 
thrombocytopenia and mucositis. A home health nurse will visit the subject at 
Screening and on study Days 1, 8, 15, and 29. Telemedicine only visits will be 
conducted by site staff on study Days 4, 12, and 22. 
Sample Size: 
Approximately 100 subjects will be randomized to 5 days of either SOC + 
brequinar 100 mg or SOC + placebo in a 1:1 ratio (approximately 50 subjects 
assigned to brequinar 100 mg and 50 subjects to placebo).  
Number of Sites: 
Approximately 15 
Study Period: 
An enrollment period of 3 months is expected. 


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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 within 14 days of first dose. 
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.  
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 


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8. AST and/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 first dose. 
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).  
Treatment 
All subjects will receive standard of care (SOC) including symptomatic care. 
Subjects will be randomly assigned to SOC + brequinar 100 mg daily x 5 or SOC 
+ placebo daily x 5. Study encounters will be conducted remotely whenever 
possible. 
DMC 
A Data Monitoring Committee (DMC) will meet periodically to review the safety 
and scientific conduct of the study. At a minimum, the DMC is to review adverse 
events and safety laboratory assessments after the first 20 subjects complete Day 
8, and again after the first 40 subjects complete Day 8.  
Procedures 
Study procedures are outlined in the Schedule of Events. 
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of first dose through Day 29. After 
Day 29, collect/record only Serious Adverse Events (SAEs) or those judged by the 
Investigator or designated person to be related to study drug. Treatment-emergent 
adverse events will be those with an onset after the date and time of first treatment. 
Subjects who develop Grade 3 or 4 toxicities or SAEs are to be re-evaluated every 
2 days, as feasible, until the toxicity returns to Grade ≤ 2 severity. 
During assessment for adverse events, investigators and site staff are to elicit from 
the subject any signs or symptoms of mucositis or thrombocytopenia, e.g.: 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 


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• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Stopping Criteria 
Individual Criteria:  
• Participants who develop a Grade 3 toxicity that is assessed by the 
investigator to be related to the study drug are to be permanently 
discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to 
study drug, are to be permanently discontinued from study treatment. 
Study-Level Stopping Criteria: 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse 
event or laboratory abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or 
laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or 
laboratory abnormality.  
All adverse events will be reviewed by the DMC during their reviews. Following 
assessment by the Data Monitoring Committee (DMC), the DMC will determine 
whether to stop the study, amend the protocol, or continue the study per protocol.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking 
the database. All analyses of safety and efficacy for this study will be descriptive 
in nature and presented by group. Subject demographics and baseline 
characteristics will be summarized. Subject data listings will also be provided.  
Summaries for quantitative variables will include the mean, median, quartiles, 
standard error, minimum, and maximum. For qualitative variables, the summaries 
will include the number and percentage of subjects for each outcome, and the 95% 
CI, when appropriate.  Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.4 or 
higher). Safety and tolerability will be assessed in terms of AEs, SAEs, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures 
will be summarized using appropriate descriptive statistics. 


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CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
Procedures 
Screen 
(days 
-14 to -1) 
HH+TMf 
D1 
HH
+ 
TM 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6, 
7 
(± 8 
hrs) 
TC 
D8 
(± 1 
day) 
HH+
TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 
day) 
HH+
TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 days) 
HH+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
D5 
only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, SpO2. Subject will be provided with a thermometer and pulse 
oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health nurse. Vital signs 
parameters will be observed and recorded by study staff via telemedicine or during a visit by the home health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms (vomiting, 
diarrhea), anosmia, dysgeusia, other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. 
dRT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-2 result. 
Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. 
Viral load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or 
similar. The home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS 
for analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no 
additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home 
visit. Arrangements for shipping viral load samples will be made by the study team. 
fHH = Home Health in-person visit; TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 


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CONFIDENTIAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
MEDICAL MONITOR 
Name:  
Norberto Soto, MD 
Title: 
Senior Medical Director 
Telephone No.: 
(609) 212-7892 
E-mail: 
Norberto.Soto@Covance.com 
 


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3 
INTRODUCTION 
3.1 
Coronavirus-19 (COVID-19) 
Beginning in December 2019, Chinese scientists isolated a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) from patients with virus-infected pneumonia which was later 
designated as coronavirus disease 2019 (COVID-19) by the World Health Organisation (WHO) (Zhou 
et al., 2020 [2]; Phelan et al., 2020 [3]).  
Approximately 14% of those affected with this virus will develop severe disease requiring 
hospitalization and oxygen support; 5% will require admission to the intensive care unit (Handel et 
al., 2020 [4]). Severe cases may be complicated by acute respiratory disease syndrome (ARDS), sepsis 
and septic shock, and multi-organ failure, including acute kidney injury and cardiac injury. Risk 
factors for death include older age and co-morbid disease such as hypertension and diabetes (Zhou, et 
al., 2020 [2]). This means that most patients will be treated as out-patients. Reducing viral load in this 
environment is critically important for both the subjects themselves by preventing worsening of 
symptoms and possibly avoiding hospitalization, but also to reduce the transmission of the disease to 
others in the patients’ households and their communities. 
3.1.1 Coronavirus Biology 
Coronaviruses, like other RNA-based viruses, do not have the machinery to synthesize their own 
nucleotides and thus depend upon the host intracellular pool of nucleotides for viral replication. In 
essence, viruses steal the host RNA building blocks, and without these building blocks they are unable 
to replicate. The SARS-CoV-2 is a single-stranded (positive sense) RNA virus with a genome that is 
29,811 nucleotides long, quite a lot larger than other RNA-based viruses (e.g. the hepatitis C genome 
comprises only 9600 nucleotides). The nucleotide composition is broken down as: 29.9% adenosines, 
18.4% cytosines, 19.6% guanines, and 32.1% uridines (Sah et al., 2020 [12]). 
3.2 
 Host Nucleotide Synthesis 
Host de novo pyrimidine synthesis generates uridine monophosphate (UMP) as the building block for 
all pyrimidine ribonucleotides and deoxyribonucleotides (Error! Reference source not found.). 
There exists no salvage pathway for the synthesis of UMP, the fundamental building block of 
pyrimidines. Inhibition of enzymatic steps upstream of UMP (Figure 3-1) leads to a rapid and profound 
depletion of intracellular pyrimidines.  


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Figure 3-1. 
DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine 
synthesis; it is completely essential for the generation of UMP.   
3.3 
 Dihydroorotate dehydrogenase (DHODH) 
The enzyme dihydroorotate dehydrogenase (DHODH) catalyzes the 4th step of de novo pyrimidine 
synthesis and inhibition of DHODH completely halts all pyrimidine production. As shown in Figure 
3-1, DHODH is located on the inner mitochondrial membrane and transfers electrons between DHO 
and complex III of the electron-transport chain via the reduction of its ubiquinone (coenzyme Q10) 
cofactor.  
DHODH is a clear therapeutic target for the inhibition of host pyrimidine synthesis. The chemical 
inhibition of DHODH in vitro or in vivo leads to the rapid depletion of UMP and subsequent depletion 
of downstream products thymine and cytosine. This forces a cell to rely on the salvage of extracellular 
pyrimidine nucleotides and this extracellular salvage is not capable of maintaining the cell’s normal 
nucleotide pool (Sykes et al., 2016) [1]).  
  
3.4 
 Brequinar 
Brequinar is an orally available and potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity against 
experimental tumors and because its water solubility made it relatively straightforward to formulate. 
In an indication such as treating SARS-CoV-2 infection, brequinar will act as a host-targeting antiviral. 
It is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH), the enzyme 


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that catalyzes the fourth step in pyrimidine synthesis, namely the conversion of dihydroorotate (DHO) 
to orotate. DHODH inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby 
leading to a depletion of a cell’s pool of uridine, cytidine and thymidine ribonucleotides and 
deoxyribonucleotides.  
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in human 
intestinal Caco-2 cells as well as in human primary intestinal organoids (Chen et al., 2019 [6]). 
Treatment with teriflunomide, another DHODHi, has been effective in vitro and in vivo in a murine 
model of foot and mouth disease virus (Mei-Jian et al., 2019 [7]). DHODH inhibition (DHODHi) also 
inhibited the growth of dengue virus in vitro (Wang et al., 2011 [8]). DHODHi also showed antiviral 
effects against RNA viruses including influenza A, Zika, Ebola and coronavirus SARS-CoV-2 (Xiong 
et al., 2020 [11]). Brequinar has also been shown to inhibit the replication of Ebola virus, vesicular 
stomatitis virus and Zika virus in vitro (Luthra et al., 2018 [9]). Brequinar inhibits the replication of 
human immunodeficiency virus (HIV) in vitro (Andersen et al., 2019 [10]). When considering 
brequinar as an antiviral for treatment of SARS-CoV-2, oral brequinar is highly bioavailable (>95%) 
and has good penetration of lung tissue with an average tissue:blood ratio of 0.5 following a single 
dose of brequinar in the rat. It is therefore expected to achieve a similar period of DHODH inhibition 
in lung tissue (Brequinar IB [5]). 
3.5 
 Rationale for the Planned Trial 
DHODH inhibition has been extensively studied as a potential therapeutic target in the treatment of 
RNA-based viruses. The inhibition of DHODH is effective in inhibiting viral replication in pre-clinical 
models involving many RNA-based viruses with nanomolar potency and a high selectivity index (see 
the Brequinar IB [5], Section 5). In these pre-clinical models, the benefit of DHODH inhibition can 
be reversed by the supplementation of exogenous nucleotides, confirming that the on-target effect of 
host pyrimidine depletion is key to the anti-viral activity.  
The CCB-CRISIS-02 trial will study standard of care (SOC) with 5 days of brequinar (DHODH 
inhibition) compared to SOC with 5 days of placebo treatment. Clear Creek Bio hypothesizes that a 
defined 5-day course of brequinar will inhibit the enzyme DHODH to a degree sufficient to result in 
the transient depletion of host pyrimidine nucleotides, thereby inhibiting viral replication. A recent 
publication demonstrated that inhibitors of DHODH could potentiate the activity of inhibitors of RNA-
dependent RNA polymerase (RdRp) in the treatment of dengue virus, another single-stranded RNA 
virus similar to SARS-CoV-2 (Liu et al., 2020 [13]). This inhibition of viral replication may restore 
the balance in favor of the host immune system for the clearance of SARS-CoV-2. 
Marketed DHODHi medications are available, including leflunomide or teriflunomide, however these 
are very weak inhibitors of DHODH with cellular potency ~500 times lower than brequinar. These 
low potency inhibitors of DHODH are not expected to have the ability to acutely lower the pool of 
intracellular pyrimidines to the degree that is required for decreasing the viral load associated with 
SARS-CoV-2 infection, making brequinar the better choice for acute SARS-CoV-2 infection.  
The CRISIS2 study is a proof-of-concept study in patients with SARS-Cov-2 infection and will serve 
as a basis for future studies to determine the safety and effectiveness of brequinar in COVID-19. 


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3.5.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with 5 days of consecutive daily 
dosing suggest that 5 days of daily doses of 100 mg p.o. will be safe and well tolerated. A dose of 
brequinar 100 mg achieves plasma concentrations of approximately 1 uM (0.4 ug/ml) that should result 
in sufficient suppression of nucleotide synthesis. When given over 5 days, these plasma concentrations 
are achieved on a daily basis without accumulation, also assuring the safety of this regimen (see 
Brequinar IB [5]).  
3.5.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive safety and pharmacokinetic database exists with 
more than 1,000 patients treated with brequinar. Cancer patients (N = 806) have been exposed to this 
compound for treatment of a variety of solid tumors at various treatment regimens, doses, and routes 
including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 
weeks, and daily times 21 days for multiple courses. Lower doses than used in the cancer studies have 
also been utilized for patients with psoriasis and organ transplant. The maximum intravenous dose 
given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. 
There has been limited testing of DHODHi to date in the clinic for infection with SARS-CoV-2. 
DHODHi therapy at relatively high doses in the context of trials for patients with cancer has the 
expected safety side-effects of mucositis and bone marrow suppression. Importantly, however, the 
prior clinical experience in 39 subjects who received daily brequinar for 5 consecutive days at or lower 
than 100 mg/day show no cases of mucositis and only 1 (2.6%) episode of mild thrombocytopenia. 
Based on these data the 100 mg per day dose proposed for administration in this study should be within 
a safe and tolerable range as well as demonstrating the predicted antiviral effect.  
The potential benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 5-day 
period of brequinar dosing will suppress host de novo pyrimidine synthesis for this period thus 
decreasing viral load. Inhibition of DHODH is expected to reduce the ability of the virus to replicate 
and it is for this reason that brequinar will be administered to patients with COVID-19 in this study.
 
 
3.6 
 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of high-dose brequinar in patients with 
refractory solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis 
have been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of brequinar administration. 
However, these effects were self-limiting, transient, required treatment in few cases, and resolved 
following discontinuation of dosing. These adverse effects have been associated with higher doses of 
brequinar given via the intravenous route and for longer durations than the 100 mg dose and 5-day 
regimen proposed for this study.  
In addition to studying a higher risk population with symptomatic COVID-19, a comprehensive safety 
monitoring plan will be utilized in this study to assess the ongoing safety and well-being of participants 
(see Section 10.8).  


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3.7 
 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in severely ill cancer patients including antibiotics, antifungals and other critical care 
medications. No formal interaction studies have been conducted for these medications, however, there 
have not been any reports of interactions with any medications during the clinical trials with more than 
800 cancer patients.  
3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with medications 
commonly used in treating hematologic malignancies. The nonclinical studies performed to date have 
demonstrated there is no first-pass metabolism and there have been no apparent hepatotoxic effects in 
the clinical studies. Brequinar itself does not appear to be a substrate for metabolism by cytochrome 
P450 enzymes when tested under a variety of conditions. (See Brequinar IB [5]; nonclinical data on 
file with Clear Creek).  
3.8 
Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated by highly experienced clinicians familiar with the treatment of viral 
infections and their complications.  
 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load for brequinar-treated 
subjects compared to placebo-treated subjects through Day 29. 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-19 subjects as 
measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with brequinar compared 
to subjects who received placebo;  
● To reduce the percentage of subjects requiring hospital admission as an inpatient for >24 hours for 
brequinar subjects compared to subjects who received placebo; 
• To reduce all-cause mortality through Day 29 for brequinar subjects compared to subjects who 
received placebo. 
4.3 
EXPLORATORY OBJECTIVES 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical symptoms and pre-
existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in the WHO Ordinal 
Scale score for the subset of subjects with baseline WHO Ordinal Scale of 2 for brequinar subjects 
compared to subjects who received placebo. 


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5 
TRIAL DESIGN 
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 per (SOC) 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 procedures 
are presented in detail in the Schedule of Events (Appendix 15.1). Study visits (virtual or in person) 
will take place at Screening and on Study Days 1 - 8, 12, 15, 22, and 29. 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 telephone, 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 with the site via telemedicine on Days 1, 4, 8, 12, 15, 22, and 29. The 
site will also have a telephone call with the subject on Study Days 2, 3, 5, 6, and 7 for changes in 
concomitant medications and assessment of adverse events, especially those that may indicate 
thrombocytopenia (see Section 10.8) and mucositis. A home health nurse will visit the subject at 
Screening and on study Days 1, 8, 15, and 29. Telemedicine only visits will be conducted by site staff 
on study Days 4, 12, and 22. 


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6 
TRIAL ENDPOINTS 
6.1 
Primary Endpoint 
Quantitative SARS-CoV-2 viral load through Day 29. 
6.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
Through Day 29: 
● Rates of AEs and SAEs including laboratory assessments; 
● Duration of viral shedding;  
• Percentage of subjects requiring admission as an inpatient for >24 hours. 
• All-cause mortality. 
6.3 
Exploratory Endpoints 
Through Day 29: 
● Time to viral clearance (two consecutive negative tests);  
● Time to resolution of new onset COVID-19-related clinical symptoms and pre-existing non-
COVID-19 symptoms returned to baseline; 
● Time to clinical improvement measured by a favorable shift in WHO Ordinal Scale score for the 
subset of subjects with baseline WHO Ordinal Scale of 2. 
 


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7 
TRIAL POPULATION 
7.1 
Number of Subjects 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 100 subjects have completed the study. Subjects will be randomized to either 
standard of care plus brequinar 100 mg or standard of care plus placebo in a 1:1 ratio (approximately 
50 subjects assigned to standard of care plus brequinar 100 mg and approximately 50 subjects assigned 
to standard of care plus placebo).  
7.2 
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 within 14 days 
of first dose. 
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. 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. 
8. Able to swallow capsules. 
7.3 
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 


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5. Hemoglobin < 10 gm/dL  
6. Absolute neutrophil count < 1500 cells/mm3 
7. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
8. AST and/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 first dose. 
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). 
 


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8 
STUDY TREATMENTS 
8.1 
Description of Study Medications 
8.1.1 Brequinar 
Brequinar and placebo will be supplied as 100 mg capsules. Dosing will be a single 5-day course of 
brequinar 100 mg capsules or placebo 100 mg capsules once daily for 5 doses.  
8.2 
Treatment Administration 
This will be a phase 2 randomized, placebo-controlled, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive standard of care (SOC) for COVID-19 infection. 
Subjects will be randomly assigned in a 1:1 ratio to standard of care plus brequinar or standard of care 
plus placebo. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit. The NIH Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) 
will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
criteria.  
Adverse events (AEs) commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure (IB) and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 cancer subjects 
treated once-weekly (DuP 785-012, see Brequinar IB [5]), the deaths of three patients were attributed 
to study drug toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades 
(Grades 3 to 4) which typically led to discontinuation in this study included hematologic toxicities 
(anemia, thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, 
vomiting, stomatitis, others including gastric hemorrhage) and mucositis.  
In three oncology studies with five consecutive days of intravenous (IV) brequinar dosing in 168 
subjects (Study 785-001 [14], 785-003 [15], and 785-005 [16]) there were no toxic deaths. For 
subjects from these three studies who were treated with a daily dose of 100 mg or below  (as will be 
dosed in CCB-CRISIS-02), AEs through 21 days showed that 2 of 39 subjects (5.1%) had a severe 
(Grades 3 or 4) AE related to study drug (1 subject each with hyperbilirubinemia and 
hyperglycemia), and no subjects discontinued from the study due to a study drug-related AE. The 
few study drug related AEs through 21 days at or below the 100 mg dose from these three studies 
included 2 subjects each with nausea, vomiting, and creatinine elevated and one subject each with 
thrombocytopenia and diarrhea. When only studies with oral dosing were considered at this dose 
level (Studies 785-022 [17], 785-031 [18] , and 785-034 [19]), the study drug related AEs through 
21 days (each observed in one subject only) included diarrhea, headache, nausea, pruritus, 
abdominal pain, anorexia, chest pain, dry mouth, fatigue, keratosis, stomatitis, and vomiting. See 
brequinar IB [5]. 


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In most instances, brequinar-related toxicities were transient, clinically manageable, and reversible 
upon discontinuation of brequinar treatment. Any of these events reported with brequinar use can be 
serious in nature and may result in death.  
A 5-day course of oral brequinar administered once daily at a low level relative to those administered 
in the cancer studies is expected to be safe and well tolerated in the COVID-19 population. 
8.3 
Study Discontinuation 
Subjects will remain in the study through at least Study Day 29 (or longer if needed to follow up study 
drug-related adverse events). Participants may discontinue from the study by withdrawing consent at 
any time or for any reason as presented in Section 9.7. 
8.4 
Stopping Criteria 
8.4.1 Individual Stopping Criteria 
• Participants who develop a Grade 3 toxicity that is assessed by the investigator to be related to 
the study drug are to be permanently discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be 
permanently discontinued from study treatment. 
• Subjects who develop Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, 
as feasible, until the toxicity returns to ≤ Grade 2 severity. 
8.4.2 Study-Level Stopping Criteria 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse event or laboratory 
abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC, see Section 10.9), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per protocol. 
8.5 
Concomitant Medication/Treatment 
Record the name, dose, start/stop date, indication for use, route, and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications taken 
during the study are to be recorded. Prohibited medications are identified in Section 8.8.  
8.6 
Treatment Compliance 
Compliance will be assessed by reviewing the subject’s medication diary and study records as 
appropriate. 


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8.7 
Storage, Stability, Labeling and Packaging 
8.7.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.7.2 Labeling and Packaging  
The bulk drug and unit-dose containers will be labeled in accordance with national laws and 
regulations. 
8.7.3 Blinding and Randomization 
The trial will be conducted in double blinded, randomized manner with random assignment to standard 
of care plus brequinar or standard of care plus placebo. The brequinar and placebo capsules will be 
provided to each participating institution in pre-numbered bottles intended for individual subjects to 
be dispensed by the institution’s pharmacist or designated person. Randomization assignments will be 
provided by an independent statistician to the drug packaging company. The pharmacist/designated 
person will dispense the next number in sequence to the next patient who qualifies for the study at an 
individual site. 
8.7.4 Unblinding/Expectedness 
Contact the Covance Medical Monitor if it is necessary to break the blind for this blinded study due 
to an adverse event (AE). Each site will be provided with a sealed envelope containing individual 
sealed envelopes for subject numbers assigned to that site. Each individual subject number sealed 
envelope will have the treatment (brequinar or placebo) randomly assigned to that subject number. Do 
not open the outer envelope or the individual sealed envelope unless it has been agreed with the 
Medical Monitor and the Sponsor that unblinding is necessary for that particular AE. Unblinding must 
be documented in the study records. Envelope seals are to be checked to ensure they remain intact 
during drug accountability monitoring. 
If after a discussion with the Medical Monitor, the investigator or treating clinician believes the AE 
leading to unblinding to be related to the study drug, no further doses of drug should be administered 
to that subject.  
Expectedness will be determined by establishing whether an adverse event is among those identified 
in the protocol and the brequinar IB or are commonly associated with COVID-19 or similar severe 
viral illnesses and their complications.   
8.7.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, administered, and discarded.  It 
must be clear from the records whether the subject received study medication and what subject number 
was assigned to which subject. Adequate drug is to be dispensed for the number of subjects expected 
to be treated at each institution.  


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The pharmacist/staff member responsible for drug accountability is to document the date and time of 
dispensing and for what subject the study drug was intended (i.e., record subject initials and birth date 
or other unique identifier). A pharmacy manual will be provided by the Sponsor.  
At the end of the study any unused study drug will be returned to the Sponsor for destruction or may 
be destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours and 
with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. Records may be electronic or paper and may be accessed remotely for monitoring/drug 
accountability purposes. 
Each subject will be provided with one bottle with five brequinar or five placebo capsules for the five 
days of dosing. 
8.8 
Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide). 
Treatment is prohibited with agents known to cause bone marrow suppression leading to 
thrombocytopenia.  
8.9 
Study Adjustments Due to COVID-19 
Due to the highly contagious nature of COVID-19, multiple adjustments and revised procedures are 
rapidly evolving regarding clinical trial management and study conduct. Reasonable procedures 
implemented by study staff to avoid spreading this disease are acceptable to Clear Creek with written 
permission. Examples include but are not limited to e-consent, telephone consent and study visits 
conducted by telemedicine, telephone or other digital media.  
Background standard of care is to be maintained in both treatment arms. The standard of care is 
expected to change as additional information, such as that from randomized controlled trials, emerges, 
and the Sponsor and the treating clinicians will need to address anticipated off-label use of any other 
drugs, devices, or interventions that might be used to manage COVID-19 (e.g. anticoagulants).  
The Sponsor and treating clinicians are to consider changes in SOC over time, for example, 
overlapping toxicities of brequinar and a SOC treatment expected to be widely used is to be 
considered. The availability of new standard of care treatment may change over time and vary from 
one clinical trial site to another. The Sponsor will discuss these issues with FDA should the need arise. 
 


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9 
CONDUCT OF THE TRIAL 
9.1 
Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) as revised in Tokyo 
(1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland (2000, Note of Clarification 
2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) (2013), and with the International 
Council on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and United States (US) FDA Regulations. 
9.2 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50),  the 
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health 
Emergency (March 2020, Updated April 16, 2020) [20], as well as local and national regulations. 
Information should be given in both oral and written form whenever possible and deemed appropriate 
by the Institutional Review Board (IRB). Subjects and their relatives, if necessary, must be given 
ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, expected 
duration and purpose of the trial, the administration of the Investigational Product (IP), and the hazards 
involved, as well as the potential benefits that may come from treatment with this IP. The trial 
procedures will be explained in lay language and any questions will be answered. The subjects will be 
given an IRB-approved consent form. The subjects will be given appropriate time to consider their 
participation in the trial and have any questions answered prior to signing the consent form. If a subject 
agrees to participate, he/she will sign and date an informed consent form and be provided with a copy 
of the signed consent. All subjects who sign an informed consent form are to be recorded on the 
applicable screening log. If the subject is unable to consent for any reason, a designated family member 
or healthcare power of attorney or other person may consent per institutional policy.  
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the FDA and other relevant regulatory 
authorities. Subjects will be informed that they are free to refuse participation in this clinical 
investigation, and if they should participate, it will be made clear to them that they may withdraw from 
the trial at any time without prejudicing further medical care they may require. The subject will receive 
a copy of the consent form as well as an information sheet about the trial.  
Informed consent must be obtained from every subject prior to any study-specific procedures. 
Standard procedures carried out prior to completing the informed consent process but within the time 
constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
Documentation of consent will be subject to review by the Sponsor; if in writing, a copy will be given 
to the subject and a copy will be filed with the subject’s medical notes. Verbal consents will be 
documented by the study team as appropriate and agreed by the IRB. 
Note that informed consent procedures have been affected by COVID-19, and the study staff may use 
any consent method that has been approved by the IRB (e.g., phone consent, verbal consent with 


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witness, e-consent, etc.) of the local institution. In-person consent, written consent signatures and 
providing hard copies to the subject are examples of procedures that may be foregone under these 
circumstances. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she meets 
the subject selection criteria. 
A sample subject information sheet and consent form are available from Clear Creek.  The final 
version at each institution may differ depending on institutional requirements and standard formats. 
This protocol will not be amended for site specific changes as such changes are to be made to the site’s 
consent when required. 
9.3 
Institutional Review Board  
It is the responsibility of the Investigator to submit the protocol, consent form and information sheet 
to the IRB. An IB will be available for review by the IRB. The protocol and informed consent form 
(ICF) must be approved by the IRB prior to the recruitment of the first subject. The template consent 
form may be revised in accordance with site-specific requirements with Sponsor review and approval. 
A copy of the IRB written approval must be provided to the Sponsor and investigator before the trial 
may start at that institution. Written approval from the IRB is also required for substantial protocol 
amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating to 
the scientific documents in support of the trial.  Amendments are “substantial” when they are likely to 
have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures taken 
as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the trial. On completion of the trial, the Investigator 
will inform the applicable IRB as per local IRB requirements that the trial has ended. If the study is 
terminated for any reason, the investigator will return all clinical supplies and study-related equipment 
supplied by the Sponsor to the Sponsor unless otherwise specified.  
9.4 
Schedule of Events 
Study activities will be conducted or supervised by experienced personnel throughout the study based 
on the Schedule of Events. The subjects may collect the saliva sample for viral load testing and perform 
other study activities such as body temperature, heart rate, respiratory rate, SpO2, and symptom 


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assessments themselves with appropriate training. Equipment will be provided to the subject for study 
purposes including a pulse oximeter with heart rate monitoring capability and a thermometer. 
Telemedicine visits such as phone calls or other remote media are to be utilized as much as possible. 
Subjects may need to come to an out-patient facility or be visited by a home health professional for 
some study assessments. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALK), 
alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
calcium, lactate dehydrogenase (LDH), and C-reactive protein (CRP). Chemistry samples may be 
banked for future analyses. 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and 
platelet count. 
Viral load sampling is to be carried out on Days 1, 4, 8, 12, 15, 22, and 29. The subject is to self- 
collect saliva samples with appropriate training for this analysis. Samples may be banked for future 
analyses. If the subject cannot provide documentation of the previous positive COVID-19 test, the site 
may perform an additional RT-PCR test as part of the Screening visit. The subject must have a 
documented positive result to be eligible for the study. 
Safety laboratory results (chemistry and hematology) are to be reviewed by investigator or designated 
site personnel within 48 hours of receipt of results. 
Hospitalization status after enrollment is to be recorded as not hospitalized or admitted to hospital as 
an in-patient with admission > 24 hours.    
As much of the study as possible will be conducted via telemedicine remote from the site (e.g., consent, 
medical history, concomitant medications may be collected remotely). Subjects will be visited at home 
(or place of residence) by a home health nurse at Screening and on study Days 1, 8, 15, and 29. On 
study Days 4, 12, and 22 the vital signs and saliva collections will be observed via telemedicine by the 
study site staff. Site staff will have a telephone call with subjects on study days 2, 3, 5, 6, and 7 to 
assess changes in concomitant medications and to assess adverse events, especially those that may 
indicate thrombocytopenia, e.g., unusual bruising, epistaxis, gingival bleeding, etc., and mucositis. 
Subjects will be provided with a pulse oximeter and thermometer during the Screening in-home visit, 
as well as being trained on the use of these devices during that visit. Training will also be provided by 
the home health nurse for the saliva collection required for viral load testing. Assessments will be 
recorded by the home nurse during home visits and by the site staff during telemedicine visits. These 
data will be entered in the eCRF by the site staff or as determined by the study team. 
9.5 
Study Conduct 
The study visits are to be conducted as shown in the Schedule of Events, Appendix 15.1. 
Study completion or the reason for study discontinuation will be recorded in the source document and 
the eCRF.  


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9.5.1 Unscheduled Visits 
Unscheduled visits and tests are permitted as needed to assess AEs/SAEs throughout the study. 
Unscheduled visits and tests are also permitted as needed to assess AEs/ SAEs with onset within two 
(2) weeks after the final study visit providing the AE is considered related to study drug 
9.6 
Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely as 
possible.  However, it is recognized in a clinical setting that protocol-specified timings may not occur 
exactly as specified in the protocol, particularly when conducted remotely by the subject. Provided 
that activities are carried out within the identified windows it will not be necessary to file a protocol 
deviation. Remote visits such as a telemedicine visit may be conducted to collect as much information 
as possible remotely. A home visit or return to the clinical site or an out-patient laboratory may be 
arranged for safety labs or other assessments, when required. Telemedicine or other remote technique 
is to be utilized to ensure subject compliance when subject is performing self-collection of study 
assessments.  
9.7 
Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after discussion 
with the other party if it is believed it would be unsafe for the subject to continue in the study.   
Subjects must discontinue study medication if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all scheduled evaluations even for subjects who discontinue study medication prior to 
completing the treatment period unless consent is withdrawn. 
9.8 
Early Termination of the Study 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any reason 
at the Sponsor’s request, the study may be terminated at that site or the entire study terminated after 
discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with the 
reasons for termination of the study. This will be conducted within 15 days of the decision to terminate 
the study.  


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If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
9.9 
Non-Childbearing Potential 
Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian 
tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the 
ovaries. Documentation of surgical procedure or physical examination is required for subjects who 
have had a hysterectomy or tubal ligation. A woman is also presumed to be infertile due to natural 
causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L. 
In the absence of such documentation, a negative serum pregnancy test is required for inclusion into 
the study. 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the medicinal product, whether or not 
considered related to the medicinal product.  
Events that occur prior to first dose will be entered as medical history; events that occur after first dose 
will be entered as adverse events (AEs) on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not judged by the 
Investigator or designated person to be related to study drug. All AEs will be documented in the 
subject's medical record and CRF. For any pre-existing condition or abnormal laboratory finding that 
changes in severity after dosing, this change should be recorded as an AE. New abnormal laboratory 
findings that are clinically significant are considered AEs. Investigators and site staff are to elicit from 
the subject and note any signs or symptoms of mucositis and thrombocytopenia (see Section 10.8). 
Adverse events will be collected from the time of first dose through Day 29. After Day 29, 
collect/record only Serious Adverse Events (SAEs) which are assessed by the Investigator or 
designated person to be related to study drug and have an onset within 14 days of study completion 
(Day 29 or earlier if discontinue prior to Day 29).  AE details are to be documented including start and 
stop date and times, whether continuous or intermittent, severity, any intervention utilized to correct 
the event (e.g., medication, surgery, or other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor by 
the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution or 
until they are considered stable or for at least 30 days after discontinuation of study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, are Grades 3 or 4, or require 
therapy. 
If a death occurs during the SAE reporting period, the cause of death such as pneumonia, ARDS, or 
respiratory failure, is considered as the AE and the death is considered its outcome. Death should be 
considered an outcome, not an event. The event or condition leading to death should be recorded and 
reported as a single medical concept on the AE eCRF. Generally, only one such event should be 
reported. “Fatal” will be recorded as the outcome of this respective event; death due to an outcome of 
an AE will not be recorded as separate event. If the primary cause of death is disease progression, the 
cause of death should be clearly identified as COVID-19. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered as 
the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim text 
to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA). For example, record appendicitis, not appendectomy. 


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The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. The medical history section of the case report form will serve as the source document for baseline 
events.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start date 
of the baseline event. 
2. Adverse events occurring after first dose are to be recorded in the eCRF using the AE form. 
3. Serious adverse events will be reported to the local IRB according to institutional policy. 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) will be used for adverse 
event reporting.   
10.1 Follow Up of Grade 3 or 4 Toxicities 
Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, as feasible, until the toxicity 
returns to Grade ≤ 2 severity. 
10.2 Infection Follow Up 
Any new infection that occurs on study regardless of infecting agent (i.e., viral or non-viral) should be 
captured. Additionally, the site of infection and source of culture (BAL, tracheal aspirate, sputum, 
blood, urine, etc.) should also be recorded. 
10.3 Classification of Causality 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the Investigator. 
10.4 Classification of Severity 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.5 Serious Adverse Event (SAE) Reporting 
The regulatory definition of an SAE is any untoward medical occurrence or effect that at any dose 
fulfills one or more of these criteria: 
• results in death; 
• is life threatening (at the time of the event); 
• requires in-patient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect; 
• or is an event considered medically serious by the Investigator. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the Investigator, 
at immediate risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. IB for an unauthorized investigational product 
or summary of product characteristics for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events which did 
not directly result in the SAE should be detailed in the description section on the SAE form and listed 
separately as AEs if necessary. For fatal SAEs, report the cause of death as an SAE with a fatal 
outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  


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• Routine treatment or monitoring of COVID-19 infection, not associated with any 
deterioration in condition;  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition; 
• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 24 
HOURS) BY EMAIL TO THE SAE REPORTING EMAIL USING THE FORM PROVIDED.  
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF WITHIN 48 
HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address for reporting SAEs can be found below and at the front 
of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted to 
Covance Patient Safety until the event has subsided or, in case of permanent impairment, it stabilizes, 
and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL:  
SAEIntake@covance.com 
Medical Monitor: 
Norberto Soto, MD  
Telephone: 
(609) 212-7892 
Covance Physician/Medical Monitor 
Email: 
Norberto.Soto@Covance.com 
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
Telephone: 
M: (484) 686-0545 
VP, Clinical Operations 
Email: 
bpowers@clearcreekbio.com  
All SAEs will be reported to the IRB periodically, at the end of the study, or per local institutional 
guidelines.   
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the study 
drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and IRB 
by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness will be 
judged by the Covance Physician and site Investigator. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require immediate 
attention and expedited reporting to relevant regulatory authorities. 
The Sponsor will ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 


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IRB(s) within seven (7) calendar days of the date of first report to Covance Patient Safety / Sponsor. 
Follow-up information will be communicated to the relevant Regulatory Authority within an 
additional eight calendar days. 
All other SUSARs will be reported to the Regulatory Authority and to the IRB(s) concerned as soon 
as possible within a maximum of fifteen calendar days of first notification to Covance Patient Safety 
/ Sponsor. 
The Sponsor or designee will also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
requested additional information on an expedited basis.   
10.7 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to Covance Patient Safety (by email to 
SAEIntake@covance.com) and to the IRB by the investigational staff within 1 working day of their 
knowledge of the event. The collection period for a pregnancy occurring in a subject or a subject’s 
partner will begin at the first dose of study drug and will continue through 90 days after the last dose 
of study drug. Monitoring of the subject or partner should continue until the conclusion of the 
pregnancy, if the subject or subject’s partner has consented to this. Monitoring of the baby should 
continue for 3 months after birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or designee 
will discontinue the pregnant subject from the treatment aspects of the study, continue to follow her 
per protocol for safety outcomes only, and advise her to seek prenatal care and counseling from her 
primary care provider. Data on fetal outcome and breast-feeding will be collected for regulatory 
reporting and drug safety evaluation, if the subject has consented to this. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as (S)AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow the 
subject until the end of pregnancy, with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. 
10.8 Safety Monitoring for Hematologic Toxicities 
Myelosuppression is a known effect of DHODH inhibition that is associated with prolonged exposure 
and high doses. To reduce the risk of this effect with brequinar in COVID-19 subjects, the extensive 
brequinar safety database with over 1,000 patients has been evaluated to select a dose level expected 
to be safe and well tolerated with regard to hematologic toxicity. In addition to enhancing safety by 


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selecting a relatively brief 5-day exposure and a low brequinar dose, all subjects in the clinical trial 
will be under the care of highly qualified medical personnel. Clinically significant out-of-range 
laboratory results will be reported as adverse events. 
In addition to real time assessments by the treating clinical team, the Covance Medical Monitor will 
assess the available hematology data on a periodic basis to identify any pathologic trends or safety 
issues. Any apparent increase in the expected rate or severity of hematologic safety events will be 
discussed with the Principal Investigators and the Sponsor. In addition, the Data Monitoring 
Committee (DMC) will assess available hematology data on a periodic basis to independently assess 
any pathologic trends or safety issues. If the rate or severity of hematologic toxicities appears to be 
above the expected rate or the severity appears worse than that expected, the trial enrollment will be 
suspended and no further subjects will be treated while a comprehensive data review is conducted. 
Depending on the outcome of the safety review the study may be stopped, the design adjusted, or the 
study may continue as designed. Individual and Study stopping rules are provided in Section 8.4. 
Safety laboratory results are to be initially assessed in real time by the Principal Investigator or 
designated person. Any study drug-related clinically significant out-of-range laboratories or study 
drug-related adverse events will be followed as needed until resolution or stable. 
The in-clinic assessments and telemedicine/phone call visits will specifically ask about possible 
hematologic toxicity including any evidence of the list below. Subjects will be provided with a list of 
the following events in lay terms and will be instructed to call the research team if any of these events 
occur. 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Any of these symptoms considered clinically significant will be recorded as an adverse event and must 
be followed until resolved or stable. 
10.9 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to provide independent oversight to this 
trial. The primary responsibility of the DMC will be to review the progress and conduct of the trial in 
order to maintain scientific rigor and to ensure the wellbeing of subjects participating in the trial. The 
specific responsibilities of the DMC will be detailed in a separate DMC charter. The DMC will include 
at a minimum at least one statistician and two clinicians who will perform periodic data review to 
assess whether there are clinically significant differences between treatment arms that could affect 
participant safety.  All adverse events will be reviewed by the DMC during their reviews. Following 


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such a review, the DMC Chair will advise the Sponsor that the study be stopped, the design changed, 
or that the study may continue per protocol. 
10.9.1 DMC Safety Review Schedule 
The DMC is to review adverse events and safety laboratory assessments after the first 20 subjects 
complete the Day 8 visit, and again after the first 40 subjects complete the Day 8 visit. 
 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. All 
analyses will be descriptive in nature and presented by group.   
Summaries for quantitative variables will include the mean, median, quartiles, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and 95% confidence interval (CI), when appropriate. Any 
statistical testing will be considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.4 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. Subject 
data listings will also be provided. The following sections will briefly summarize of the planned 
statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 Study Populations for Analysis 
All safety analyses will be based on the ITT population, which is defined as all randomized subjects. 
As will be described in the SAP, efficacy analyses of changes in viral load will be based on the 
population of subjects with detectable viral load at baseline or similar qualification. Sample size may 
be adjusted if an inadequate number of subjects have detectable viral load at baseline. 
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, WHO Assessments, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data listings. The 
incidence of post-first dose (treatment-emergent) adverse events will be tabulated by MedDRA 
preferred term and system organ class, and by severity and relationship to study treatment. All 
laboratory results and study assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will primarily be assessed via viral load changes. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this proof-of-concept study. The sample size of 
approximately 100 subjects planned to be entered in this trial is expected to be adequate to provide 
safety and efficacy information to advise future study design. 
11.5 Randomization 
A randomization scheme will be provided by an independent statistician to the drug packaging 
company to ensure subjects are randomly assigned to SOC + brequinar or SOC + placebo in a 1:1 
ratio.  


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11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 


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12 INVESTIGATOR RESPONSIBILITIES 
12.1 Investigator’s Performance 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement found in Section 15.2 to 
indicate commitment to comply with the contents. 
12.2 Confidentiality 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality will 
be maintained during all audits and inspections of the trial site and documentation. A unique number 
will be assigned to each subject at the start of the trial and this, with the subject’s initials, will be used 
to identify the subject. In some cases, a further step may be taken to assign “fake initials” to the subject, 
per individual site requirements. The subject’s number will be the site number followed by the number 
of this subject at this site and will be used as the unique identifier in the source records and on the 
eCRF, on all trial correspondence and in the trial database. The Investigator will keep a list of 
identification codes or initials used for each subject along with the unique number assigned. 
All information provided to the Investigator relevant to the investigational product (IP), as well as 
information obtained during the course of the trial will be regarded as confidential. The Investigator 
and members of his/her research team agree not to disclose or publish such information in any way to 
any third-party without prior written permission from the Sponsor which will not be unreasonably 
withheld, except as required by law, or as permitted by the Publications section of this protocol, 
Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 Source Documentation 
Investigators are to maintain adequate source documentation of the original study data, for example 
medication records, laboratory reports and pharmacy records as appropriate. The Investigator will 
allow inspections of the trial site and documentation by clinical research and audit personnel from the 
Sponsor, external auditors or representatives of regulatory authorities. The purpose of these 
inspections is to verify and corroborate the data collected on the eCRFs. In order to do this, direct 
access to the subjects' medical or clinic records is necessary. The Investigator will ensure that certain 
information is contained in the medical or clinic written or electronic records of the subject and that 
the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IP being evaluated, 
the trial number assigned to that subject and a statement that consent was obtained; 


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• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each subject 
during the clinical phase of the study. A signed copy should also be filed in the investigator file. 
12.4 Data Collection 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. In 
addition, suitably qualified and trained clinical research personnel of the Sponsor will visit the trial 
site at regular intervals during the trial for monitoring purposes and to assist the research staff with 
any queries. All queries and discrepancies relating to the data collection are to be resolved at the 
completion of the trial. Remote data capture is encouraged whenever possible. 
12.5 Case Report Forms, Investigator’s Site File and Record Retention 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will be 
reviewed against source documentation at each monitoring visit. All CRFs and supporting source 
documentation must be completed and available to the Sponsor in a timely manner. Changes or 
corrections due to data clarification and resolutions will be tracked by paper or electronically with an 
audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed for 
completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the IB, 
the protocol plus any amendments, all correspondence with the IRB including the approval for the 
trial to proceed, Regulatory Authority approval/ notification (if applicable) including a sample of an 
approved informed consent, IP accountability, Source Documents, investigator and staff curricula 
vitae (CVs,) trial documentation, and all trial correspondence. The original signed informed consent 
forms and the final report will be kept in the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of time 
permitted by the hospital, institution or private practice. The Investigator has a responsibility to retain 
essential documents for as long as is required by the Sponsor and applicable regulatory authorities. It 
is the responsibility of the Sponsor to inform the Investigator as to when these documents no longer 
need to be retained. Investigators will be asked to contact the Sponsor prior to the destruction of any 
data or removal to another site if this occurs prior to the Sponsor notification that the documentation 
is no longer required. Any transfer of ownership of the data or of documents will be documented in 
writing. The new owner will assume responsibility for data retention and archiving. 


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Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials and 
intends to publish the results of this trial. All publications resulting from the clinical trial must be in a 
form that does not reveal technical information that the Sponsor considers confidential or proprietary.  
A copy of any abstract, presentation or manuscript proposed for publication must be submitted to the 
Sponsor for review at least 30 days before its submission for any meeting or journal. In addition, if 
deemed necessary by the Sponsor for protection of proprietary information prior to patent filing, the 
Investigator agrees to a further delay of 60 days before any presentation or publication is submitted. 
The Sponsor reserves the right to include the report of this trial in any regulatory documentation or 
submission or in any informational materials prepared for the medical profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of the 
following criteria: Investigator must participate in the review of and content of the protocol; review 
and comment on the study results; participate in the writing, reviewing and commenting of the 
manuscript; and approve the final manuscript for submission. 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 4.0 DATE: 01 OCT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
13 SPONSOR RESPONSIBILITIES 
13.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on GCP (CPMP/ICH/135/95, Jan.97) and 
US FDA Regulations. It is the Sponsor's responsibility to obtain appropriate regulatory approval to 
perform the trial (if applicable). The Sponsor should notify promptly all concerned investigator(s), 
IRB(s) and the Regulatory Authority of findings that could adversely affect the health of the patients/ 
subjects, impact on the conduct of the trial or alter the Regulatory Authority’s authorization to continue 
the trial. If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to 
the subjects the Sponsor will notify the relevant regulatory authority and relevant IRB of the new 
events, the measures taken and the plan for further action as soon as possible.  This will be by telephone 
in the first instance followed by a written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  If 
the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be conducted 
within 15 days of the decision to terminate the trial.  The Sponsor will report in an expeditious manner 
all SUSARs to the relevant regulatory authority and IRBs.   
13.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result of 
participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site or will 
access the electronic health record (EHR) or conduct remote monitoring visits at regular intervals 
during the trial for monitoring purposes and to assist the research staff with any queries. CRFs and 
source documentation will be available for review during monitoring visits to the trial site. The 
function of this monitoring is to ensure compliance with the protocol, adherence to regulatory and 
GCP obligations, proper maintenance of records including IP accountability records, correct 
administration of IP including storage conditions and accurate reporting of AEs. On-site visits are not 
required for any monitoring visits for this study.   
Once the data from the case report forms have been entered onto the database, they will be reviewed, 
and the data verified against the subject’s source data. Any discrepancies will be tracked by paper or 
electronically with an electronic audit trail. 
13.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place while 
the trial is being conducted or up to several years later.   


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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CONFIDENTIAL 
13.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
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PROTOCOL VERSION 4.0 DATE: 01 OCT 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
14 REFERENCES  
1. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 171-186. 
2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality 
of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Published 
online March 9, 2020. https://doi.org/10.1016/S0140-6736(20)30566-3 
3. Phelan A, Katz R, and Gostin L. The novel coronavirus originating in Wuhan, China. 
Challenges for global health governance. Jama. 2020;323(8):709-710.   
4. Handel A, Mille J, Yang G, Fung I. If containment is not possible, how do we minimize 
mortality for COVID-19 and other emerging disease outbreaks. March 13, 2020. 
https://doi.org/10.1101/2020.03.13.20034892. 
5. Brequinar Investigator’s Brochure 
6. Chen S, Ding S, Yin Y, Xu L, Li P, Peppelenbosch MP, et al. Suppression of pyrimidine 
biosynthesis by targeting DHODH enzyme robustly inhibits rotavirus replication. Antiviral 
Res. 2019 Jul;167:35–44.  
7. Mei-Jiao G, Shi-Fang L, Yan-Yan C, Jun-Jun S, Yue-Feng S, Ting-Ting R, et al. Antiviral 
effects of selected IMPDH and DHODH inhibitors against foot and mouth disease virus. 
Biomed Pharmacother. 2019 Oct;118:109305.  
8. Wang QY, Bushell S, Qing M, Xu HY, Bonavia A, Nunes S, et al. Inhibition of Dengue 
Virus through Suppression of Host Pyrimidine Biosynthesis. 2011 Jun 9;85(13):6548–56.  
9. Luthra P, Naidoo J, Pietzsch CA, De S, Khadka S, Anantpadma M, et al. Inhibiting 
pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside 
pools and activation of innate immune responses. Antiviral Res. 2018 Oct;158:288–302.  
10. Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, et al. Novel Antiviral Activities 
of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine. Viruses. 2019 Oct 
18;11(10).  
11. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang, Y, et al. Novel and potent inhibitors 
targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-
spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. 
12. Sah R, Rodriguez-Morales AJ, Jha R, Chu DKW, Gu H, Peiris M, et al. Complete Genome 
Sequence of a 2019 Novel Coronavirus (SARS-CoV-2) Strain Isolated in Nepal. Microbiol 
Resour Announc. 2020 Mar 12;9(11). 
13. Liu Q, Gupta A, Okesli-Armlovich A, Qiao W, Fischer C, Smith M, et al. Enhancing the 
Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with 
Modulators of Pyrimidine Metabolism. bioRxiv. 2020 Jan 1;2020.03.24.992230. 
14. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
15. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
16. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
18. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
20. FDA Guidance “COVID-19: Developing Drugs and Biological Products for the Treatment or 
Prevention (https://www.fda.gov/media/137926/download) 
 


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CONFIDENTIAL 
15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
 
Procedures 
Screen 
(days  
-14 to -1) 
HH+TMf 
D1 
HH+
TM 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6,
7 
(± 8 
hrs) 
TC 
D8 
(± 1 
day) 
HH+
TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 
day) 
HH+
TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 days) 
HH+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
D5 
Only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, and SpO2. Subject will be provided with a thermometer and pulse 
oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health nurse. Vital signs 
parameters will be observed and recorded by study staff via telemedicine or during a visit by the home health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms (vomiting, 
diarrhea), anosmia, dysgeusia, other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. 
d RT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-2 result. 
Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. 
Viral load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or 
similar. The home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS 
for analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no 
additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home 
visit. Arrangements for shipping viral load samples will be made by the study team. 
fHH = Home Health in-person visit; TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
 
 
 


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CONFIDENTIAL 
15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-02 
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.  
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all of 
its provisions.  It is further agreed that the details of this trial and all information provided to me by 
Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be revealed for 
any reason without written authorization from Clear Creek Bio, Inc. except to those who are to 
participate in the conduct of the trial. 
I agree that all data, the case report forms, and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that Clear 
Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as for 
submission to government regulatory agencies, required internal reports, and presentations without 
violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in accordance 
with current Good Clinical Practice Guidelines, to all data generated by this trial and the source 
documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: ____________________________________ 
 
Signature: ____________________________________________ Date: __________________ 
 
 
 


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CONFIDENTIAL 
15.3 Appendix C: WHO Ordinal Scale 
 
Patient State 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized: moderate disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized: severe disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Dead 
10 
 
WHO clinical progression scale 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
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PROTOCOL VERSION 5.0 DATE: 19 NOV 2020 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
STUDY PROTOCOL 
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 No: CCB-CRISIS-02 
Version: 5.0 
Version Date:  19 November 2020 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 149291 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein may 
be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in accordance with 
the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration of Helsinki (1964, 
1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations and locally applicable 
regulations. 


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CONFIDENTIAL 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 17 
3.1 Coronavirus-19 (COVID-19) ..................................................................................... 17 
3.1.1 Coronavirus Biology .................................................................................................... 17 
3.2 Host Nucleotide Synthesis ......................................................................................... 17 
3.3 Dihydroorotate dehydrogenase (DHODH) ................................................................ 18 
3.4 Brequinar .................................................................................................................... 18 
3.5 Rationale for the Planned Trial .................................................................................. 19 
3.5.1 Brequinar Dose Selection ............................................................................................. 20 
3.5.2 Risk/Benefit of Brequinar ............................................................................................ 20 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 21 
3.7.1 CYP Interactions .......................................................................................................... 21 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 21 
4 TRIAL OBJECTIVES ........................................................................................................ 22 
4.1 Primary Objective ...................................................................................................... 22 
4.2 Secondary Objectives ................................................................................................. 22 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 22 
5 TRIAL DESIGN ................................................................................................................. 23 
6 TRIAL ENDPOINTS.......................................................................................................... 24 
6.1 Primary Endpoint ....................................................................................................... 24 
6.2 Secondary Endpoints .................................................................................................. 24 
6.3 Exploratory Endpoints................................................................................................ 24 
7 TRIAL POPULATION ....................................................................................................... 25 
7.1 Number of Subjects .................................................................................................... 25 
7.2 Inclusion criteria ......................................................................................................... 25 
7.3 Exclusion Criteria ....................................................................................................... 25 
8 STUDY TREATMENTS .................................................................................................... 27 


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CONFIDENTIAL 
8.1 Description of Study Medications .............................................................................. 27 
8.1.1 Brequinar ...................................................................................................................... 27 
8.2 Treatment Administration .......................................................................................... 27 
8.2.1 Safety/Tolerability ........................................................................................................ 27 
8.3 Study Discontinuation ................................................................................................ 28 
8.4 Stopping Criteria ........................................................................................................ 28 
8.4.1 Individual Stopping Criteria ......................................................................................... 28 
8.4.2 Study-Level Stopping Criteria...................................................................................... 28 
8.5 Concomitant Medication/Treatment .......................................................................... 28 
8.6 Treatment Compliance ............................................................................................... 28 
8.7 Storage, Stability, Labeling and Packaging ............................................................... 29 
8.7.1 Storage and Stability .................................................................................................... 29 
8.7.2 Labeling and Packaging ............................................................................................... 29 
8.7.3 Blinding and Randomization ........................................................................................ 29 
8.7.4 Unblinding/Expectedness ............................................................................................. 29 
8.7.5 Study Drug Accountability ........................................................................................... 29 
8.8 Prohibited Medications .............................................................................................. 30 
8.9 Study Adjustments Due to COVID-19....................................................................... 30 
9 CONDUCT OF THE TRIAL.............................................................................................. 31 
9.1 Ethical and Regulatory Considerations ...................................................................... 31 
9.2 Informed Consent ....................................................................................................... 31 
9.3 Institutional Review Board......................................................................................... 32 
9.4 Schedule of Events ..................................................................................................... 32 
9.5 Study Conduct ............................................................................................................ 33 
9.5.1 Unscheduled Visits ....................................................................................................... 34 
9.6 Compliance with Study Procedures ........................................................................... 34 
9.7 Early Withdrawal from the Study .............................................................................. 34 
9.8 Early Termination of the Study .................................................................................. 34 
9.9 Non-Childbearing Potential........................................................................................ 35 
10 ADVERSE EVENT REPORTING..................................................................................... 36 


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CONFIDENTIAL 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 37 
10.2 Infection Follow Up ................................................................................................... 37 
10.3 Classification of Causality ......................................................................................... 37 
10.4 Classification of Severity ........................................................................................... 38 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 38 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 39 
10.7 Pregnancies................................................................................................................. 40 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 40 
10.9 Data Monitoring Committee ...................................................................................... 41 
10.9.1 
DMC Safety Review Schedule ............................................................................... 42 
11 STATISTICAL CONSIDERATIONS................................................................................ 43 
11.1 Study Populations for Analysis .................................................................................. 43 
11.2 Safety Analyses .......................................................................................................... 43 
11.3 Efficacy Analyses ....................................................................................................... 43 
11.4 Sample Size Considerations ....................................................................................... 43 
11.5 Randomization ........................................................................................................... 43 
11.6 Pooling of Study Centers............................................................................................ 44 
11.7 Interim Analysis ......................................................................................................... 44 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 45 
12.1 Investigator’s Performance ........................................................................................ 45 
12.2 Confidentiality ............................................................................................................ 45 
12.3 Source Documentation ............................................................................................... 45 
12.4 Data Collection ........................................................................................................... 46 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 46 
12.6 Non-Protocol Research .............................................................................................. 47 
12.7 Publication .................................................................................................................. 47 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 48 
13.1 General ....................................................................................................................... 48 
13.2 Indemnity ................................................................................................................... 48 
13.3 Data Monitoring ......................................................................................................... 48 


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CONFIDENTIAL 
13.4 Audit ........................................................................................................................... 48 
13.5 Confidentiality ............................................................................................................ 49 
13.6 Finance ....................................................................................................................... 49 
14 REFERENCES ................................................................................................................... 50 
15 APPENDICES .................................................................................................................... 51 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events .................................................. 51 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 52 
15.3 Appendix C: WHO Ordinal Scale .............................................................................. 53 
 
 
 
 


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CONFIDENTIAL 
LIST OF FIGURES 
Figure 3-1. 
DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine synthesis; 
it is completely essential for the generation of UMP. ................................................. 18 
 
 
  


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CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine amino transferase 
AML 
Acute myeloid leukemia 
ARDS 
Acute respiratory disease syndrome 
AST 
Aspartate amino transferase 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus-19 infection 
CRP 
c-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Curricula vitae 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DHODHi 
Dihydroorotate dehydrogenase inhibitor 
DMC 
Data Safety Monitoring Board 
ECMO 
Extra corporeal membrane oxygenation 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
EUA 
Emergency Use Authorization 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IMP 
Inosine-5’ phosphate 
IP 
Investigational product 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NEWS2 
National Early Warning System (NEWS) 2 Score 
RNA 
Ribonucleic Acid 
RdRp 
RNA-dependent RNA polymerase 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
SARS Coronavirus 2 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
SpO2 
Peripheral capillary oxygen saturation 


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CONFIDENTIAL 
Abbreviation 
Definition 
UMP 
Uridine 5’-monophosphatase 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 


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CONFIDENTIAL 
2 
SYNOPSIS  
CCB-CRISIS-02 SYNOPSIS  
IND 
149291 
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  
Protocol Number 
CCB-CRISIS-02 
Rationale 
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.  
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) + 5 days 
of brequinar 100 mg or SOC + 5 days of placebo.  
Investigational product will be supplied as either brequinar 100 mg oral capsules 
or placebo capsules. The subjects are to self-administer one capsule on Study Days 
1 – 5.  
Treatment assignment will be randomized, double-blind. 
Primary 
Objectives 
● To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load 
for brequinar-treated subjects compared to placebo-treated subjects through 
Day 29. 
Secondary 
Objectives 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-
19 subjects as measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  


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Clear Creek Bio, Inc. 
CONFIDENTIAL 
● To reduce the percentage of subjects requiring hospital admission as an in-
patient for > 24 hours for brequinar subjects compared to subjects who received 
placebo; 
● To reduce all-cause mortality through Day 29 for brequinar subjects compared 
to subjects who received placebo. 
Exploratory 
Objectives 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in 
the WHO Ordinal Scale score measured for the subset of subjects with baseline 
WHO Ordinal Scale of 2 or 3 for brequinar subjects compared to subjects who 
received placebo.  
Design 
This will be a phase 2 randomized, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive SOC per relevant guidelines 
for treatment of out-patients with COVID-19 infection. In addition to SOC, 
subjects will self-administer one capsule once daily for 5 days.  
To be eligible for screening, subjects must have a documented positive SARs-
CoV-2 test result and have at least one symptom consistent with SARS-CoV-2 
infection in the opinion of the investigator. Subjects will have a Screening Visit 
followed as soon as possible with randomization on Study Day 1. First dose of 
study drug must take place ≤ 7 days from onset of first symptom. Study procedures 
are presented in detail in the Schedule of Events. Study visits (virtual or in person) 
will take place at Screening and on Study Days 1 - 8, 12, 15, 22, and 29. 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 telephone, 
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 with the site via telemedicine on Days 1, 4, 8, 12, 
15, 22, and 29. The site will also have a telephone call with the subject on Study 
Days 2, 3, 5, 6, and 7 for changes in concomitant medications and assessment of 
adverse events, especially those that may indicate thrombocytopenia and 
mucositis. Screening and study Day 1 are to be conducted at the site unless the site 
is unable to accommodate in-person visits. If the site is unable to accommodate in-
person visits, a home visit may be arranged as long as first dose can be achieved 
within 7 days of symptom onset. Days 8, 15, and 29 require in-person visits and 
will be conducted via home visit. Any in-person visit may also have telemedicine 
or telephone components if all study activities cannot be completed in person. 
Telemedicine only visits will be conducted by site staff on study Days 4, 12, and 
22. 


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Sample Size: 
Approximately 100 subjects will be randomized to 5 days of either SOC + 
brequinar 100 mg or SOC + placebo in a 1:1 ratio (approximately 50 subjects 
assigned to brequinar 100 mg and 50 subjects to placebo).  
Number of Sites: 
Approximately 15 
Study Period: 
An enrollment period of 3 months is expected. 
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 


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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 first dose. 
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).  
Treatment 
All subjects will receive standard of care (SOC) including symptomatic care. 
Subjects will be randomly assigned to SOC + brequinar 100 mg daily x 5 or SOC 
+ placebo daily x 5. Study encounters will be conducted remotely whenever 
possible. 
DMC 
A Data Monitoring Committee (DMC) will meet periodically to review the safety 
and scientific conduct of the study. At a minimum, the DMC is to review adverse 
events and safety laboratory assessments after the first 20 subjects complete Day 
8, and again after the first 40 subjects complete Day 8.  
Procedures 
Study procedures are outlined in the Schedule of Events. 
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of first dose through Day 29. After 
Day 29, collect/record only Serious Adverse Events (SAEs) or those judged by the 


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CONFIDENTIAL 
Investigator or designated person to be related to study drug. Treatment-emergent 
adverse events will be those with an onset after the date and time of first treatment. 
Subjects who develop Grade 3 or 4 toxicities or SAEs are to be re-evaluated every 
2 days, as feasible, until the toxicity returns to Grade ≤ 2 severity. 
During assessment for adverse events, investigators and site staff are to elicit from 
the subject any signs or symptoms of mucositis or thrombocytopenia, e.g.: 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Stopping Criteria 
Individual Criteria:  
• Participants who develop a Grade 3 toxicity that is assessed by the 
investigator to be related to the study drug are to be permanently 
discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to 
study drug, are to be permanently discontinued from study treatment. 
Study-Level Stopping Criteria: 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse 
event or laboratory abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or 
laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or 
laboratory abnormality.  
All adverse events will be reviewed by the DMC during their reviews. Following 
assessment by the Data Monitoring Committee (DMC), the DMC will determine 
whether to stop the study, amend the protocol, or continue the study per protocol.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking 
the database. All analyses of safety and efficacy for this study will be descriptive 
in nature and presented by group. Subject demographics and baseline 
characteristics will be summarized. Subject data listings will also be provided.  
Summaries for quantitative variables will include the mean, median, quartiles, 


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standard error, minimum, and maximum. For qualitative variables, the summaries 
will include the number and percentage of subjects for each outcome, and the 95% 
CI, when appropriate.  Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.4 or 
higher). Safety and tolerability will be assessed in terms of AEs, SAEs, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures 
will be summarized using appropriate descriptive statistics. 


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CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
Procedures 
Screen 
(D -7 to  
-1) 
IPVf 
D1 
IPV 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5, 6, 7 
(± 8 hrs) 
TC 
D8 
(± 8 hrs) 
IPV+TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 day) 
IPV+TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 
days) 
IPV+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, 
duration or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) (serum at Screen and 
urine at D29) 
X 
 
 
 
 
 
 
 
 
X 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCRd 
X 
 
 
 
 
 
 
 
 
 
Viral load sample (Day 1 pre-dose)e 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administration (Days 1 – 5 only)f 
 
X 
X 
X 
X 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, SpO2. Subject will be provided with a thermometer and pulse oximeter 
with heart rate monitoring capability. Training will be provided during the first visit. Vital signs parameters will be observed and recorded 
by study staff via telemedicine or in-person visit (IPV) (at the study site or home visit by the home health nurse). 
cSymptom Assessment will capture symptoms such as sore throat, cough, GI symptoms (vomiting, diarrhea), anosmia, dysgeusia, other 
(specify), etc. Severity None, Mild, Moderate, or Severe will be collected. Symptom(s) onset date must be within 7 days of first dose. 
dDocumentation of a positive SARS-CoV-2 result from RT-PCR or other FDA-approved test is required to qualify for Screening.  
eSamples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. Viral 
load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or similar. The 
site staff or home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS for 
analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no additional 
sample required). 
fSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home visit. 
Arrangements for shipping viral load samples will be made by the study team. 
fIPV= in-person visit (subject’s home or at clinical site, may also include TM or TC if all study visit activities cannot be completed by the 
in-person personnel); TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
 


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CONFIDENTIAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
MEDICAL MONITOR 
Name:  
Norberto Soto, MD 
Title: 
Senior Medical Director 
Telephone No.: 
(609) 212-7892 
E-mail: 
Norberto.Soto@Covance.com 
 


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CONFIDENTIAL 
3 
INTRODUCTION 
3.1 
Coronavirus-19 (COVID-19) 
Beginning in December 2019, Chinese scientists isolated a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) from patients with virus-infected pneumonia which was later 
designated as coronavirus disease 2019 (COVID-19) by the World Health Organisation (WHO) (Zhou 
et al., 2020 [2]; Phelan et al., 2020 [3]).  
Approximately 14% of those affected with this virus will develop severe disease requiring 
hospitalization and oxygen support; 5% will require admission to the intensive care unit (Handel et 
al., 2020 [4]). Severe cases may be complicated by acute respiratory disease syndrome (ARDS), sepsis 
and septic shock, and multi-organ failure, including acute kidney injury and cardiac injury. Risk 
factors for death include older age and co-morbid disease such as hypertension and diabetes (Zhou, et 
al., 2020 [2]). This means that most patients will be treated as out-patients. Reducing viral load in this 
environment is critically important for both the subjects themselves by preventing worsening of 
symptoms and possibly avoiding hospitalization, but also to reduce the transmission of the disease to 
others in the patients’ households and their communities. 
3.1.1 Coronavirus Biology 
Coronaviruses, like other RNA-based viruses, do not have the machinery to synthesize their own 
nucleotides and thus depend upon the host intracellular pool of nucleotides for viral replication. In 
essence, viruses steal the host RNA building blocks, and without these building blocks they are unable 
to replicate. The SARS-CoV-2 is a single-stranded (positive sense) RNA virus with a genome that is 
29,811 nucleotides long, quite a lot larger than other RNA-based viruses (e.g. the hepatitis C genome 
comprises only 9600 nucleotides). The nucleotide composition is broken down as: 29.9% adenosines, 
18.4% cytosines, 19.6% guanines, and 32.1% uridines (Sah et al., 2020 [12]). 
3.2 
 Host Nucleotide Synthesis 
Host de novo pyrimidine synthesis generates uridine monophosphate (UMP) as the building block for 
all pyrimidine ribonucleotides and deoxyribonucleotides (Error! Reference source not found.). 
There exists no salvage pathway for the synthesis of UMP, the fundamental building block of 
pyrimidines. Inhibition of enzymatic steps upstream of UMP (Figure 3-1) leads to a rapid and profound 
depletion of intracellular pyrimidines.  


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Figure 3-1. 
DHODH is a mitochondrial enzyme that catalyzes the 4th step of pyrimidine 
synthesis; it is completely essential for the generation of UMP.   
3.3 
 Dihydroorotate dehydrogenase (DHODH) 
The enzyme dihydroorotate dehydrogenase (DHODH) catalyzes the 4th step of de novo pyrimidine 
synthesis and inhibition of DHODH completely halts all pyrimidine production. As shown in Figure 
3-1, DHODH is located on the inner mitochondrial membrane and transfers electrons between DHO 
and complex III of the electron-transport chain via the reduction of its ubiquinone (coenzyme Q10) 
cofactor.  
DHODH is a clear therapeutic target for the inhibition of host pyrimidine synthesis. The chemical 
inhibition of DHODH in vitro or in vivo leads to the rapid depletion of UMP and subsequent depletion 
of downstream products thymine and cytosine. This forces a cell to rely on the salvage of extracellular 
pyrimidine nucleotides and this extracellular salvage is not capable of maintaining the cell’s normal 
nucleotide pool (Sykes et al., 2016) [1]).  
  
3.4 
 Brequinar 
Brequinar is an orally available and potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity against 
experimental tumors and because its water solubility made it relatively straightforward to formulate. 
In an indication such as treating SARS-CoV-2 infection, brequinar will act as a host-targeting antiviral. 
It is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH), the enzyme 


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that catalyzes the fourth step in pyrimidine synthesis, namely the conversion of dihydroorotate (DHO) 
to orotate. DHODH inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby 
leading to a depletion of a cell’s pool of uridine, cytidine and thymidine ribonucleotides and 
deoxyribonucleotides.  
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in human 
intestinal Caco-2 cells as well as in human primary intestinal organoids (Chen et al., 2019 [6]). 
Treatment with teriflunomide, another DHODHi, has been effective in vitro and in vivo in a murine 
model of foot and mouth disease virus (Mei-Jian et al., 2019 [7]). DHODH inhibition (DHODHi) also 
inhibited the growth of dengue virus in vitro (Wang et al., 2011 [8]). DHODHi also showed antiviral 
effects against RNA viruses including influenza A, Zika, Ebola and coronavirus SARS-CoV-2 (Xiong 
et al., 2020 [11]). Brequinar has also been shown to inhibit the replication of Ebola virus, vesicular 
stomatitis virus and Zika virus in vitro (Luthra et al., 2018 [9]). Brequinar inhibits the replication of 
human immunodeficiency virus (HIV) in vitro (Andersen et al., 2019 [10]). When considering 
brequinar as an antiviral for treatment of SARS-CoV-2, oral brequinar is highly bioavailable (>95%) 
and has good penetration of lung tissue with an average tissue:blood ratio of 0.5 following a single 
dose of brequinar in the rat. It is therefore expected to achieve a similar period of DHODH inhibition 
in lung tissue (Brequinar IB [5]). 
3.5 
 Rationale for the Planned Trial 
DHODH inhibition has been extensively studied as a potential therapeutic target in the treatment of 
RNA-based viruses. The inhibition of DHODH is effective in inhibiting viral replication in pre-clinical 
models involving many RNA-based viruses with nanomolar potency and a high selectivity index (see 
the Brequinar IB [5], Section 5). In these pre-clinical models, the benefit of DHODH inhibition can 
be reversed by the supplementation of exogenous nucleotides, confirming that the on-target effect of 
host pyrimidine depletion is key to the anti-viral activity.  
The CCB-CRISIS-02 trial will study standard of care (SOC) with 5 days of brequinar (DHODH 
inhibition) compared to SOC with 5 days of placebo treatment. Clear Creek Bio hypothesizes that a 
defined 5-day course of brequinar will inhibit the enzyme DHODH to a degree sufficient to result in 
the transient depletion of host pyrimidine nucleotides, thereby inhibiting viral replication. A recent 
publication demonstrated that inhibitors of DHODH could potentiate the activity of inhibitors of RNA-
dependent RNA polymerase (RdRp) in the treatment of dengue virus, another single-stranded RNA 
virus similar to SARS-CoV-2 (Liu et al., 2020 [13]). This inhibition of viral replication may restore 
the balance in favor of the host immune system for the clearance of SARS-CoV-2. 
Marketed DHODHi medications are available, including leflunomide or teriflunomide, however these 
are very weak inhibitors of DHODH with cellular potency ~500 times lower than brequinar. These 
low potency inhibitors of DHODH are not expected to have the ability to acutely lower the pool of 
intracellular pyrimidines to the degree that is required for decreasing the viral load associated with 
SARS-CoV-2 infection, making brequinar the better choice for acute SARS-CoV-2 infection.  
The CRISIS2 study is a proof-of-concept study in patients with SARS-Cov-2 infection and will serve 
as a basis for future studies to determine the safety and effectiveness of brequinar in COVID-19. 


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3.5.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with 5 days of consecutive daily 
dosing suggest that 5 days of daily doses of 100 mg p.o. will be safe and well tolerated. A dose of 
brequinar 100 mg achieves plasma concentrations of approximately 1 uM (0.4 ug/ml) that should result 
in sufficient suppression of nucleotide synthesis. When given over 5 days, these plasma concentrations 
are achieved on a daily basis without accumulation, also assuring the safety of this regimen (see 
Brequinar IB [5]).  
3.5.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive safety and pharmacokinetic database exists with 
more than 1,000 patients treated with brequinar. Cancer patients (N = 806) have been exposed to this 
compound for treatment of a variety of solid tumors at various treatment regimens, doses, and routes 
including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 
weeks, and daily times 21 days for multiple courses. Lower doses than used in the cancer studies have 
also been utilized for patients with psoriasis and organ transplant. The maximum intravenous dose 
given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. 
There has been limited testing of DHODHi to date in the clinic for infection with SARS-CoV-2. 
DHODHi therapy at relatively high doses in the context of trials for patients with cancer has the 
expected safety side-effects of mucositis and bone marrow suppression. Importantly, however, the 
prior clinical experience in 39 subjects who received daily brequinar for 5 consecutive days at or lower 
than 100 mg/day show no cases of mucositis and only 1 (2.6%) episode of mild thrombocytopenia. 
Based on these data the 100 mg per day dose proposed for administration in this study should be within 
a safe and tolerable range as well as demonstrating the predicted antiviral effect.  
The potential benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 5-day 
period of brequinar dosing will suppress host de novo pyrimidine synthesis for this period thus 
decreasing viral load. Inhibition of DHODH is expected to reduce the ability of the virus to replicate 
and it is for this reason that brequinar will be administered to patients with COVID-19 in this study.
 
 
3.6 
 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of high-dose brequinar in patients with 
refractory solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis 
have been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of brequinar administration. 
However, these effects were self-limiting, transient, required treatment in few cases, and resolved 
following discontinuation of dosing. These adverse effects have been associated with higher doses of 
brequinar given via the intravenous route and for longer durations than the 100 mg dose and 5-day 
regimen proposed for this study.  
In addition to studying a higher risk population with symptomatic COVID-19, a comprehensive safety 
monitoring plan will be utilized in this study to assess the ongoing safety and well-being of participants 
(see Section 10.8).  


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3.7 
 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in severely ill cancer patients including antibiotics, antifungals and other critical care 
medications. No formal interaction studies have been conducted for these medications, however, there 
have not been any reports of interactions with any medications during the clinical trials with more than 
800 cancer patients.  
3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with medications 
commonly used in treating hematologic malignancies. The nonclinical studies performed to date have 
demonstrated there is no first-pass metabolism and there have been no apparent hepatotoxic effects in 
the clinical studies. Brequinar itself does not appear to be a substrate for metabolism by cytochrome 
P450 enzymes when tested under a variety of conditions. (See Brequinar IB [5]; nonclinical data on 
file with Clear Creek).  
3.8 
Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated by highly experienced clinicians familiar with the treatment of viral 
infections and their complications.  
 


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4 
TRIAL OBJECTIVES 
4.1 
Primary Objective 
To demonstrate a change from baseline in quantitative SARS-CoV-2 viral load for brequinar-treated 
subjects compared to placebo-treated subjects through Day 29. 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
Through Day 29: 
● To characterize the safety and tolerability of brequinar in out-patient COVID-19 subjects as 
measured by frequencies of grade 3 and 4 AEs and SAEs; 
● To demonstrate a shorter duration of viral shedding in subjects treated with brequinar compared 
to subjects who received placebo;  
● To reduce the percentage of subjects requiring hospital admission as an inpatient for >24 hours for 
brequinar subjects compared to subjects who received placebo; 
• To reduce all-cause mortality through Day 29 for brequinar subjects compared to subjects who 
received placebo. 
4.3 
EXPLORATORY OBJECTIVES 
Through Day 29: 
● To determine time to viral clearance (two consecutive negative tests);  
● To determine time to resolution of new onset COVID-19-related clinical symptoms and pre-
existing non-COVID-19 symptoms returned to baseline; 
● To determine time to clinical improvement as measured by a favorable shift in the WHO Ordinal 
Scale score for the subset of subjects with baseline WHO Ordinal Scale of 2 or 3 for brequinar 
subjects compared to subjects who received placebo. 


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5 
TRIAL DESIGN 
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 per (SOC) 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 must have at least one symptom consistent with SARS-CoV-2 infection according to the 
investigator and first symptom onset must be ≤7 days prior to first dose. Subjects will have a Screening 
Visit followed as soon as possible with Study Day 1. Study procedures are presented in detail in the 
Schedule of Events (Appendix 15.1). Study visits (virtual or in person) will take place at Screening 
and on Study Days 1 - 8, 12, 15, 22, and 29. 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 telephone, 
telemedicine or other remote technique. Subjects are to self-collect a viral load sample. Subjects will 
obtain their own respiratory rate, heart rate, body temperature and SpO2 during telemedicine visits or 
study staff will collect these parameters during an in-person visit at the clinic or subject’s home. The 
symptom assessment can be conducted with the study staff via telemedicine or in the clinic on Days 
1, 4, 8, 12, 15, 22, and 29. The site will also have a telephone call with the subject on Study Days 2, 
3, 5, 6, and 7 for changes in concomitant medications and assessment of adverse events, especially 
those that may indicate thrombocytopenia (see Section 10.8) and mucositis. An in-person visit will be 
conducted (at the clinic or home visit) at Screening and on study Days 1, 8, 15, and 29; in-person visits 
may be combined with telemedicine or telephone visits if all required study visit activities cannot be 
completed by the in-person personnel. Telemedicine only visits will be conducted by site staff on study 
Days 4, 12, and 22. 


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6 
TRIAL ENDPOINTS 
6.1 
Primary Endpoint 
Quantitative SARS-CoV-2 viral load through Day 29. 
6.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
Through Day 29: 
● Rates of AEs and SAEs including laboratory assessments; 
● Duration of viral shedding;  
• Percentage of subjects requiring admission as an inpatient for >24 hours. 
• All-cause mortality. 
6.3 
Exploratory Endpoints 
Through Day 29: 
● Time to viral clearance (two consecutive negative tests);  
● Time to resolution of new onset COVID-19-related clinical symptoms and pre-existing non-
COVID-19 symptoms returned to baseline; 
● Time to clinical improvement measured by a favorable shift in WHO Ordinal Scale score for the 
subset of subjects with baseline WHO Ordinal Scale of 2. 
 


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7 
TRIAL POPULATION 
7.1 
Number of Subjects 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 100 subjects have completed the study. Subjects will be randomized to either 
standard of care plus brequinar 100 mg or standard of care plus placebo in a 1:1 ratio (approximately 
50 subjects assigned to standard of care plus brequinar 100 mg and approximately 50 subjects assigned 
to standard of care plus placebo).  
7.2 
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. 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. 
7.3 
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 


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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 first dose. 
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). 
 


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8 
STUDY TREATMENTS 
8.1 
Description of Study Medications 
8.1.1 Brequinar 
Brequinar and placebo will be supplied as 100 mg capsules. Dosing will be a single 5-day course of 
brequinar 100 mg capsules or placebo 100 mg capsules once daily for 5 doses.  
8.2 
Treatment Administration 
This will be a phase 2 randomized, placebo-controlled, double blind, multi-center study with 
approximately 100 subjects. All subjects will receive standard of care (SOC) for COVID-19 infection. 
Subjects will be randomly assigned in a 1:1 ratio to standard of care plus brequinar or standard of care 
plus placebo. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit. The NIH Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) 
will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
criteria.  
Adverse events (AEs) commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure (IB) and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 cancer subjects 
treated once-weekly (DuP 785-012, see Brequinar IB [5]), the deaths of three patients were attributed 
to study drug toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades 
(Grades 3 to 4) which typically led to discontinuation in this study included hematologic toxicities 
(anemia, thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, 
vomiting, stomatitis, others including gastric hemorrhage) and mucositis.  
In three oncology studies with five consecutive days of intravenous (IV) brequinar dosing in 168 
subjects (Study 785-001 [14], 785-003 [15], and 785-005 [16]) there were no toxic deaths. For 
subjects from these three studies who were treated with a daily dose of 100 mg or below  (as will be 
dosed in CCB-CRISIS-02), AEs through 21 days showed that 2 of 39 subjects (5.1%) had a severe 
(Grades 3 or 4) AE related to study drug (1 subject each with hyperbilirubinemia and 
hyperglycemia), and no subjects discontinued from the study due to a study drug-related AE. The 
few study drug related AEs through 21 days at or below the 100 mg dose from these three studies 
included 2 subjects each with nausea, vomiting, and creatinine elevated and one subject each with 
thrombocytopenia and diarrhea. When only studies with oral dosing were considered at this dose 
level (Studies 785-022 [17], 785-031 [18] , and 785-034 [19]), the study drug related AEs through 
21 days (each observed in one subject only) included diarrhea, headache, nausea, pruritus, 
abdominal pain, anorexia, chest pain, dry mouth, fatigue, keratosis, stomatitis, and vomiting. See 
brequinar IB [5]. 


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In most instances, brequinar-related toxicities were transient, clinically manageable, and reversible 
upon discontinuation of brequinar treatment. Any of these events reported with brequinar use can be 
serious in nature and may result in death.  
A 5-day course of oral brequinar administered once daily at a low level relative to those administered 
in the cancer studies is expected to be safe and well tolerated in the COVID-19 population. 
8.3 
Study Discontinuation 
Subjects will remain in the study through at least Study Day 29 (or longer if needed to follow up study 
drug-related adverse events). Participants may discontinue from the study by withdrawing consent at 
any time or for any reason as presented in Section 9.7. 
8.4 
Stopping Criteria 
8.4.1 Individual Stopping Criteria 
• Participants who develop a Grade 3 toxicity that is assessed by the investigator to be related to 
the study drug are to be permanently discontinued from study treatment. 
• Participants who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be 
permanently discontinued from study treatment. 
• Subjects who develop Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, 
as feasible, until the toxicity returns to ≤ Grade 2 severity. 
8.4.2 Study-Level Stopping Criteria 
Study enrollment is to be paused if any of the below criteria are met: 
• If ≥ 3 subjects develop the same related Grade 4 (life-threatening) adverse event or laboratory 
abnormality; 
• If ≥ 5 subjects develop the same related Grade 3 or 4 adverse event or laboratory abnormality; 
• If ≥ 10 subjects develop any related Grade 3 or 4 adverse event or laboratory abnormality.  
Following assessment by the Data Monitoring Committee (DMC, see Section 10.9), the DMC will 
determine whether to stop the study, amend the protocol, or continue the study per protocol. 
8.5 
Concomitant Medication/Treatment 
Record the name, dose, start/stop date, indication for use, route, and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications taken 
during the study are to be recorded. Prohibited medications are identified in Section 8.8.  
8.6 
Treatment Compliance 
Compliance will be assessed by reviewing the subject’s medication diary and study records as 
appropriate. 


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8.7 
Storage, Stability, Labeling and Packaging 
8.7.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.7.2 Labeling and Packaging  
The bulk drug and unit-dose containers will be labeled in accordance with national laws and 
regulations. 
8.7.3 Blinding and Randomization 
The trial will be conducted in double blinded, randomized manner with random assignment to standard 
of care plus brequinar or standard of care plus placebo. The brequinar and placebo capsules will be 
provided to each participating institution in pre-numbered bottles intended for individual subjects to 
be dispensed by the institution’s pharmacist or designated person. Randomization assignments will be 
provided by an independent statistician to the drug packaging company. The pharmacist/designated 
person will dispense the next number in sequence to the next patient who qualifies for the study at an 
individual site. 
8.7.4 Unblinding/Expectedness 
Contact the Covance Medical Monitor if it is necessary to break the blind for this blinded study due 
to an adverse event (AE). Each site will be provided with a sealed envelope containing individual 
sealed envelopes for subject numbers assigned to that site. Each individual subject number sealed 
envelope will have the treatment (brequinar or placebo) randomly assigned to that subject number. Do 
not open the outer envelope or the individual sealed envelope unless it has been agreed with the 
Medical Monitor and the Sponsor that unblinding is necessary for that particular AE. Unblinding must 
be documented in the study records. Envelope seals are to be checked to ensure they remain intact 
during drug accountability monitoring. 
If after a discussion with the Medical Monitor, the investigator or treating clinician believes the AE 
leading to unblinding to be related to the study drug, no further doses of drug should be administered 
to that subject.  
Expectedness will be determined by establishing whether an adverse event is among those identified 
in the protocol and the brequinar IB or are commonly associated with COVID-19 or similar severe 
viral illnesses and their complications.   
8.7.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, administered, and discarded.  It 
must be clear from the records whether the subject received study medication and what subject number 
was assigned to which subject. Adequate drug is to be dispensed for the number of subjects expected 
to be treated at each institution.  


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The pharmacist/staff member responsible for drug accountability is to document the date and time of 
dispensing and for what subject the study drug was intended (i.e., record subject initials and birth date 
or other unique identifier). A pharmacy manual will be provided by the Sponsor.  
At the end of the study any unused study drug will be returned to the Sponsor for destruction or may 
be destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours and 
with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. Records may be electronic or paper and may be accessed remotely for monitoring/drug 
accountability purposes. 
Each subject will be provided with one bottle with five brequinar or five placebo capsules for the five 
days of dosing. 
8.8 
Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide). 
Treatment is prohibited with agents known to cause bone marrow suppression leading to 
thrombocytopenia.  
8.9 
Study Adjustments Due to COVID-19 
Due to the highly contagious nature of COVID-19, multiple adjustments and revised procedures are 
rapidly evolving regarding clinical trial management and study conduct. Reasonable procedures 
implemented by study staff to avoid spreading this disease are acceptable to Clear Creek with written 
permission. Examples include but are not limited to e-consent, telephone consent and study visits 
conducted by telemedicine, telephone or other digital media.  
Background standard of care is to be maintained in both treatment arms. The standard of care is 
expected to change as additional information, such as that from randomized controlled trials, emerges, 
and the Sponsor and the treating clinicians will need to address anticipated off-label use of any other 
drugs, devices, or interventions that might be used to manage COVID-19 (e.g. anticoagulants).  
The Sponsor and treating clinicians are to consider changes in SOC over time, for example, 
overlapping toxicities of brequinar and a SOC treatment expected to be widely used is to be 
considered. The availability of new standard of care treatment may change over time and vary from 
one clinical trial site to another. The Sponsor will discuss these issues with FDA should the need arise. 
 


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9 
CONDUCT OF THE TRIAL 
9.1 
Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) as revised in Tokyo 
(1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland (2000, Note of Clarification 
2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) (2013), and with the International 
Council on Harmonization (ICH) Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and United States (US) FDA Regulations. 
9.2 
Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50),  the 
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health 
Emergency (March 2020, Updated April 16, 2020) [20], as well as local and national regulations. 
Information should be given in both oral and written form whenever possible and deemed appropriate 
by the Institutional Review Board (IRB). Subjects and their relatives, if necessary, must be given 
ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, expected 
duration and purpose of the trial, the administration of the Investigational Product (IP), and the hazards 
involved, as well as the potential benefits that may come from treatment with this IP. The trial 
procedures will be explained in lay language and any questions will be answered. The subjects will be 
given an IRB-approved consent form. The subjects will be given appropriate time to consider their 
participation in the trial and have any questions answered prior to signing the consent form. If a subject 
agrees to participate, he/she will sign and date an informed consent form and be provided with a copy 
of the signed consent. All subjects who sign an informed consent form are to be recorded on the 
applicable screening log. If the subject is unable to consent for any reason, a designated family member 
or healthcare power of attorney or other person may consent per institutional policy.  
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the FDA and other relevant regulatory 
authorities. Subjects will be informed that they are free to refuse participation in this clinical 
investigation, and if they should participate, it will be made clear to them that they may withdraw from 
the trial at any time without prejudicing further medical care they may require. The subject will receive 
a copy of the consent form as well as an information sheet about the trial.  
Informed consent must be obtained from every subject prior to any study-specific procedures. 
Standard procedures carried out prior to completing the informed consent process but within the time 
constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
Documentation of consent will be subject to review by the Sponsor; if in writing, a copy will be given 
to the subject and a copy will be filed with the subject’s medical notes. Verbal consents will be 
documented by the study team as appropriate and agreed by the IRB. 
Note that informed consent procedures have been affected by COVID-19, and the study staff may use 
any consent method that has been approved by the IRB (e.g., phone consent, verbal consent with 


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witness, e-consent, etc.) of the local institution. In-person consent, written consent signatures and 
providing hard copies to the subject are examples of procedures that may be foregone under these 
circumstances. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she meets 
the subject selection criteria. 
A sample subject information sheet and consent form are available from Clear Creek.  The final 
version at each institution may differ depending on institutional requirements and standard formats. 
This protocol will not be amended for site specific changes as such changes are to be made to the site’s 
consent when required. 
9.3 
Institutional Review Board  
It is the responsibility of the Investigator to submit the protocol, consent form and information sheet 
to the IRB. An IB will be available for review by the IRB. The protocol and informed consent form 
(ICF) must be approved by the IRB prior to the recruitment of the first subject. The template consent 
form may be revised in accordance with site-specific requirements with Sponsor review and approval. 
A copy of the IRB written approval must be provided to the Sponsor and investigator before the trial 
may start at that institution. Written approval from the IRB is also required for substantial protocol 
amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating to 
the scientific documents in support of the trial.  Amendments are “substantial” when they are likely to 
have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures taken 
as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the trial. On completion of the trial, the Investigator 
will inform the applicable IRB as per local IRB requirements that the trial has ended. If the study is 
terminated for any reason, the investigator will return all clinical supplies and study-related equipment 
supplied by the Sponsor to the Sponsor unless otherwise specified.  
9.4 
Schedule of Events 
Study activities will be conducted or supervised by experienced personnel throughout the study based 
on the Schedule of Events. The subjects may self-collect the saliva sample for viral load testing and 
perform other study activities such as body temperature, heart rate, respiratory rate, SpO2, and 


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symptom assessments themselves with appropriate training. Equipment will be provided to the subject 
for study purposes including a pulse oximeter with heart rate monitoring capability and a thermometer. 
Telemedicine visits such as phone calls or other remote media are to be utilized as much as possible. 
Subjects may need to come to an out-patient facility or be visited by a home health professional for 
some study assessments. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALK), 
alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
calcium, lactate dehydrogenase (LDH), and C-reactive protein (CRP). Chemistry samples may be 
banked for future analyses. 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and 
platelet count. 
Viral load sampling is to be carried out on Days 1, 4, 8, 12, 15, 22, and 29. The subject is to self- 
collect saliva samples with appropriate training for this analysis. Samples may be banked for future 
analyses. The subject must have a documented positive SARS-C0V-2 result to be eligible for 
Screening. Eligible subjects must have symptom(s) consistent with SARS-CoV-2 infection at time of 
randomization in the opinion of the investigator and onset of first COVID-19 symptom must be ≤ 7 
days prior to first dose. 
Safety laboratory results (chemistry and hematology) are to be reviewed by investigator or designated 
site personnel within 48 hours of receipt of results. 
Hospitalization status after enrollment is to be recorded as not hospitalized or admitted to hospital as 
an in-patient with admission > 24 hours.    
As much of the study as possible will be conducted via telemedicine remote from the site (e.g., consent, 
medical history, concomitant medications may be collected remotely). Subjects will be visited at home 
(or place of residence) by a home health nurse or come to the site for an in-person visit at Screening 
and on study Day 1. The subjects will be visited at home for Study Days 8, 15, and 29. On study Days 
4, 12, and 22 the vital signs and saliva collections will be observed via telemedicine by the study site 
staff. Site staff will have a telephone call with subjects on study days 2, 3, 5, 6, and 7 to assess changes 
in concomitant medications and to assess adverse events, especially those that may indicate 
thrombocytopenia, e.g., unusual bruising, epistaxis, gingival bleeding, etc., and mucositis. Subjects 
will be provided with a pulse oximeter and thermometer during the Screening or Day 1 visit, as well 
as being trained on the use of these devices during the visit. Training will also be provided for the 
saliva collection required for viral load testing. Assessments will be recorded by the study staff during 
home and clinic visits and by the site staff during telemedicine visits. These data will be entered in the 
eCRF by the site staff or as determined by the study team. 
9.5 
Study Conduct 
The study visits are to be conducted as shown in the Schedule of Events, Appendix 15.1. 


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Study completion or the reason for study discontinuation will be recorded in the source document and 
the eCRF.  
9.5.1 Unscheduled Visits 
Unscheduled visits and tests are permitted as needed to assess AEs/SAEs throughout the study. 
Unscheduled visits and tests are also permitted as needed to assess AEs/ SAEs with onset within two 
(2) weeks after the final study visit providing the AE is considered related to study drug 
9.6 
Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely as 
possible.  However, it is recognized in a clinical setting that protocol-specified timings may not occur 
exactly as specified in the protocol, particularly when conducted remotely by the subject. Provided 
that activities are carried out within the identified windows it will not be necessary to file a protocol 
deviation. Remote visits such as a telemedicine visit may be conducted to collect as much information 
as possible remotely. A home visit or return to the clinical site or an out-patient laboratory may be 
arranged for safety labs or other assessments, when required. Telemedicine or other remote technique 
is to be utilized to ensure subject compliance when subject is performing self-collection of study 
assessments.  
9.7 
Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after discussion 
with the other party if it is believed it would be unsafe for the subject to continue in the study.   
Subjects must discontinue study medication if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all scheduled evaluations even for subjects who discontinue study medication prior to 
completing the treatment period unless consent is withdrawn. 
9.8 
Early Termination of the Study 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any reason 
at the Sponsor’s request, the study may be terminated at that site or the entire study terminated after 
discussion with the other parties. 


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The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with the 
reasons for termination of the study. This will be conducted within 15 days of the decision to terminate 
the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
9.9 
Non-Childbearing Potential 
Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian 
tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the 
ovaries. Documentation of surgical procedure or physical examination is required for subjects who 
have had a hysterectomy or tubal ligation. A woman is also presumed to be infertile due to natural 
causes if she has been amenorrheic for greater than 12 months and has an FSH greater than 40 IU/L. 
In the absence of such documentation, a negative serum pregnancy test is required for inclusion into 
the study. 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the medicinal product, whether or not 
considered related to the medicinal product.  
Events that occur prior to first dose will be entered as medical history; events that occur after first dose 
will be entered as adverse events (AEs) on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not judged by the 
Investigator or designated person to be related to study drug. All AEs will be documented in the 
subject's medical record and CRF. For any pre-existing condition or abnormal laboratory finding that 
changes in severity after dosing, this change should be recorded as an AE. New abnormal laboratory 
findings that are clinically significant are considered AEs. Investigators and site staff are to elicit from 
the subject and note any signs or symptoms of mucositis and thrombocytopenia (see Section 10.8). 
Adverse events will be collected from the time of first dose through Day 29. After Day 29, 
collect/record only Serious Adverse Events (SAEs) which are assessed by the Investigator or 
designated person to be related to study drug and have an onset within 14 days of study completion 
(Day 29 or earlier if discontinue prior to Day 29).  AE details are to be documented including start and 
stop date and times, whether continuous or intermittent, severity, any intervention utilized to correct 
the event (e.g., medication, surgery, or other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor by 
the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution or 
until they are considered stable or for at least 30 days after discontinuation of study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, are Grades 3 or 4, or require 
therapy. 
If a death occurs during the SAE reporting period, the cause of death such as pneumonia, ARDS, or 
respiratory failure, is considered as the AE and the death is considered its outcome. Death should be 
considered an outcome, not an event. The event or condition leading to death should be recorded and 
reported as a single medical concept on the AE eCRF. Generally, only one such event should be 
reported. “Fatal” will be recorded as the outcome of this respective event; death due to an outcome of 
an AE will not be recorded as separate event. If the primary cause of death is disease progression, the 
cause of death should be clearly identified as COVID-19. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered as 
the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim text 
to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA). For example, record appendicitis, not appendectomy. 


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The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. The medical history section of the case report form will serve as the source document for baseline 
events.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start date 
of the baseline event. 
2. Adverse events occurring after first dose are to be recorded in the eCRF using the AE form. 
3. Serious adverse events will be reported to the local IRB according to institutional policy. 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) will be used for adverse 
event reporting.   
10.1 Follow Up of Grade 3 or 4 Toxicities 
Grade 3 or 4 toxicities are to be followed by re-evaluation every 2 days, as feasible, until the toxicity 
returns to Grade ≤ 2 severity. 
10.2 Infection Follow Up 
Any new infection that occurs on study regardless of infecting agent (i.e., viral or non-viral) should be 
captured. Additionally, the site of infection and source of culture (BAL, tracheal aspirate, sputum, 
blood, urine, etc.) should also be recorded. 
10.3 Classification of Causality 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the Investigator. 
10.4 Classification of Severity 
The NIH Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Corrected Version 2.1 (July 2017) will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.5 Serious Adverse Event (SAE) Reporting 
The regulatory definition of an SAE is any untoward medical occurrence or effect that at any dose 
fulfills one or more of these criteria: 
• results in death; 
• is life threatening (at the time of the event); 
• requires in-patient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity 
• is a congenital anomaly / birth defect; 
• or is an event considered medically serious by the Investigator. 
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the Investigator, 
at immediate risk of death from the event as it occurred.  It does not include an event that, had it 
occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. IB for an unauthorized investigational product 
or summary of product characteristics for an authorized product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events which did 
not directly result in the SAE should be detailed in the description section on the SAE form and listed 
separately as AEs if necessary. For fatal SAEs, report the cause of death as an SAE with a fatal 
outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  


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• Routine treatment or monitoring of COVID-19 infection, not associated with any 
deterioration in condition;  
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  
• Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition; 
• Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of an SAE given above.  
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 24 
HOURS) BY EMAIL TO THE SAE REPORTING EMAIL USING THE FORM PROVIDED.  
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE eCRF WITHIN 48 
HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address for reporting SAEs can be found below and at the front 
of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted to 
Covance Patient Safety until the event has subsided or, in case of permanent impairment, it stabilizes, 
and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL:  
SAEIntake@covance.com 
Medical Monitor: 
Norberto Soto, MD  
Telephone: 
(609) 212-7892 
Covance Physician/Medical Monitor 
Email: 
Norberto.Soto@Covance.com 
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
Telephone: 
M: (484) 686-0545 
VP, Clinical Operations 
Email: 
bpowers@clearcreekbio.com  
All SAEs will be reported to the IRB periodically, at the end of the study, or per local institutional 
guidelines.   
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the study 
drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and IRB 
by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness will be 
judged by the Covance Physician and site Investigator. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require immediate 
attention and expedited reporting to relevant regulatory authorities. 
The Sponsor will ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 


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IRB(s) within seven (7) calendar days of the date of first report to Covance Patient Safety / Sponsor. 
Follow-up information will be communicated to the relevant Regulatory Authority within an 
additional eight calendar days. 
All other SUSARs will be reported to the Regulatory Authority and to the IRB(s) concerned as soon 
as possible within a maximum of fifteen calendar days of first notification to Covance Patient Safety 
/ Sponsor. 
The Sponsor or designee will also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
requested additional information on an expedited basis.   
10.7 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to Covance Patient Safety (by email to 
SAEIntake@covance.com) and to the IRB by the investigational staff within 1 working day of their 
knowledge of the event. The collection period for a pregnancy occurring in a subject or a subject’s 
partner will begin at the first dose of study drug and will continue through 90 days after the last dose 
of study drug. Monitoring of the subject or partner should continue until the conclusion of the 
pregnancy, if the subject or subject’s partner has consented to this. Monitoring of the baby should 
continue for 3 months after birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or designee 
will discontinue the pregnant subject from the treatment aspects of the study, continue to follow her 
per protocol for safety outcomes only, and advise her to seek prenatal care and counseling from her 
primary care provider. Data on fetal outcome and breast-feeding will be collected for regulatory 
reporting and drug safety evaluation, if the subject has consented to this. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as (S)AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow the 
subject until the end of pregnancy, with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. 
10.8 Safety Monitoring for Hematologic Toxicities 
Myelosuppression is a known effect of DHODH inhibition that is associated with prolonged exposure 
and high doses. To reduce the risk of this effect with brequinar in COVID-19 subjects, the extensive 
brequinar safety database with over 1,000 patients has been evaluated to select a dose level expected 
to be safe and well tolerated with regard to hematologic toxicity. In addition to enhancing safety by 


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selecting a relatively brief 5-day exposure and a low brequinar dose, all subjects in the clinical trial 
will be under the care of highly qualified medical personnel. Clinically significant out-of-range 
laboratory results will be reported as adverse events. 
In addition to real time assessments by the treating clinical team, the Covance Medical Monitor will 
assess the available hematology data on a periodic basis to identify any pathologic trends or safety 
issues. Any apparent increase in the expected rate or severity of hematologic safety events will be 
discussed with the Principal Investigators and the Sponsor. In addition, the Data Monitoring 
Committee (DMC) will assess available hematology data on a periodic basis to independently assess 
any pathologic trends or safety issues. If the rate or severity of hematologic toxicities appears to be 
above the expected rate or the severity appears worse than that expected, the trial enrollment will be 
suspended and no further subjects will be treated while a comprehensive data review is conducted. 
Depending on the outcome of the safety review the study may be stopped, the design adjusted, or the 
study may continue as designed. Individual and Study stopping rules are provided in Section 8.4. 
Safety laboratory results are to be initially assessed in real time by the Principal Investigator or 
designated person. Any study drug-related clinically significant out-of-range laboratories or study 
drug-related adverse events will be followed as needed until resolution or stable. 
The in-clinic assessments and telemedicine/phone call visits will specifically ask about possible 
hematologic toxicity including any evidence of the list below. Subjects will be provided with a list of 
the following events in lay terms and will be instructed to call the research team if any of these events 
occur. 
• Ecchymosis/purpura/petechiae 
• Epistaxis 
• Hemoptysis 
• Hematuria 
• Gingival bleeding 
• Prolonged bleeding time from needle sticks, abrasions or lacerations 
• Hematemesis 
• Rectal bleeding 
• Blood in stool 
• Any other unusual bleeding noted by the subject or caregiver 
Any of these symptoms considered clinically significant will be recorded as an adverse event and must 
be followed until resolved or stable. 
10.9 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established to provide independent oversight to this 
trial. The primary responsibility of the DMC will be to review the progress and conduct of the trial in 
order to maintain scientific rigor and to ensure the wellbeing of subjects participating in the trial. The 
specific responsibilities of the DMC will be detailed in a separate DMC charter. The DMC will include 
at a minimum at least one statistician and two clinicians who will perform periodic data review to 
assess whether there are clinically significant differences between treatment arms that could affect 
participant safety.  All adverse events will be reviewed by the DMC during their reviews. Following 


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such a review, the DMC Chair will advise the Sponsor that the study be stopped, the design changed, 
or that the study may continue per protocol. 
10.9.1 DMC Safety Review Schedule 
The DMC is to review adverse events and safety laboratory assessments after the first 20 subjects 
complete the Day 8 visit, and again after the first 40 subjects complete the Day 8 visit. 
 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. All 
analyses will be descriptive in nature and presented by group.   
Summaries for quantitative variables will include the mean, median, quartiles, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and 95% confidence interval (CI), when appropriate. Any 
statistical testing will be considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.4 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. Subject 
data listings will also be provided. The following sections will briefly summarize of the planned 
statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 Study Populations for Analysis 
All safety analyses will be based on the ITT population, which is defined as all randomized subjects. 
As will be described in the SAP, efficacy analyses of changes in viral load will be based on the 
population of subjects with detectable viral load at baseline or similar qualification. Sample size may 
be adjusted if an inadequate number of subjects have detectable viral load at baseline. 
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, WHO Assessments, and safety 
laboratory data.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data listings. The 
incidence of post-first dose (treatment-emergent) adverse events will be tabulated by MedDRA 
preferred term and system organ class, and by severity and relationship to study treatment. All 
laboratory results and study assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will primarily be assessed via viral load changes. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this proof-of-concept study. The sample size of 
approximately 100 subjects planned to be entered in this trial is expected to be adequate to provide 
safety and efficacy information to advise future study design. 
11.5 Randomization 
A randomization scheme will be provided by an independent statistician to the drug packaging 
company to ensure subjects are randomly assigned to SOC + brequinar or SOC + placebo in a 1:1 
ratio.  


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11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 


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12 INVESTIGATOR RESPONSIBILITIES 
12.1 Investigator’s Performance 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement found in Section 15.2 to 
indicate commitment to comply with the contents. 
12.2 Confidentiality 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality will 
be maintained during all audits and inspections of the trial site and documentation. A unique number 
will be assigned to each subject at the start of the trial and this, with the subject’s initials, will be used 
to identify the subject. In some cases, a further step may be taken to assign “fake initials” to the subject, 
per individual site requirements. The subject’s number will be the site number followed by the number 
of this subject at this site and will be used as the unique identifier in the source records and on the 
eCRF, on all trial correspondence and in the trial database. The Investigator will keep a list of 
identification codes or initials used for each subject along with the unique number assigned. 
All information provided to the Investigator relevant to the investigational product (IP), as well as 
information obtained during the course of the trial will be regarded as confidential. The Investigator 
and members of his/her research team agree not to disclose or publish such information in any way to 
any third-party without prior written permission from the Sponsor which will not be unreasonably 
withheld, except as required by law, or as permitted by the Publications section of this protocol, 
Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 Source Documentation 
Investigators are to maintain adequate source documentation of the original study data, for example 
medication records, laboratory reports and pharmacy records as appropriate. The Investigator will 
allow inspections of the trial site and documentation by clinical research and audit personnel from the 
Sponsor, external auditors or representatives of regulatory authorities. The purpose of these 
inspections is to verify and corroborate the data collected on the eCRFs. In order to do this, direct 
access to the subjects' medical or clinic records is necessary. The Investigator will ensure that certain 
information is contained in the medical or clinic written or electronic records of the subject and that 
the entries are signed and dated, as follows: 
• sufficient data to allow verification of the entry criteria in terms of past and present medical and 
medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IP being evaluated, 
the trial number assigned to that subject and a statement that consent was obtained; 


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• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each subject 
during the clinical phase of the study. A signed copy should also be filed in the investigator file. 
12.4 Data Collection 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IP accountability 
records, correct administration of IP including storage conditions and accurate reporting of AEs. In 
addition, suitably qualified and trained clinical research personnel of the Sponsor will visit the trial 
site at regular intervals during the trial for monitoring purposes and to assist the research staff with 
any queries. All queries and discrepancies relating to the data collection are to be resolved at the 
completion of the trial. Remote data capture is encouraged whenever possible. 
12.5 Case Report Forms, Investigator’s Site File and Record Retention 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will be 
reviewed against source documentation at each monitoring visit. All CRFs and supporting source 
documentation must be completed and available to the Sponsor in a timely manner. Changes or 
corrections due to data clarification and resolutions will be tracked by paper or electronically with an 
audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed for 
completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the IB, 
the protocol plus any amendments, all correspondence with the IRB including the approval for the 
trial to proceed, Regulatory Authority approval/ notification (if applicable) including a sample of an 
approved informed consent, IP accountability, Source Documents, investigator and staff curricula 
vitae (CVs,) trial documentation, and all trial correspondence. The original signed informed consent 
forms and the final report will be kept in the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of time 
permitted by the hospital, institution or private practice. The Investigator has a responsibility to retain 
essential documents for as long as is required by the Sponsor and applicable regulatory authorities. It 
is the responsibility of the Sponsor to inform the Investigator as to when these documents no longer 
need to be retained. Investigators will be asked to contact the Sponsor prior to the destruction of any 
data or removal to another site if this occurs prior to the Sponsor notification that the documentation 
is no longer required. Any transfer of ownership of the data or of documents will be documented in 
writing. The new owner will assume responsibility for data retention and archiving. 


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Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials and 
intends to publish the results of this trial. All publications resulting from the clinical trial must be in a 
form that does not reveal technical information that the Sponsor considers confidential or proprietary.  
A copy of any abstract, presentation or manuscript proposed for publication must be submitted to the 
Sponsor for review at least 30 days before its submission for any meeting or journal. In addition, if 
deemed necessary by the Sponsor for protection of proprietary information prior to patent filing, the 
Investigator agrees to a further delay of 60 days before any presentation or publication is submitted. 
The Sponsor reserves the right to include the report of this trial in any regulatory documentation or 
submission or in any informational materials prepared for the medical profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of the 
following criteria: Investigator must participate in the review of and content of the protocol; review 
and comment on the study results; participate in the writing, reviewing and commenting of the 
manuscript; and approve the final manuscript for submission. 
 


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13 SPONSOR RESPONSIBILITIES 
13.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on GCP (CPMP/ICH/135/95, Jan.97) and 
US FDA Regulations. It is the Sponsor's responsibility to obtain appropriate regulatory approval to 
perform the trial (if applicable). The Sponsor should notify promptly all concerned investigator(s), 
IRB(s) and the Regulatory Authority of findings that could adversely affect the health of the patients/ 
subjects, impact on the conduct of the trial or alter the Regulatory Authority’s authorization to continue 
the trial. If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to 
the subjects the Sponsor will notify the relevant regulatory authority and relevant IRB of the new 
events, the measures taken and the plan for further action as soon as possible.  This will be by telephone 
in the first instance followed by a written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  If 
the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be conducted 
within 15 days of the decision to terminate the trial.  The Sponsor will report in an expeditious manner 
all SUSARs to the relevant regulatory authority and IRBs.   
13.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result of 
participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site or will 
access the electronic health record (EHR) or conduct remote monitoring visits at regular intervals 
during the trial for monitoring purposes and to assist the research staff with any queries. CRFs and 
source documentation will be available for review during monitoring visits to the trial site. The 
function of this monitoring is to ensure compliance with the protocol, adherence to regulatory and 
GCP obligations, proper maintenance of records including IP accountability records, correct 
administration of IP including storage conditions and accurate reporting of AEs. On-site visits are not 
required for any monitoring visits for this study.   
Once the data from the case report forms have been entered onto the database, they will be reviewed, 
and the data verified against the subject’s source data. Any discrepancies will be tracked by paper or 
electronically with an electronic audit trail. 
13.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place while 
the trial is being conducted or up to several years later.   


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13.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


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11. Xiong R, Zhang L, Li S, Sun Y, Ding M, Wang, Y, et al. Novel and potent inhibitors 
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spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. 
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Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with 
Modulators of Pyrimidine Metabolism. bioRxiv. 2020 Jan 1;2020.03.24.992230. 
14. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
15. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
16. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
18. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
20. FDA Guidance “COVID-19: Developing Drugs and Biological Products for the Treatment or 
Prevention (https://www.fda.gov/media/137926/download) 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 51 of 53 
PROTOCOL VERSION 5.0 DATE: 19 NOV 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
Procedures 
Screen 
(D -7 to 
 -1) 
IPVf 
D1 
IPV 
 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6,7 
(± 8 hrs) 
TC 
D8 
(± 8 hrs) 
IPV+TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 day) 
IPV+TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 
days) 
IPV+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCRd 
X 
 
 
 
 
 
 
 
 
 
Viral load sample (pre-dose Day 1)e 
 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administrationf 
 
X 
X 
X 
X 
D5 
Only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, and SpO2. Subject will be provided with a thermometer and pulse oximeter 
with heart rate monitoring capability. Training will be provided during the first visit. Vital signs parameters will be observed and recorded 
by study staff via telemedicine or in person (IPV) (at the study site or home visit). 
cSymptom Assessment will capture symptoms such as sore throat, cough, GI symptoms (vomiting, diarrhea), anosmia, dysgeusia, other 
(specify), etc. Severity None, Mild, Moderate, or Severe will be collected. Symptom(s) onset date must be within 7 days of first dose. 
dDocumentation of a positive SARS-CoV-2 result from RT-PCR or other FDA-approved test is required to qualify for Screening.  
eSamples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. Viral 
load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or similar. The 
site staff or home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS for 
analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no additional sample 
required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home visit. 
Arrangements for shipping viral load samples will be made by the study team. 
fIPV = in-person visit (subject’s home or at clinical site; may also include TM or TC if all study visit activities cannot be completed by the 
in-person personnel); TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 52 of 53 
PROTOCOL VERSION 5.0 DATE: 19 NOV 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-02 
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.  
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all of 
its provisions.  It is further agreed that the details of this trial and all information provided to me by 
Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be revealed for 
any reason without written authorization from Clear Creek Bio, Inc. except to those who are to 
participate in the conduct of the trial. 
I agree that all data, the case report forms, and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that Clear 
Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as for 
submission to government regulatory agencies, required internal reports, and presentations without 
violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in accordance 
with current Good Clinical Practice Guidelines, to all data generated by this trial and the source 
documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: ____________________________________ 
 
Signature: ____________________________________________ Date: __________________ 
 
 
 


PROTOCOL NUMBER:  CCB-CRISIS-02  
 
 
 
 
Page 53 of 53 
PROTOCOL VERSION 5.0 DATE: 19 NOV 2020 
 
Clear Creek Bio, Inc. 
CONFIDENTIAL 
15.3 Appendix C: WHO Ordinal Scale 
 
Patient State 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized: moderate disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized: severe disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Dead 
10 
 
WHO clinical progression scale 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
Page 1 of 23 
 
 
ST-AD-008 version 05 
 
Statistical Analysis Plan 
 
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 
Clear Creek Bio, Inc. 
CCB-CRISIS-02 
 
NCT 04575038 
 
Document Version: Final 1.0 
Document Date: 04Nov2020 
 
 
 
 
 
 
 
Covance Inc. CDCS 
Clinical Development Commercialization Services 
 
Table of Contents 
1. 
Source Documents .............................................................................. 6 
2. 
Protocol Details ................................................................................... 6 
2.1 
Study Objectives .............................................................................. 6 
2.2 
Overall Study Design......................................................................... 7 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 2 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
2.3 
Sample Size and Power ..................................................................... 9 
2.4 
Randomization ................................................................................. 9 
3. 
Efficacy and Safety Variables ................................................................ 9 
3.1 
Primary Efficacy Endpoint .................................................................. 9 
3.2 
Secondary Efficacy and Clinical Endpoints ............................................. 9 
3.3 
Exploratory Efficacy and Clinical Endpoints ........................................... 9 
3.4 
Safety Variables ............................................................................. 10 
4. 
Pharmacokinetic/Pharmacodynamic variables ........................................ 10 
5. 
Analysis populations .......................................................................... 10 
5.1 
Screened ...................................................................................... 10 
5.2 
Safety Analysis Set ......................................................................... 10 
5.3 
Intent-to-treat Set .......................................................................... 10 
5.4 
Microbiology Evaluable Set ............................................................... 10 
5.5 
Per Protocol Set ............................................................................. 10 
6. 
Data Handling ................................................................................... 11 
6.1 
Time points and Visit Windows .......................................................... 11 
6.2 
Handling of Dropouts, Missing Data, and Outliers ................................. 11 
7. 
Statistical Methods ............................................................................ 12 
7.1 
General Principles ........................................................................... 12 
7.2 
Subject Disposition and Data Sets Analyzed ........................................ 13 
7.3 
Protocol Deviations ......................................................................... 13 
7.4 
Demographics and Other Baseline Characteristics ................................ 13 
7.4.1 
Medical History ................................................................................................................... 14 
7.4.2 
Previous and Concomitant Medications ............................................................................. 14 
7.5 
Measurements of Study Drug Compliance ........................................... 15 
7.6 
Efficacy ......................................................................................... 15 
7.6.1 
Primary Efficacy Analysis ..................................................................................................... 15 
7.6.2 
Secondary Efficacy Analysis ................................................................................................ 16 
7.6.3 
Exploratory Efficacy Analysis ............................................................................................... 16 
7.6.4 
Secondary Clinical Analysis ................................................................................................. 17 
7.6.5 
Exploratory Clinical Analysis ............................................................................................... 17 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 3 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
7.7 
Safety .......................................................................................... 18 
7.7.1 
Extent of Exposure .............................................................................................................. 18 
7.7.2 
Adverse Events .................................................................................................................... 19 
7.7.3 
Laboratory Evaluations ....................................................................................................... 20 
7.7.4 
Vital Signs ............................................................................................................................ 21 
7.7.5 
Electrocardiograms ............................................................................................................. 22 
7.7.6 
Physical Examination ........................................................................................................... 22 
7.7.7 
Other Safety Variables ........................................................................................................ 22 
7.8 
Interim Analysis ............................................................................. 22 
8. 
Changes in Planned Analysis ............................................................... 22 
9. 
Data Issues ...................................................................................... 22 
10. 
References ....................................................................................... 22 
11. 
Appendices ...................................................................................... 23 
Appendix 1: Document History .......................................................... 23 
 
 
 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 4 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
Reviewers 
The following reviews of the SAP were conducted: 
 
Glossary of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence Interval 
COVID-19 
Coronavirus-19 infection 
CRF 
Case report form 
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
ITT 
Intent-to-treat 
LLOQ 
Lower limit of quantification 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MES 
Microbiology Evaluable Set 
MMRM 
Mixed model for repeated measures 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SI 
International System of Units 
SOC 
Standard of care 
SOC 
System Organ Class 
SpO2 
Peripheral capillary oxygen saturation 
TFLs 
Tables, Figures and Listings 
WHO 
World Health Organization 
 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Margaret Connolly 
Peer Review 
Statistician 
Internal draft 
Covance 
Julija Jasauskiene 
Lead Programmer 
Internal draft 
Covance 
Norberto Soto 
Project Physician 
Internal draft 
Covance 
Vikram Kumar 
Chief Executive Officer 
Final 1.0 
Clear Creek Bio 
Barbara Powers 
Vice President, Clinical 
Operations 
Final 1.0 
Clear Creek Bio 
John Pottage 
Medical Director 
Final 1.0 
Clear Creek Bio 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 5 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 1 
This section is not required at this time, but will be populated in a future approved 
version of this document. 
 
 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 6 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol 
01-Oct-2020 
4.0 
CRF 
21-Oct-2020 
PROD 2.00 
2. Protocol Details 
2.1 Study Objectives 
Primary Objective: 
To demonstrate a change from baseline in quantitative severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) viral load for brequinar-treated subjects 
compared to placebo-treated subjects through Day 29. 
Secondary Objectives: 
Through Day 29: 
• 
To characterize the safety and tolerability of brequinar in out-patient 
coronavirus-19 infection (COVID-19) subjects as measured by frequencies of 
grade 3 and 4 adverse events (AEs) and serious adverse events (SAEs); 
• 
To demonstrate a shorter duration of viral shedding in subjects treated with 
brequinar compared to subjects who received placebo;  
• 
To reduce the percentage of subjects requiring hospital admission as an 
inpatient for >24 hours for brequinar subjects compared to subjects who 
received placebo; 
• 
To reduce all-cause mortality through Day 29 for brequinar subjects 
compared to subjects who received placebo. 
Exploratory Objectives: 
Through Day 29: 
• 
To determine time to viral clearance (two consecutive undetectable tests);  
• 
To determine time to resolution of new onset COVID-19-related clinical 
symptoms and pre-existing non-COVID-19 symptoms returned to baseline; 
• 
To determine time to clinical improvement as measured by a favorable shift 
in the WHO Ordinal Scale score for the subset of subjects with baseline WHO 
Ordinal Scale of 2 or 3 for brequinar subjects compared to subjects who 
received placebo. 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 7 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
2.2 Overall Study Design 
This is 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 procedures are presented in detail in the Schedule of Events (Table 1). Study 
visits (virtual or in person) will take place at Screening and on Study Days 1 - 8, 
12, 15, 22, and 29. 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 telephone, telemedicine or other remote technique. 
Subjects are to self-collect a viral load sample, obtain their respiratory rate, heart 
rate, body temperature and peripheral capillary oxygen saturation (SpO2), and 
complete a symptom assessment checklist with the site via telemedicine on Days 1, 
4, 8, 12, 15, 22, and 29. The site will also have a telephone call with the subject on 
Study Days 2, 3, 5, 6, and 7 for changes in concomitant medications and 
assessment of adverse events, especially those that may indicate thrombocytopenia 
and mucositis. A home health nurse will visit the subject at Screening and on study 
Days 1, 8, 15, and 29. Telemedicine only visits will be conducted by site staff on 
study Days 4, 12, and 22. 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 8 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
Table 1 
CCB-CRISIS-02 Schedule of Events 
CCB-CRISIS-02  
Schedule of Events 
Windows are relative to first dose time 
 
Procedures 
Screen 
(days  
-14 to -1) 
HH+TMf 
D1 
HH+
TM 
D2, 3 
(± 8 
hrs) 
TCf 
D4 
(± 8 
hrs) 
TM 
D5,6,
7 
(± 8 
hrs) 
TC 
D8 
(± 1 
day) 
HH+
TM 
D12 
(± 1 
day) 
TM 
D15 
(± 1 
day) 
HH+
TM 
D22 
(±1 
day) 
TM 
Final 
Visit  
D29 
(± 2 days) 
HH+TM 
Informed Consent (note Date and Time) 
X 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications (dose, route, duration 
or ongoing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history (relevant within one year or 
ongoing)/ History of current illness (date of 
symptom onset or change in baseline co-morbidity 
thought to be due to COVID-19 infection) 
X 
 
 
 
 
 
 
 
 
 
Demographics (subject reported height and weight, 
date of birth, gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Check for Physical Exam abnormalities (subject 
self-reported) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP) 
X 
(serum) 
 
 
 
 
 
 
 
 
X 
(urine) 
Hematology/Chemistrya 
X 
X  
 
 
 
X 
 
X 
 
 
Vital Signsb 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Symptom Assessmentc 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 RT-PCR/Viral load sampled 
X 
X  
 
X 
 
X 
X 
X 
X 
X 
Hospital Status 
 
 
 
 
 
X 
 
X 
X 
X 
WHO Ordinal Scale Assessment 
 
X 
 
 
 
X 
 
X 
X 
X 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
Randomize subject and dispense Study Medication 
 
X 
 
 
 
 
 
 
 
 
Study drug administratione 
 
X 
X 
X 
X 
D5 
Only 
 
 
 
 
 
Drug Accountability 
 
 
 
 
 
X 
 
 
 
 
aDo not repeat if within 48h of Day 1 visit. Send to Covance Central Laboratory Services (CCLS) for analysis. 
bVital signs include heart rate, respiratory rate, body temperature, and SpO2. Subject will be provided with a thermometer and pulse 
oximeter with heart rate monitoring capability. Training will be provided during the first visit by the home health nurse. Vital signs 
parameters will be observed and recorded by study staff via telemedicine or during a visit by the home health nurse. 
cSymptom Assessment will use a checklist provided to the subject with symptoms such as sore throat, cough, GI symptoms (vomiting, 
diarrhea), anosmia, dysgeusia, other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. 
d RT-PCR at Screening may be performed by the site if the subject cannot provide documentation of a positive SARS-CoV-2 result. 
Samples collected after Screening will be saliva samples sent for viral load analysis. Day 1 sample must be obtained prior to dosing. 
Viral load specimens after Screening will be saliva samples self-collected by the subject using an Omnigene® collection system or 
similar. The home health nurse will train the subject and observe sample collection on Day 1. These samples are to be sent to CCLS 
for analysis. The viral load sample may also be used to perform viral cultures (sample can be split by the central laboratory, no 
additional sample required). 
eSubject will self-administer study drug once daily Days 1 – 5 and record doses in a medication diary. Note that any visits/visit activities 
may be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology sample 
collection. These labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home 
visit. Arrangements for shipping viral load samples will be made by the study team. 
fHH = Home Health in-person visit; TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
 
 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 9 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
2.3 Sample Size and Power 
Formal sample size calculations are not applicable for this proof-of-concept study. 
The sample size of approximately 100 subjects planned to be entered in this trial is 
expected to be adequate to provide safety and efficacy information to advise future 
study design. Subjects who meet all of the inclusion and none of the exclusion 
criteria will be enrolled in the study until approximately 100 subjects have 
completed the study. 
2.4 Randomization 
The trial will be conducted in double blinded, randomized manner with random 
assignment to standard of care plus brequinar or standard of care plus placebo in a 
1:1 ratio at each site. The brequinar and placebo capsules will be provided to each 
participating institution in pre-numbered bottles intended for individual subjects to 
be dispensed by the institution’s pharmacist or designated person. Randomization 
assignments will be provided by an independent statistician at Prosoft Clinical to the 
drug packaging company. The pharmacist/designated person will dispense the next 
number in sequence to the next patient who qualifies for the study at an individual 
site. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint 
• 
Quantitative SARS-CoV-2 viral load through Day 29 
3.2 Secondary Efficacy and Clinical Endpoints 
Through Day 29: 
• 
Duration of viral shedding; 
• 
Percentage of subjects requiring admission as an inpatient for >24 hours; 
• 
All-cause mortality. 
3.3 Exploratory Efficacy and Clinical Endpoints 
Through Day 29: 
• 
Time to viral clearance (two consecutive undetectable tests);  
• 
Viral culture through Day 29; 
• 
Time to resolution of new onset COVID-19-related clinical symptoms and 
pre-existing non-COVID-19 symptoms returned to baseline; 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 10 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
• 
Time to clinical improvement measured by a favorable shift in WHO Ordinal 
Scale score for the subset of subjects with baseline WHO Ordinal Scale of 2 
or 3. 
3.4 Safety Variables 
• 
Rates of AEs and SAEs; 
• 
Laboratory assessments through Day 29; 
• 
Vital signs through Day 29. 
4. Pharmacokinetic/Pharmacodynamic variables 
Not applicable. 
5. Analysis populations 
5.1 Screened 
All subjects who consent to participate and who undergo screening will be included 
in the Screened population. 
5.2 Safety Analysis Set 
The Safety Analysis Set (Safety) will consist of all subjects who received at least 
one dose of study drug. Safety analysis subjects are analyzed according to their 
actual treatment received. 
5.3 Intent-to-treat Set 
The Intent-to-treat Set (ITT) will consist of all randomized subjects. ITT subjects are 
analyzed according to their randomized treatment. 
5.4 Microbiology Evaluable Set 
The Microbiology Evaluable Set (MES) will consist of all randomized subjects with 
detectable SARS-CoV-2 viral load at baseline and at least one non-missing post-
baseline viral load assessment. Microbiology evaluable subjects are analyzed 
according to their randomized treatment. 
5.5 Per Protocol Set 
Not applicable. 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 11 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
6. Data Handling 
6.1 Time points and Visit Windows 
Day 1 is defined as the day of first dose of study drug.  Relative days after Day 1 are 
calculated as (assessment date – Day 1 date) + 1. Relative days prior to Day 1 are 
calculated as (assessment date – Day 1 date). The day prior to Day 1 is Day -1.  
All data will be analyzed using nominal study visits as defined in the Study Schedule 
and eCRF. No visit windows will be applied for summary and analysis. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
A subject may withdraw from the study at any time for any reason. The Sponsor or 
Investigator may also terminate a subject’s study participation after discussion with 
the other party if it is believed it would be unsafe for the subject to continue in the 
study. All scheduled evaluations will be collected/conducted even for subjects who 
discontinue study medication prior to completing the treatment period unless consent 
is withdrawn. 
Missing efficacy data will not be imputed except for the automatic imputation done 
by the statistical modeling. Viral load values of the form of “<x” (i.e. below the lower 
limit of quantification) will be imputed as “x” in the analysis of viral load changes but 
displayed as “<x” in the listing. 
Missing safety data will generally not be imputed. However, laboratory values of the 
form of “<x” (i.e. below the lower limit of quantification) or “>x” (i.e. above the upper 
limit of quantification) will be imputed as “x” in the calculation of summary statistics 
but displayed as “<x” or “>x” in the listings. Additionally, AEs that have missing 
causality (after data querying) will be assumed to be related to study drug. 
If start date of a prior/concomitant medication is partially missing, impute as follows: 
• 
If both Month and Day are missing, then set to January 1 
• 
If only Day is missing, then set to the first day of the month 
If end date of a prior/concomitant medication is partially missing, impute as follows: 
• 
If both Month and Day are missing, then set to December 31 
• 
If only Day is missing, then set to last day of the month 
If start date and/or end date of a prior/concomitant medication is completely missing, 
do not impute. 
Listings will present the actual partial dates; imputed dates will not be shown. 
No rules for outlier detection are planned. 


Statistical Analysis Plan 
Sponsor Name: Clear Creek Bio, Inc. 
Sponsor Protocol ID: CCB-CRISIS-02 
 
Covance Study ID: 000000207395 
 
 
CONFIDENTIAL 
Page 12 of 23 
Document Date: 04Nov2020 
 
ST-AD-008 version 05 
 
7. Statistical Methods 
7.1 General Principles 
All data processing, summarization and analyses will be performed using Covance’s 
SAS Environment / Version 9.3 (or later) of the SAS statistical software package. 
The following principles will be applied to all tables, figures, and listings (TFLs) unless 
otherwise stated: 
Principle 
Value 
Significant tests 
Two-sided and use a 5% significance. 
Treatment group labels 
and order presented 
SOC + Brequinar 100 mg 
SOC + Placebo 
Tables 
Data in summary tables presented by treatment group, 
assessment and visit (where applicable), unless otherwise 
specified. 
Listings 
All data collected presented by treatment group, site, 
subject, assessment and visit (where applicable), unless 
otherwise specified.  
Descriptive summary 
statistics for continuous 
variables 
Number of subjects/observations (N), mean, standard 
deviation (SD), median and range.  
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)] 
Denominator for 
percentages 
Number of subjects in the analysis population, unless stated 
otherwise in table shell(s)  
Include “Missing” as 
category 
Yes, when the number missing is greater than zero for at 
least one treatment group. 
Display for 0 
percentages 
Blank 
Display to one more 
decimal place than 
collected value 
Mean 
Standard Error 
Mean Difference 
Median 
Display to two more 
decimal places than 
collected value 
Standard Deviation 
Confidence Interval 
Limit of precision for 
displays 
3 decimal places 
Date Format 
DDMMMYYYY 
Dictionary names and 
versions 
The dictionary names and versions will be included in a 
footnote in all AE, medical history, prior and concomitant 
medication TFLs that present coded terms from the 
dictionaries. 
Time to event or duration of event endpoints will be based on the actual date rather 
than Visit Day. 


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7.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be listed and summarized by treatment group and overall and 
will include the number and percentage of subjects: 
• 
screened; 
• 
randomized; 
• 
randomized and not treated; 
• 
treated; 
• 
included in each analysis population (ITT, MES, Safety). 
In addition, the number and percentage of subjects who complete the study and who 
discontinue early, including a breakdown of the primary reasons for discontinuation, 
will be presented for ITT population. 
A summary of subject enrollment by site will also be provided.   
A summary of the reasons for screen failure as well as the number of subjects 
screened but not randomized will be produced. No other information for screen 
failures will be presented. 
7.3 Protocol Deviations 
Protocol deviation management process, including project specific protocol deviations 
list, deviation detection, management and escalation, and review of protocol 
deviations, is defined in the Protocol Deviation Management Plan. Protocol deviations 
will be identified before data are unblinded. All protocol deviations will be listed. 
Important protocol deviations will be summarized by treatment group for the ITT 
population. 
7.4 Demographics and Other Baseline Characteristics 
Demographics will be listed and summarized by treatment group and overall for the 
ITT population. Standard descriptive statistics will be presented for the continuous 
variables of: 
• 
age (years) [calculated as (year of informed consent – year of birth) if age 
is not recorded on the eCRF]; 
• 
weight (kg); 
• 
height (cm); 
• 
body mass index (kg/m2) [calculated as (weight/height2) where weight is in 
kg and height is in m]. 


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The total counts and percentages of subjects will be presented for the categorical 
variables of: 
• 
age group (years) (grouped as <65, ≥65); 
• 
gender; 
• 
race; 
• 
ethnicity. 
In addition, baseline characteristics collected prior to the first dose of study drug will 
be listed and summarized by treatment group and overall for the ITT population. 
Standard descriptive statistics will be presented for the continuous variables of: 
• 
temperature (0C); 
• 
oxygen saturation, SpO2 (%); 
• 
respiratory rate (breaths/min). 
The total counts and percentages of subjects will be presented for the categorical 
variables of: 
• 
SARS-CoV-2 viral load (detectable, undetectable); 
• 
COVID-19 symptom type; 
• 
WHO Ordinal Scale. 
No formal tests of statistical significance will be performed on the demographic and 
baseline data.     
Other baseline measurements, such as vital signs, laboratory results will be 
summarized by treatment group with the post-baseline measurements. 
7.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.1 (or a later version if updated during the study). All medical 
history will be listed, and the number and percentage of subjects with any medical 
history will be summarized for the ITT population by system organ class (SOC) and 
preferred term (PT) for each treatment group and overall.   
7.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with study drug will be coded by 
Covance using the WHODrug Dictionary Version March 2019 Global Dictionary 
Version B3 (or a later version if updated during the study), Anatomical Therapeutic 
Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
Prior medications are those taken prior to study drug with a stop date prior to the 
first dose of study drug.  


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Concomitant medications are those with a start date on or after the first dose date 
of study drug, or those with a start date before the first dose date of study drug and 
a stop date on or after the first dose date of study drug or ongoing end of study. 
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior medications and concomitant medications will be listed together and 
summarized separately for the ITT population. 
The number and percentage of subjects using each medication will be displayed 
together with the number and percentage of subjects using at least one medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term. 
7.5 Measurements of Study Drug Compliance 
Percentage compliance is calculated as: 
100 * actual number of capsules taken/expected number of capsules taken, where 
expected capsules taken is specified to be 5. 
Percentage compliance will be summarized descriptively by treatment group for the 
Safety population. 
The number and percentage of compliant subjects will be presented for the Safety 
population, where compliant is defined as percentage compliance between 80.0% 
and 100.0% inclusive. The number and percentage of subjects with compliance 
<80.0% as well as number and percentage of subjects who received more than one 
capsule in a calendar day will also be presented. 
7.6 Efficacy 
7.6.1 Primary Efficacy Analysis 
SARS-CoV-2 Viral load will be reported as below.  
• 
# of copies/mL; 
• 
<# of copies/mL, if detected but under the lower limit of quantification 
(LLOQ); 
• 
no SARS CoV-2 detected, if not detected. 
SARS-CoV-2 Viral load (log10 copies/mL) and change from baseline will be 
summarized by visit using standard descriptive statistics for the MES population. The 
baseline value is defined as last scheduled or unscheduled viral load collected prior 
to the first dose of study drug. For post-baseline, only data from scheduled visits will 
be included in the summary tables. For the analysis purpose, viral load below the 


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LLOQ will be considered equal to the LLOQ. Number of subjects with undetectable 
SARS-CoV-2 viral load at each visit will be presented as well. 
Changes from baseline in SARS-CoV-2 viral load data (log10 copies/mL) will be 
statistically analyzed using a mixed model for repeated measures (MMRM) in the 
MES population. The model will contain baseline as a covariate, treatment, day and 
treatment-by-day interaction as fixed effects. The unstructured covariance matrix 
will be selected initially; if this analysis fails to converge another covariance 
structure will be selected based on AIC and BIC values. The least square (LS) 
means and treatment difference at Days 4, 8, 12, 15, 22 and 29 will be calculated 
and presented with their corresponding 95% confidence intervals (CIs). All available 
data will be used in the analysis. 
7.6.2 Secondary Efficacy Analysis 
The duration of viral shedding is defined as the time (in days) from Day 1 to the 
first time where no SARS-CoV-2 is detected. When deriving viral shedding, any 
missing viral load data will be considered detectable. Subjects will be censored at 
the last SARS-CoV-2 viral load test if SARS-CoV-2 is detected at all tests.  
Kaplan-Meier curves will be used to estimate the distribution of duration of viral 
shedding in the MES population. The 50th percentile of Kaplan-Meier estimates will 
be used to estimate the median duration of viral shedding. A two-sided 95% CI will 
be provided for this estimate. The 25th and 75th percentiles, and the range 
(minimum, maximum) will be presented as well. The range will be determined 
including censored observations. Duration of viral shedding will be compared 
between treatment groups using a unstratified log rank test. The two-sided p-value 
for the log rank test will be presented. 
7.6.3 Exploratory Efficacy Analysis 
7.6.3.1 Time to Viral Clearance 
The time to viral clearance is defined as the time (in days) from Day 1 to the first 
time where no SARS-CoV-2 is detected for subjects with two consecutive tests of 
undetectable SARS-CoV-2. When deriving viral clearance, any missing viral load data 
will be considered detectable.  Subjects without two consecutive tests of undetectable 
SARS-CoV-2 will be censored at the last SARS-CoV-2 viral load test. 
Time to viral clearance will be analyzed using the same method as specified in 
section 7.6.2 for the secondary efficacy endpoint in the MES population. 
7.6.3.2 Viral Culture 
Viral culture will be listed and summarized by treatment group and visit. 
Viral culture data and changes from baseline in viral culture will be summarized by 
visit using standard descriptive statistics for the MES population. The baseline value 


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is defined as last scheduled or unscheduled value collected prior to the first dose of 
study drug. For post-baseline, only data from scheduled visits will be included in the 
summary table.  
7.6.4 Secondary Clinical Analysis 
7.6.4.1 Hospital Admission 
Subjects requiring hospital admission as an inpatient for >24 hours will be analyzed 
in the ITT population. Number and proportion of subjects requiring hospital 
admission along with 95% exact binomial CI (Clopper-Pearson) will be presented 
for each treatment group. Two-sided 95% CI will also be presented for the 
difference in percent of subjects requiring hospital admission between treatment 
groups with an approximate normal distribution. The Fisher’s exact test will be used 
to compare the proportion of subjects requiring hospital admission. The two-sided 
p-value for the Fisher’s exact test will be presented. 
7.6.4.2 Death 
Number of subjects who died and the cause of death will be presented for each 
treatment group for the ITT population. The proportion of subjects who died along 
with 95% exact binomial CI (Clopper-Pearson) will be presented for each treatment 
group. Two-sided 95% CI will also be presented for the difference in percent of 
subjects who died between treatment groups with an approximate normal 
distribution. The Fisher’s exact test will be used to compare the proportion of 
subjects who died. The two-sided p-value for the Fisher’s exact test will be 
presented. 
7.6.5 Exploratory Clinical Analysis 
7.6.5.1 Time to Resolution of Symptoms 
Symptom assessment will use a checklist provided to the subject with symptoms 
such as sore throat, cough, gastrointestinal symptoms (vomiting, diarrhea), 
anosmia, dysgeusia, other (specify), etc. Symptoms start date, end date (or 
ongoing), severity “None”, “Mild”, “Moderate”, or “Severe” and symptoms status 
“Resolved”, “Ongoing”, or “Returned to Baseline” will be collected.  
Resolution of symptoms is defined as new COVID-19 symptoms are completely 
resolved (i.e. status of “Resolved”) and pre-existing non-COVID-19 symptoms 
return to baseline (i.e. status of “Returned to Baseline”) reported on the eCRF of 
“COVID-19 Symptom Assessment”. The time to resolution of symptoms is defined 
as the time (in days) from Day 1 to the first date where symptoms have been 
resolved. Subjects didn’t achieve resolution of symptoms will be censored at the 
date of last assessment of symptoms. The median (95% CI) time to resolution of 
symptoms will be presented by treatment groups using the Kaplan-Meier method 
for the ITT population. 


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7.6.5.2 Time to Clinical Improvement 
Clinical progression will be assessed using the WHO Ordinal Scale (Table 2). 
Baseline is defined as last non-missing assessment prior to the first dose of study 
drug. Frequency counts and percentages will be presented by visit for WHO Ordinal 
Scale. 
Table 2 
Who Ordinal Scale 
Patient State 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized: moderate 
disease 
Hospitalized; no oxygen therapy* 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized: severe 
disease 
Hospitalized; oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 < 200) or vasopressors 
8 
Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Dead 
10 
 
Clinical improvement is defined as at least 1-point decrease from baseline in WHO 
Ordinal Scale. Time to clinical improvement will be analyzed in the subset of ITT 
subjects with baseline WHO Ordinal Scale of 2 or 3. The time to clinical 
improvement is defined as the time (in days) from Day 1 to the first date of clinical 
improvement. Subjects didn’t achieve clinical improvement will be censored at the 
date of last assessment of WHO Ordinal Scale. The median (95% CI) time to clinical 
improvement will be presented by treatment groups using the Kaplan-Meier 
method. 
7.7 Safety 
7.7.1 Extent of Exposure 
Not applicable. 


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7.7.2 Adverse Events 
AEs will be collected from the time of first dose of study drug through Day 29. After 
Day 29, only SAEs which are assessed by the Investigator or designated person to 
be related to study drug and have an onset within 14 days of study completion (Day 
29 or earlier if discontinue prior to Day 29) will be collected/recorded. All AEs 
recorded on the eCRF will be coded using the MedDRA dictionary Version 23.1 (or a 
later version if updated during the study). 
All AE data will be listed by treatment group. In addition, corresponding listings of 
study drug-related AEs and SAEs will be produced. 
The relationship between an AE and study drug is assessed as definite, probable, 
possible, unlikely, or unrelated. A study drug-related AE is an AE considered by the 
investigator as definitely, possibly, or probably related to study drug or with missing 
relationship to study drug.   
An overview table will summarize the number and percentage of subjects with at 
least one of the following AEs, where subjects with more than one AE in a particular 
category are counted only once in that category: 
• 
any AE;  
• 
AE by maximum severity grade; 
• 
study drug-related AE;  
• 
AE leading to study drug discontinuation;  
• 
study drug-related AE leading to study drug discontinuation;  
• 
severity grade 3 or higher study drug-related AE;  
• 
SAE;  
• 
study drug-related SAE;  
• 
SAE leading to study drug discontinuation;  
• 
AE leading to death; 
• 
study drug-related AE leading to death.  
The number and percentage of subjects reporting each AE will be summarized for 
each treatment group and overall, by System Organ Class (SOC) (sorted 
alphabetically) and Preferred Term (PT) (sorted by descending overall total) for the 
Safety population. The following summaries will be produced: 
• 
AEs, by SOC and PT; 
• 
AEs by PT; 
• 
study drug-related AEs, by SOC and PT; 
• 
study drug-related AEs, by PT; 
• 
AEs by relationship to study drug, by SOC and PT; 


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• 
AEs by severity grade, by SOC and PT; 
• 
study drug-related AEs by severity grade, by SOC and PT; 
• 
AEs leading to discontinuation of study drug, by SOC and PT; 
• 
study drug-related AEs leading to discontinuation of study drug, by SOC and 
PT; 
• 
severity grade 3 or higher AEs, by SOC and PT; 
• 
severity grade 3 or higher study-drug related AEs, by SOC and PT; 
• 
SAEs, by SOC and PT; 
• 
study drug-related SAEs, by SOC and PT; 
• 
SAEs leading to discontinuation of study drug, by SOC and PT; 
• 
AEs leading to death, by SOC and PT; 
• 
study drug-related AEs leading to death, by SOC and PT. 
In the above summaries, subjects with more than one AE within a particular SOC are 
counted only once for that SOC. Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT. For summaries by relationship to 
study drug, subjects with multiple AEs within a particular SOC or PT will be counted 
under the strongest relationship within that SOC or PT. For summaries by severity 
grade, subjects with multiple AEs within a particular SOC or PT will be counted under 
the maximum severity grade within that SOC or PT.  
No statistical comparisons of AEs between treatment groups will be performed. 
7.7.3 Laboratory Evaluations 
Data for the following hematology and chemistry received from central laboratory will 
be listed and summarized by treatment group and visit. If data for any additional 
analytes are also recorded, then these will be listed only. 


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Hematology 
Chemistry 
Hemoglobin 
Hematocrit 
Platelets  
Neutrophils Absolute 
Lymphocytes Absolute 
Monocytes Absolute 
Eosinophils Absolute 
Basophils Absolute 
Neutrophils % 
Lymphocytes % 
Monocytes % 
Eosinophils % 
Basophils % 
White Blood Cell Count 
Red Blood Cell Count (RBC) 
RBC Morphology and Mean Corpuscular 
Volume 
Albumin 
Alkaline Phosphatase 
Alanine Amino Transferase 
Aspartate Amino Transferase 
Total Bilirubin 
Calcium 
Chloride 
Creatinine 
Glucose 
Potassium 
Sodium 
Total Protein 
Lactate Dehydrogenase 
Blood Urea Nitrogen 
Carbon Dioxide/Bicarbonate 
C-Reactive Protein 
 
 
All laboratory data will be reported in International System of Units (SI) units. Out-
of-reference-range values will be flagged as high (H) or low (L) in the listings for all 
laboratory parameters except C-reactive protein.  
For analysis purposes, values preceded by a “<” or a “>” sign (i.e. those below or 
above the limits of quantification) will be considered equal to the lower or upper limit 
of quantification, respectively. 
Laboratory data will be summarized by visit using standard descriptive statistics for 
the Safety population. Changes from baseline will also be summarized. 
For hematology and chemistry parameters, number and percentage of subjects with 
abnormal results (not clinically significant, clinically significant) at each visit will be 
provided for each treatment group. 
For each laboratory analyte, the baseline value is defined as last scheduled or 
unscheduled value collected prior to the first dose of study drug. Assessments carried 
out on day of first study drug administration are considered to have taken place 
before the study drug administration, if the corresponding times have not been 
recorded. For post-baseline, only data from scheduled visits will be included in the 
summary tables.  
7.7.4 Vital Signs 
The following vital signs will be listed and summarized by treatment group and visit. 
• 
heart rate (bpm); 
• 
respiration rate (breaths/min); 
• 
body temperature (°C); 
• 
oxygen saturation, SpO2 (%). 


Statistical Analysis Plan 
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Vital signs data and changes from baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the Safety population. The baseline value is 
defined as last scheduled or unscheduled value collected prior to the first dose of 
study drug. For post-baseline, only data from scheduled visits will be included in the 
summary table.  
7.7.5 Electrocardiograms 
Not applicable.  
7.7.6 Physical Examination 
Abnormalities identified from physical examination are recorded in the eCRF as 
Medical History as appropriate and will be listed and summarized as such [See 
Sections 7.4.1 (Medical History)]. 
7.7.7 Other Safety Variables 
Pregnancy test data will be presented in the subject data listing. 
7.8 Interim Analysis 
A Data Monitoring Committee (DMC) will be established to provide independent 
oversight to this trial. The primary responsibility of the DMC will be to review the 
progress and conduct of the trial in order to maintain scientific rigor and to ensure 
the wellbeing of subjects participating in the trial. The specific responsibilities of the 
DMC will be detailed in a separate DMC charter. The DMC will perform periodic data 
review to assess whether there are clinically significant differences between 
treatment groups that could affect participant safety. The DMC will review AEs and 
safety laboratory assessments after the first 20 subjects complete the Day 8 visit, 
and again after the first 40 subjects complete the Day 8 visit. Following such a 
review, the DMC Chair will advise the Sponsor that the study be stopped, the 
design changed, or that the study may continue per protocol. 
8. Changes in Planned Analysis 
This section is not required at this time, but will be populated in a future approved 
version of this document. 
9. Data Issues 
This section is not required at this time, but will be populated in a future approved 
version of this document 
10. References 
1 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf 


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2 
Phillips A and Haudiquet V. ICH E9 guideline “Statistical principles for clinical 
trials”: a case study. Statistics in Medicine 2003; 22:1-11 
3 
Brown D J. ICH E9 guideline “Statistical principles for clinical trials”: a case 
study. Response to A. Phillips and V. Haudiquet. Statistics in Medicine 2003; 
22:13-17 
4 
ICH. ICH E3 Guideline: Structure and Content of Clinical Study Reports 
Questions & Answers, 2012. Available at 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E3/E3_QAs_R1_Step4.pdf 
 
11. Appendices 
Appendix 1: 
Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version 1, Final, 04 November 2020 Not applicable; the first version